Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3, Randomized Study Of SU011248 Versus Interferon-Alfa As First-Line Systemic Therapy For Patients With Metastatic Renal Cell Carcinoma
Brief Summary: The purpose of this study is to test whether SU011248 has activity and is safe compared to interferon-alfa as first-line therapy in patients with metastatic renal cell carcinoma (RCC).


Options:
A: Inclusion Criteria:

* Histologically confirmed renal cell carcinoma of clear cell histology with metastases
* Evidence of measurable disease by radiographic technique
* Eastern Cooperative Oncology Group \[ECOG\] performance status of 0 or 1

Exclusion Criteria:

* Prior systemic (including adjuvant or neoadjuvant) therapy of any kind for RCC
* History of or known brain metastases
* Serious acute or chronic illness or recent history of significant cardiac abnormality
B: Inclusion Criteria:

* metastatic renal cell cancer (clear cell type);
* nephrectomy;
* absence of proteinuria.

Exclusion Criteria:

* prior systemic treatment for metastatic renal cell cancer;
* major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to study treatment start;
* presence of brain metastases or spinal cord compression;
* ongoing need for full dose anticoagulants;
* uncontrolled hypertension;
* clinically significant cardiovascular disease.
C: For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

* Subjects with histological confirmation of RCC
* Advanced or metastatic disease
* Measurable disease as defined by RECIST 1.1 criteria
* Karnofsky Performance Status (KPS) ≥80%
* Available tumor tissue (archival or recent acquisition)
* Subjects enrolled in the I-1, I-3 expansion arms and IN-3 addition arms must not have received any prior systemic therapy for RCC with the following exceptions:

  1. One prior adjuvant or neoadjuvant therapy for localized or locally advanced RCC is allowed provided recurrence occurred ≥ 6 months after the last dose of the adjuvant or neoadjuvant therapy
  2. Only prior cytokine based treatment for metastatic RCC \[eg, interferon-alpha (IFN-alpha) or interleukin 2 (IL-2)\] as prior therapy is allowed

Exclusion Criteria:

* Active central nervous system (CNS) metastases
* Active or history of autoimmune disease
* Ongoing symptomatic cardiac dysrhythmias or uncontrolled atrial fibrillation
* History of cerebrovascular accident including transient ischemic attack within the past 12 months
* History of pulmonary embolism or deep vein thrombosis (DVT) within the past 6 months
* Chronic systemic steroids (\>10 mg/day Prednisone equivalents) or any other immunosuppressive agents
* White blood cell (WBC) \<2,000/mm3
* Neutrophiles \<1,500/mm3
* Platelets \<100,000/mm3
* Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) \>3x upper limit of normal (ULN)
* Total Bilirubin \>1.5x ULN (except subjects with Gilbert syndrome, total bilirubin \<3.0 mg/dL)
* Cardiac ejection fraction \<LLN (lower limit of normal)
* Serum creatinine \>1.5x ULN or creatinine clearance \<40 mL/min (Cockroft-Gault formula)

Exclusion Criteria for Arm S and Arm P only:

* For dose escalation cohorts - subjects who received prior Sunitinib or Pazopanib and required permanent discontinuation due to toxicity or required dose reduction or delay during the first 12 weeks of therapy due to toxicity, or received both prior Sunitinib and Pazopanib
* Poorly controlled hypertension
* Active bleeding or bleeding susceptibility
D: Key Inclusion Criteria:

* Histological confirmation of RCC with a clear-cell component. Patients with TFE3 or TFEB translocation proven by cytogenetic analysis or by fluorescence in situ hybridization (FISH) are eligible.
* Metastatic (American Joint Committee on Cancer \[AJCC\] Stage IV) RCC
* No prior systemic therapy for mRCC
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2
* Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
* Frozen tumor samples (primary tumor and/or metastasis biopsies) must be available and received by the central laboratory (Cordelier Research Center) to determine molecular groups. (Note: fine needle aspiration \[FNA\] and bone metastases samples are not acceptable for submission).
* Molecular group has to be determined prior to randomization.
* Formalin-fixed, paraffin-embedded (FFPE) tumor tissue available for biomarker (gene expression and immunohistochemistry (IHC)) analysis.

Key Exclusion Criteria:

* Any untreated CNS metastases. Patients with CNS metastases will be eligible if they are: asymptomatic, without significant oedema, not on corticosteroids, not eligible for radiation therapy/surgery or have already received radiation therapy.
* Prior systemic treatment with vascular endothelial growth factor (VEGF) or VEGF receptor-targeted therapy (including, but not limited to, sunitinib, pazopanib, axitinib, tivozanib, and bevacizumab) except in an adjuvant setting with a free interval of more than 1 year.
* Prior treatment with an anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
* Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (\>10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type 1 diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll.
* Any condition requiring systemic treatment with corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses \>10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
* Uncontrolled adrenal insufficiency.
* Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation of the Fridericia corrected QT (QTcF) interval defined as \>450 msec for males and \>470 msec for females, where QTcF = QT / 3√RR.
* Poorly controlled hypertension (defined as systolic blood pressure (SBP) of \>150 mmHg or diastolic blood pressure (DBP) of \>90 mmHg), despite antihypertensive therapy.
* History of any of the following cardiovascular conditions within 12 months of enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association.
* History of cerebrovascular accident including transient ischemic attack within the past 12 months.
* History of deep vein thrombosis (DVT) unless adequately treated with low molecular weight heparin.
* History of pulmonary embolism within the past 6 months unless stable, asymptomatic, and treated with low molecular weight heparin for at least 6 weeks.
* Known history of COPD (of any stage).
* Known history of uveitis or complaint of double vision.
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months.
* Serious, non-healing wound or ulcer.
* Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 30 days.
* Any requirement for anti-coagulation, except for low molecular weight heparin.
* Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
* Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
* Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
* Known medical condition (e.g., a condition associated with diarrhea or acute diverticulitis) that, in the Investigator's opinion, would increase the risk associated with study participation or study drug administration, or interfere with the interpretation of safety results.
* Known history of hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory, neuropathy, and polyneuropathy.
* Major surgery (e.g., nephrectomy) less than 35 days prior to the first dose of study drug.
* Focal radiation therapy less than 14 days prior to the first dose of study drug.
* Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors
* Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of cabozantinib (e.g., malabsorptive disorder, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or small bowel resection).
* Any of the following laboratory test findings:

  1. WBC \<2,000/mm3
  2. Hemoglobin ≤9.0 g/dL
  3. Neutrophils \<1,500/mm3
  4. Platelets \<100,000/mm3
  5. AST or ALT \>3 x ULN (\>5 x ULN if liver metastases are present)
  6. Lipase and amylase \> 1.5 ULN
  7. Total Bilirubin \>1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \<3.0 mg/dL)
  8. Serum creatinine \>1.5 x ULN or creatinine clearance \<40 mL/min (measured or calculated by Cockroft-Gault formula)
  9. Proteinuria: patients with ≥2+ protein on urine dipstick at baseline must undergo a 24-hour urine collection for protein then if \> 1.0 g of protein patient will not be included.

Answer: A