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

Study Overview
=================
Brief Summary
-----------------
This randomized phase II trial studies how well cabozantinib-s-malate works compared to sunitinib malate in treating patients with previously untreated kidney cancer that has spread from where it started to nearby tissue or lymph nodes or to other places in the body. Cabozantinib-s-malate and sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether cabozantinib-s-malate is more effective than sunitinib malate in treating patients with kidney cancer.

Detailed Description
-----------------
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.

Official Title
-----------------
Randomized Phase II Study Comparing Cabozantinib (NSC #761968) With Commercially Supplied Sunitinib in Patients With Previously Untreated Locally Advanced or Metastatic Renal Cell Carcinoma

Conditions
-----------------
Clear Cell Renal Cell Carcinoma, Metastatic Kidney Carcinoma, Stage III Renal Cell Cancer AJCC v7, Stage IV Renal Cell Cancer AJCC v7

Intervention / Treatment
-----------------
* Drug: Cabozantinib S-malate
* Other: Laboratory Biomarker Analysis
* Drug: Sunitinib Malate


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (cabozantinib-s-malate)<br>Patients receive cabozantinib-s-malate PO QD for 6 weeks. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. | Drug: Cabozantinib S-malate<br>* Given PO<br>* Other names: XL184;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Active Comparator: Arm II (sunitinib malate)<br>Patients receive sunitinib malate PO QD for 4 weeks. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Sunitinib Malate<br>* Given PO<br>* Other names: Sutent;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Progression free survival (PFS) was investigator assessed and is measured from the beginning of treatment until patient progression or death. Progression was determined using RECIST 1.1 criteria, progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).The primary analysis will be based on the stratified log-rank statistic to compare the two treatment arms on PFS. The Kaplan-Meier product-limit estimator will be used to estimate PFS distributions.Progression Free Survival was assessed per investigator, as this was the protocol-specified endpoint, and both investigator and independent review analyses of the PFS endpoint have been published | Up to 5 years | 
| Overall Survival (OS) | The primary analysis will be based on the stratified log-rank statistic to compare the two treatment arms on OS. The Kaplan-Meier product-limit estimator will be used to estimate OS distributions. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rates | Objective response rates (ORR) was investigator assessed. ORR is the rate of complete or partial responses, based on RECIST 1.1 criteria. A response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. The Fisher exact test will be used to compare the two treatment arms. | Up to 5 years |