Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Blinded, Phase 2 Dose-Ranging Study Of BMS-936558 (MDX-1106) In Subjects With Progressive, Advanced/Metastatic Clear-Cell Renal Cell Carcinoma Who Have Received Prior Anti-Angiogenic Therapy
Brief Summary: The purpose of this study is to measure how active BMS-936558 (nivolumab) is against Renal Cell Carcinoma (RCC) as measured by the disease not progressing and whether a dose response relationship exists.


Options:
A: Inclusion Criteria:

* Subjects must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow-up.
* Age ≥ 18 years.
* Histologically confirmed diagnosis of progressive metastatic clear cell renal cell cancer defined as \>10% of the tumor cells having the clear cell phenotype.
* Locally advanced (defined as disease not amenable to curative surgery or radiation therapy) or metastatic RCC (equivalent to Stage IV RCC according to AJCC staging).
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
* Measurable disease.
* No prior systemic anti-cancer treatment against clear cell renal carcinoma.
* Adequate organ system function.
* Non-childbearing potential.

Exclusion Criteria:

* Prior malignancy.
* History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis.
* Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding.
* Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product.
* Presence of uncontrolled infection.
* Known past or present infection with Hepatitis B virus (HBV), Hepatitis C virus (HCV) or Human Immunodeficiency Virus (HIV).
* Corrected QT interval (QTc) \> 480 msecs using Bazett's formula.
* History of one or more of the following cardiovascular conditions within the past 6 months:

  1. Cardiac angioplasty or stenting
  2. Myocardial infarction
  3. Stable or unstable angina pectoris.
  4. Coronary artery bypass graft surgery.
  5. Symptomatic peripheral vascular disease
  6. Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA).
* Poorly controlled hypertension \[defined as systolic blood pressure (SBP) of ≥160 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg\].
* History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
* Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any nonhealing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major).
* Evidence of active bleeding or bleeding diathesis.
* Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
* Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of study drug.
* Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures.
* Unable or unwilling to discontinue use of prohibited medications or modify the dosing of interacting drugs for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study.
* Pregnant or lactating female.
* Treatment with any of the following anti-cancer therapies: Radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of Pazopanib OR Chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy.
B: Inclusion Criteria:

* This study will be conducted in subjects with histologically confirmed, advanced (stage IV or recurrent disease) RCC who have not received prior systemic therapy for their disease,

Exclusion Criteria:

* Subjects with central nervous system (CNS) metastases
* Prior anticancer therapy for RCC
* Prior investigational therapy/agents within 4 weeks of randomization
C: Inclusion Criteria:

* Written informed consent and any locally-required authorization (EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
* Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
* Age ≥ 18 years at time of study entry
* Eastern Co-operative Oncology Group (ECOG) performance status 0-2.
* Metastatic or locally advanced RCC with clear cell component, not amenable to surgery with curative intention.
* First-line treatment with a TKI for 10-12 weeks (limited to sunitinib or pazopanib).
* Patients with measurable disease (at least one uni-dimensionally measurable target lesion by CT-scan or MRI) according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1). If prior palliative radiotherapy to metastatic lesions: ≥ 1 measurable lesion that has not been irradiated. Patients with bone lesions as the only measurable lesion are eligible, provided that lesions consist of soft tissue, which is assessed via CT or MRI.
* Documented partial response or stable disease to first-line TKI exposure at 10-12 weeks.
* Prior therapies other than indicated in the exclusion criteria and surgeries are allowed if completed 4 weeks (for minor surgery and palliative radiotherapy for bone pain: 2 weeks) prior to start of treatment and patient recovered from toxic effects.
* Adequate blood count, liver-enzymes, and renal function (obtained no later than 14 days prior to start of study treatment):

White Blood Cells (WBC) ≥ 2000/μL

Neutrophils ≥ 1500/μL

Platelets ≥ 100 x10\^3/μL

Hemoglobin \> 9.0 g/dL

Serum creatinine ≤ 1.5 x Upper limit of normal (ULN) or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):

Female CrCl = ((140-age in years) x weight in kg x 0.85)/(72 x serum creatinine in mg/dL)

Male CrCl=((140-age in years) x weight in kg x 1.00)/(72 x serum creatinine in mg/dL)

Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) ≤ 3 x ULN

Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)

* Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of nivolumab.
* Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab
* Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic) men do not require contraception.

Exclusion Criteria:

* Prior systemic therapy other than 10-12 weeks SOC TKI treatment for advanced or metastatic RCC.
* Standard of care 1st-line TKI treatment for advanced or metastatic RCC for longer than 12 weeks.
* Complete remission (CR) or progression during SOC TKI 1st-line treatment.
* Termination of first-line treatment with TKI due to intolerance
* Previous malignancy (other than renal cell cancer), requiring active treatment or diagnosed in metastatic state. Basal cell cancer of the skin, pre-invasive cancer of the cervix, T1a prostate carcinoma or superficial bladder tumor \[Ta, Tis and T1\] are exempted.
* Brain metastases mandating active treatment. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 4 weeks after treatment is completed and within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (\> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
* Prior therapy with anti-tumor vaccines or other immuno-stimulatory antitumor agents.
* Administration of a live, attenuated vaccine within 4 weeks of start of therapy
* Any previous treatment with a an anti-Programmed Cell Death 1 protein (anti-PD-1), anti-PD-L1, anti-PD-L2, anti-Cytotoxic T-Lymphocyte-Associated protein (anti-CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
* Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment.
* Patients should be excluded if they have an active, known or suspected autoimmune disease. Note: Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
* Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. NOTE: Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
* Known chronic infection (i.e. hepatitis B or C, HIV)
* Patients should be excluded if they have been positively tested for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
* Patients should be excluded if they have a known history of testing positive for human immunodeficiency virus (HIV) or a known acquired immunodeficiency syndrome (AIDS).
* History of severe hypersensitivity reaction to any monoclonal antibody or any constituent of the product.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have a psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
* Uncontrolled severe hypertension (failure of diastolic blood pressure to fall below 95 mmHg under adequate medication)
* Current cardiac events such as arrhythmias, myocardial infarction, Congestive heart failure (CHF), apoplexy, lung embolism
* Idiopathic pulmonary fibrosis or other risk for pneumonitis
* History of allogeneic solid organ or tissue transplant including allogeneic hematopoetic stem cell transplantation
* Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control (failure rate of less than 1% per year)
* Any other serious or uncontrolled medical disorder, active infection, physical exam finding, laboratory finding, altered mental status, or psychiatric condition that, in the opinion of the investigator, would limit a subject's ability to comply with the study requirements, substantially increase risk to the subject, or impact the interpretability of study results.
* Previous enrollment or randomization in the present study. (Not applicable to screening failures)
* Involvement in the planning and/or conduct of the study (applies to both Bristol-Myers Squibb (BMS) staff and/or staff of sponsor and study site)
* Patient who might be dependent on the sponsor, site or the investigator.
* Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts \[§ 40 Abs. 1 S. 3 Nr. 3a Arzneimittelgesetz (AMG)\].
* Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
D: Inclusion Criteria:

* Histologic confirmation of Renal cell carcinoma (RCC) with a clear cell component
* Previous treatment with at least one anti-angiogenic agent
* Progressed within 6 months of study enrollment
* Subjects should not have had more than 3 prior treatments for locally advanced or metastatic disease
* Must have available tumor tissue for submission
* Subjects must also meet various laboratory parameters for inclusion

Exclusion Criteria:

* Subjects with any active autoimmune disease or a history of known autoimmune disease

Other protocol-defined inclusion/exclusion criteria apply

Answer: D