Cabozantinib-s-malate or Sunitinib Malate in Treating Patients With Previously Untreated Locally Advanced or Metastatic Kidney Cancer

PRIMARY OBJECTIVES:

I. To determine if patients with renal cancer treated with cabozantinib
(cabozantinib-s-malate) will have improved progression-free survival compared to patients
treated with sunitinib (sunitinib malate).

SECONDARY OBJECTIVES:

I. To determine whether the response rate of patients with renal cancer treated with
cabozantinib will be higher when compared with patients treated with sunitinib.

II. To determine whether patients with renal cancer treated with cabozantinib will have an
improved overall survival when compared with patients treated with sunitinib.

TERTIARY OBJECTIVES:

I. To determine whether renal cancer patients with high MET expression by
immunohistochemistry (IHC) have improvement in progression-free survival compared to patients
with low MET expression on both arms of this study.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cabozantinib-s-malate orally (PO) once daily (QD) for 6 weeks.
Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive sunitinib malate PO QD for 4 weeks. Courses repeat every 6 weeks in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 5 years.

Inclusion Criteria:

- Renal cell carcinoma with some component of clear cell histology; histologic
documentation of metastatic disease is not required

- Locally advanced (defined as disease not amenable to curative surgery or radiation
therapy) or metastatic renal cell carcinoma (RCC) (equivalent to stage IV RCC,
according to American Joint Committee on Cancer [AJCC] staging)

- Eligible patients must be intermediate/poor risk, per the International Metastatic
Renal Cell Carcinoma (mRCC) Database Consortium (Heng) criteria; patients must
therefore have as one or more of the following six factors:

- Time from diagnosis of RCC to systemic treatment < 1 year

- Note: systemic treatment refers to the initiation of A031203 protocol
treatment

- Hemoglobin < the lower limit of normal (LLN)

- Corrected calcium > the upper limit of normal (ULN)

- Karnofsky performance status < 80%

- Neutrophil count > ULN

- Platelet count > ULN

- No radiographic evidence of cavitating pulmonary lesion(s)

- No tumor invading the inferior vena cava (IVC) or superior vena cava (SVC) blood
vessels

- No evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach,
small or large bowel, rectum or anus), or any evidence of endotracheal or
endobronchial tumor within 28 days prior to registration

- No prior systemic treatment for RCC; supportive therapies such as bisphosphonates
(zoledronic acid) or denosumab are permitted

- Patients must not have had a major surgical procedure or significant traumatic injury
within 6 weeks prior to study registration, and must have fully recovered from any
such procedure; however, patients who have had a nephrectomy may be enrolled 4 weeks
after surgery, providing there are no wound-healing complications; the following are
not considered to be major procedures: thoracentesis, paracentesis, port placement,
laparoscopy, thoracoscopy, bronchoscopy, endoscopic ultrasonographic procedures,
mediastinoscopy, skin biopsies, incisional biopsies, imaging-guided biopsy for
diagnostic purposes, and routine dental procedures

- Radiation:

- To the brain, thoracic cavity, abdomen, or pelvis must be completed at least 90
days before registration;

- To bone must be completed at least 14 days before registration; and

- To any other sites must be completed at least 28 days before registration In all
cases, there must be complete recovery and no ongoing complications from prior
radiation therapy

- No chronic concomitant treatment of strong cytochrome P450, family 3, subfamily A,
polypeptide 4 (CYP3A4) inducers or inhibitors; patients may not have received a strong
CYP3A4 inducer within 12 days prior to registration nor a strong CYP3A4 inhibitor
within 7 days prior to registration

- Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) criteria; lesions that can be accurately measured in at least one dimension
(longest diameter to be recorded) as >= 2 cm with conventional techniques or as >= 1
cm with spiral computed tomography (CT) scan

- No active brain metastases; patients with treated, stable brain metastases for at
least three months are eligible as long as they meet the following criteria:

- Treated brain metastases are defined as having no ongoing requirement for
steroids and no evidence of progression or hemorrhage after treatment for at
least 3 months, as ascertained by clinical examination and brain imaging
(magnetic resonance imaging [MRI] or CT); (stable dose of anticonvulsants are
allowed); treatment for brain metastases may include whole brain radiotherapy
(WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or equivalent)
or a combination as deemed appropriate by the treating physician; patients with
central nervous system (CNS) metastases treated by neurosurgical resection or
brain biopsy performed within 3 months prior to registration are not eligible

- Baseline brain imaging (MRI/CT) is required

- No serious non-healing wound, ulcer, or bone fracture requiring intervention within 28
days prior to registration

- No arterial thrombotic events within 6 months prior to registration, including
transient ischemic attack (TIA), cerebrovascular accident (CVA), peripheral arterial
thrombus, unstable angina or angina requiring surgical or medical intervention in the
6 months prior to registration, or myocardial infarction (MI); patients with
clinically significant peripheral artery disease (i.e., claudication on less than one
block), significant vascular disease (i.e., aortic aneurysm, history of aortic
dissection), or any other arterial thrombotic event are ineligible

- No history of pulmonary embolism or untreated deep venous thrombosis (DVT) within 6
months prior to registration; note: patients with recent DVT who have been treated
with therapeutic anticoagulation with low molecular weight heparin for at least 6
weeks are eligible; patients receiving therapeutic warfarin (> 2 mg/day) are not
eligible; patients on warfarin may be switched to low molecular weight heparin at the
discretion of the treating physician

- No inadequately controlled hypertension (defined as a blood pressure of >= 150 mmHg
systolic and/or >= 90 mmHg diastolic), or any prior history of hypertensive crisis or
hypertensive encephalopathy

- No New York Heart Association (NYHA) class >= 2 congestive heart failure

- Ejection fraction on echocardiogram (Echo) or multi gated acquisition scan (MUGA) >
50%

- No corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within
28 days before randomization; note: if initial QTcF is found to be > 500 ms, two
additional electrocardiograms (EKGs) separated by at least 3 minutes should be
performed; if the average of these three consecutive results for QTcF is =< 500 ms,
the subject meets eligibility in this regard

- No history of congenital QT syndrome

- No unstable cardiac arrhythmia within 6 months prior to registration

- No evidence of any of the following:

- Clinically-significant gastrointestinal bleeding within 6 months before
registration; or

- Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months before
registration; or

- Any other signs indicative of pulmonary hemorrhage within 3 months before
registration

- No history of abdominal fistula, gastrointestinal perforation, intra-abdominal
abscess, bowel obstruction, or gastric outlet obstruction within 6 months prior to
registration and complete healing/resolution prior to registration; no percutaneous
endoscopic gastrostomy (PEG) tube placement within 3 months prior to registration

- No active peptic ulcer disease, within 28 days before registration

- No inflammatory bowel disease (including ulcerative colitis and Crohn's disease),
diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis within 28 days
before registration

- No malabsorption syndrome within 28 days before registration

- No uncompensated hypothyroidism; patients with hypothyroidism on therapy are required
to have thyroid stimulating hormone (TSH) within normal limits

- No radiologic or clinical evidence of pancreatitis

- No history of organ transplant

- Patients with active infection requiring systemic treatment within 28 days prior to
registration are not eligible

- Patients who are pregnant or nursing are not eligible; women of child bearing
potential must have a negative serum or urine pregnancy test within 16 days prior to
registration; women of child-bearing potential include:

- Any female who has experienced menarche and who has not undergone surgical
sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy)
or is not postmenopausal (defined as amenorrhea >= 12 consecutive months)

- Women on hormone replacement therapy (HRT) with documented serum follicle
stimulating hormone (FSH) level > 35m IU/mL

- Women who are using oral, implanted or injectable contraceptive hormones or
mechanical products such as an intrauterine device or barrier methods (diaphragm,
condoms, spermicides) to prevent pregnancy or practicing abstinence or where
partner is sterile (e.g., vasectomy)

- Performance status: Eastern Cooperative Oncology Group (ECOG) 0-2

- Archival tissue must be available for submission, though it is optional for patients
to choose to participate in the correlative sub studies

- Absolute neutrophil count (ANC) >= 1,500/uL

- Platelet count >= 100,000/uL

- Hemoglobin >= 9 g/dL; patients may not have had a transfusion within 7 days prior to
screening assessment

- Total bilirubin =< 1.5 x upper limits of normal

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN

- Albumin >= 2.8 g/dL

- Serum creatinine =< 1.5 x ULN, OR calculated creatinine clearance >= 30 mL/minute
(modified Cockcroft and Gault formula)

- Urine protein to creatinine (UPC) ratio < 1.0; if UPC >= 1, then a 24-hour urine
protein must be assessed; eligible patients must have a 24-hour urine protein value <
1 g

- Total serum calcium < 12 mg/dL

- International normalized ratio (INR) =< 1.2 x ULN; subjects receiving anticoagulant
therapy are eligible if their INR is stable and within the recommended range for the
desired level of anticoagulation

- TSH within normal limits (WNL); TSH only required for patients on thyroid
supplementation