Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase II Study With NIVOlumab or Continuation of Therapy as an Early SWITCH Approach in Patients With Advanced or Metastatic Renal Cell Carcinoma (RCC) and Disease Control After 3 Months of Treatment With a Tyrosine Kinase Inhibitor
Brief Summary: This study aims to assess the survival benefit from an early switch approach from sunitinib or pazopanib (10-12 weeks of 1st-line therapy) to nivolumab (anti-angiogenic to immunotherapy switch).


Options:
A: 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.
B: Select Inclusion Criteria:

* Histologically confirmed diagnosis of renal cell carcinoma.
* Phase 2: Histological or cytological confirmation of predominant clear cell renal cell carcinoma (RCC) (original tissue diagnosis of RCC is acceptable).
* Documented evidence of unresectable advanced or metastatic RCC. Phase 2: Radiographic evidence of disease progression according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
* Phase 2: One prior vascular endothelial growth factor (VEGF)-targeted treatment (for example, but not limited to, sunitinib, sorafenib, pazopanib, bevacizumab, axitinib, vatalanib, AV951/tivozanib) for unresectable advanced or metastatic RCC.
* Phase 2: Measurable disease meeting the following criteria: a.) at least 1 lesion of greater than or equal to 1.5 cm in the longest diameter for a non-lymph node or greater than or equal to 1.5 cm in the short axis diameter for a lymph node which is serially measurable according to Modified RECIST 1.1 using computerized tomography/magnetic resonance imaging (CT/MRI) or photography. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
* Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than or equal to 150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to the Screening Visit.

Select Exclusion Criteria:

Phase 1b or Phase 2 specific per below:

* Phase 1b only: Subjects with untreated or unstable metastasis to the central nervous system (CNS) are excluded. Subjects who have completed local therapy and have discontinued the use of steroids for this indication at least 4 weeks prior to commencing treatment and in whom stability has been proven by at least 2 CT or MRI scans obtained at least 4 weeks apart are eligible for Phase 1b only. Phase 2 only: Subjects with CNS (e.g., brain or leptomeningeal) metastasis are excluded.
* Phase 2 only: More than one prior VEGF-targeted treatment for unresectable advanced or metastatic RCC.

Phase 1b or Phase 2 specific per below:

* Phase 1b only: Prior exposure to lenvatinib. Phase 2 only: Prior exposure to lenvatinib or mammalian target of rapamycin (mTOR) inhibitor.
* Subjects should not have received any anticancer treatment within 21 days or any investigational agent within 30 days prior to the first dose of study drug and should have recovered from any toxicity related to previous anticancer treatment. Major surgery within 3 weeks prior to the first dose of study drug.
* Subjects having greater than 1+ proteinuria on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria.
* Subjects with urine protein greater than or equal to 1 g/24 hours will be ineligible. Uncontrolled diabetes as defined by fasting serum glucose at 1.5 x ULN.
* Phase 2 only: Active malignancy (except for renal cell carcinoma, melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 24 months.
* Known intolerance to any of the study drugs (or any of the excipients) and/or known hypersensitivity to rapamycins (e.g., sirolimus, everolimus, temsirolimus) or any of the excipients.
* Phase 1b only: Subjects who discontinued prior tyrosine kinase inhibitor due to toxicity will be ineligible.
C: Inclusion Criteria:

* Histologically or cytologically confirmed renal cell cancer with a component of clear cell subtype, with metastasis
* Evidence of measurable disease
* Must have failed one prior systemic first-line regimen for metastatic renal cell cancer

Exclusion Criteria:

* Prior treatment for metastatic renal cell cancer with more that one systemic first line therapy
* Major surgery less than 4 weeks or radiation less than 2 weeks of starting study drug
D: Inclusion Criteria:

* Patients with metastatic renal cell carcinoma (mRCC) with histological or cytological confirmation of clear cell carcinoma or a component of clear cell
* Patients must have received one and only one prior VEGF-targeted therapy and one and only one prior mTOR inhibitor therapy in the metastatic setting. One VEGF targeted therapy (e.g. sunitinib, or pazopanib, or axitinib, or tivozanib or bevacizumab) and one prior mTOR inhibitor therapy (everolimus, or temsirolimus or ridaforolimus)
* Prior cytokines therapy and prior vaccines in the adjuvant setting is permitted.
* Patients must have had disease progression on or within 6 months of stopping the last therapy.
* Patients must have at least one measurable lesion at baseline (by RECIST Criteria Guidelines v1.1) assessed by Computer Tomography (CT) Scan or Magnetic Resonance Imaging (MRI).
* Karnofsky performance status ≥ 70%
* Patients must have the following laboratory values:

  * Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
  * Platelets ≥ 100 x 109/L
  * Hemoglobin (Hgb) \> 9 g/dL
  * Serum total bilirubin: ≤ 1.5 x ULN
  * ALT and AST ≤ 3.0 x ULN (Patients with known liver metastases: AST and ALT ≤ 5.0 x ULN)
  * Serum creatinine ≤ 1.5 x ULN

Exclusion Criteria:

* Patients who have previously received sorafenib therapy in the neoadjuvant, adjuvant or metastatic setting.
* Patients who have previously received Dovitinib or brivanib in the neoadjuvant, adjuvant or metastatic setting.
* Patients with brain metastases. Radiological imaging (e.g. CT or MRI scan) of the brain is required at screening/baseline
* Patients with another primary malignancy within 3 years prior to starting study treatment, with the exception of adequately treated basal cell carcinoma, squamous cell carcinoma or non-melanomatous skin cancer, or in-situ carcinoma of the uterine cervix
* Patients who have received the last administration of an anticancer targeted small molecule therapy ≤ 2 weeks prior to starting study treatment (e.g. sunitinib, pazopanib, axitinib, everolimus, temsirolimus), or who have not recovered from the side effects of such therapy
* Patients who have received the last administration of nitrosurea or mitomycin-C ≤ 6 weeks prior to starting study treatment, or who have not recovered from the side effects of such therapy
* Patients who have undergone major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) ≤ 4 weeks prior to starting study treatment or who have not recovered from side effects of such therapy
* Patients with a history of pulmonary embolism (PE), or untreated deep venous thrombosis (DVT) within the past 6 months
* Patients with concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study

Other protocol-defined inclusion/exclusion criteria may apply

Answer: A