Please select the eligibility criteria that correspond to the clinical trial below.
Title: A PHASE 3, MULTINATIONAL, RANDOMIZED, OPEN-LABEL, PARALLEL-ARM STUDY OF AVELUMAB (MSB0010718C) IN COMBINATION WITH AXITINIB (INLYTA(REGISTERED)) VERSUS SUNITINIB (SUTENT(REGISTERED)) MONOTHERAPY IN THE FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED RENAL CELL CARCINOMA
Brief Summary: This is a phase 3 randomized trial evaluating the anti-tumor activity and safety of avelumab in combination with axitinib and of sunitinib monotherapy, administered as first-line treatment, in patients with advanced renal cell carcinoma


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: Inclusion Criteria:

1. Aged at least 18 years.
2. HLA type: HLA-A\*02-positive
3. Metastatic and/or locally advanced RCC with clear cell histology (histological confirmation by local pathologist required). NOTE: prior nephrectomy is NOT required.
4. Measurable and/or non-measurable tumor lesions as per RECIST 1.1
5. Patients who are candidates for a first-line therapy with sunitinib.
6. Favorable or intermediate risk according to the 6-score risk criteria in patients treated with VEGF-targeted agents according to Heng \[Heng et al. 2009\]. The patient has a favorable risk if none, or intermediate risk if one or two of the following criteria apply (if three or more criteria apply the patient is not eligible):

   1. Hemoglobin \< LLN,
   2. Serum corrected calcium \> ULN,
   3. Karnofsky performance status \< 80%,
   4. Time from initial diagnosis to initiation of therapy \< 1 year,
   5. Absolute neutrophil count \> ULN,
   6. Platelets \> ULN.
7. Able to understand the nature of the study and give written informed consent.
8. Willingness and ability to comply with the study protocol for the duration of the study.
9. Female patients who are post menopausal (no menstrual period for a minimum of 1 year), or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or practice a medically acceptable method of birth control.
10. Male patients willing to use contraception (upon study entry and during the course of the study or have undergone vasectomy.

Exclusion Criteria:

1. Prior systemic therapy for metastatic disease. (Note: prior adjuvant treatment for non-metastatic disease is allowed, however adjuvant therapy must have been stopped ≥ 1 year before Visit C).
2. History of or current brain metastases.
3. Abnormal ≥ CTC Grade 3 laboratory values for hematology (Hb, WBC, neutrophils, lymphocytes, platelets), liver (serum bilirubin, ALAT or ASAT) and renal function (serum creatinine).
4. Metastatic second malignancy.
5. Localized second malignancy expected to influence the patient's life span.
6. Patients with a history or evidence of systemic autoimmune disease, e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematodes (SLE), scleroderma, Sjögren's syndrome, Wegener's granulomatosis, Guillain-Barre syndrome.
7. Known active hepatitis B or C infection.
8. Known HIV infection.
9. Active infections requiring oral or intravenous antibiotics.
10. Any other known infection with a biological agent that can cause a severe disease and poses a severe danger to lab personnel working on patients' blood or tissue.
11. Received study drug within any clinical study (including approved and experimental drugs) within 4 weeks before sunitinib start.
12. Serious intercurrent illness, which according to the investigator, poses an undue risk for the patient when participating in the trial, including, but not limited to, any of the following:

    * Clinically significant cardiovascular disease (e.g., uncontrolled hypertension; clinically significant cardiac arrhythmia, clinically significant QT-prolongation),
    * New York Heart Association class III-IV congestive heart failure,
    * Symptomatic peripheral vascular disease,
    * Severe pulmonary dysfunction,
    * Psychiatric illness or social situation that would preclude study compliance.
13. Less than 12 months since any of the following:

    * Myocardial infarction,
    * Severe or unstable angina,
    * Coronary or peripheral artery bypass graft,
    * Cerebrovascular event incl. transient ischemic attack,
    * Pulmonary embolism / deep vein thrombosis (DVT).
14. Pregnancy or breastfeeding.
15. Any condition which in the judgment of the investigator would place the patient at undue risk or interfere with the results of the study.
C: Inclusion Criteria:

* Histologically or cytologically confirmed advanced or metastatic RCC with clear cell component
* Availability of a formalin-fixed, paraffin-embedded (FFPE) tumor tissue block from a de novo tumor biopsy during screening (biopsied tumor lesion should not be a RECIST target lesion). Alternatively, a recently obtained archival FFPE tumor tissue block (not cut slides) from a primary or metastatic tumor resection or biopsy can be provided if the following criteria are met: 1) the biopsy or resection was performed within 1 year of randomization AND 2) the patient has not received any intervening systemic anti-cancer treatment from the time the tissue was obtained and randomization onto the current study. If an FFPE tissue block cannot be provided as per documented regulations then, 15 unstained slides (10 minimum) will be acceptable
* Availability of an archival FFPE tumor tissue from primary tumor resection specimen (if not provided per above). If an FFPE tissue block cannot be provided as per documented regulations 15 unstained slides (10 minimum) will be acceptable
* At least one measurable lesion as defined by RECIST version 1.1 that has not been previously irradiated
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
* Adequate bone marrow function, renal and liver functions

Exclusion Criteria:

* Prior systemic therapy directed at advanced or metastatic RCC
* Prior adjuvant or neoadjuvant therapy for RCC if disease progression or relapse has occurred during or within 12 months after the last dose of treatment.
* Prior immunotherapy with IL-2, IFN-α, or anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti cytotoxic T lymphocyte associated antigen 4 (CTLA 4) antibody (including ipilimumab), or any other antibody or drug specifically targeting T cell co stimulation or immune checkpoint pathways
* Prior therapy with axitinib and/or sunitinib as well as any prior therapies with other VEGF pathway inhibitors
* Newly diagnosed or active brain metastasis
* Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3), any history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of partially controlled asthma Global Initiative for Asthma 2011)
* Any of the following in the previous 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, LVEF less than LLN, clinically significant pericardial effusion, cerebrovascular accident, transient ischemic attack
* Any of the following in the previous 6 months: deep vein thrombosis or symptomatic pulmonary embolism
* Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines (for example, inactivated influenza vaccines)
D: Inclusion Criteria:

* Evidence of histologically confirmed renal cell carcinoma (RCC) with metastases with a component of clear (conventional) cell histology
* A diagnosis of metastatic renal cell carcinoma (RCC) and have not received prior treatment with systemic (adjuvant or neoadjuvant) therapy for renal cell carcinoma (RCC) (including targeted therapy such as tyrosine kinase inhibitors or bevacizumab, immunotherapy, chemotherapy, hormonal, or investigational therapy)
* Evidence of measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Computed tomography (CT) or magnetic resonance imaging (MRI) should be performed within 4 weeks prior to study entry
* Participants who have or have not had their primary tumor removed by nephrectomy are allowed. Participants who have not had a nephrectomy should not be considered to need a nephrectomy as part of their overall therapy at the time of enrollment
* Performance status score of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale
* Adequate bone marrow, liver, and renal function, as assessed by the following laboratory requirements, to be conducted within seven days prior to treatment: (upper limit of normal/lower limit of normal \[ULN/LLN\])

  * hemoglobin (greater than) \>8.0 g/dL (grams per deciliter)
  * absolute neutrophil count (ANC) (greater than or equal to) ≥1.5 × 10\^9/L (liter)
  * platelet count (greater than or equal to) ≥100 × 10\^9/L (liter)
  * total bilirubin (less than or equal to) ≤ 1.5 × ULN (upper limit of normal)
  * serum creatinine (less than or equal to) ≤2 × ULN (upper limit of normal)
  * alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (less than or equal to) ≤2.5 × ULN (upper limits of normal) \[or (less than or equal to) ≤5 × ULN (upper limits of normal) for patients with liver involvement of their cancer\]
  * Prothrombin Time (PT) or International Normalized Ratio (INR) and activated Partial Thromboplastin Time (aPTT) (less than or equal to) ≤1.5 x ULN (upper limit of normal)
* For women: Must be surgically sterile (surgical procedure: bilateral tubal ligation, hysterectomy, bilateral oophorectomy), post-menopausal (at least 12 consecutive months of amenorrhea), or have a negative pregnancy test. Women of childbearing potential should be compliant with a medically approved contraceptive regimen (intrauterine device \[IUD\], birth control pills, or barrier device) during and for 3 months after the treatment period; must have a negative serum pregnancy test within 7 days before study enrollment, and must not be breastfeeding
* For men: Must be surgically sterile or compliant with a contraceptive regimen during and for 3 months after the treatment period
* Estimated life expectancy of at least 12 weeks
* Provide written informed consent/assent prior to any study-specific procedures
* No prior malignancies with the exception of stage 1 cancers definitively treated, carcinoma in situ (any primary site), treated non-melanoma skin cancer, superficial bladder tumors (Ta, Tis, and T1) or any cancer curatively treated 5 or more years prior to study entry
* Capable and willing to learn to self-administer LY2510924, or have a caregiver who is willing to learn and able to administer LY2510924 by subcutaneous (SC) injection and are able to swallow tablets
* Left ventricular ejection fraction (LVEF) greater than or equal to LLN as defined by the institution performing the scan, as assessed by Multiple Gated Acquisition (MUGA) scan, or from echocardiogram to be performed within 28 days prior to start of treatment

Exclusion Criteria:

* Received prior treatment with sunitinib or LY2510924
* Received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry
* History of active cardiovascular disease within the previous 12 months, including any of the following:

  * Myocardial infarction
  * Unstable angina
  * Coronary artery/peripheral artery bypass graft
  * Congestive heart failure
  * Malignant hypertension
  * Cerebrovascular accident or transient ischemic attack
  * Symptomatic cardiac arrhythmias (Patients with chronic, stable, rate- controlled atrial fibrillation are eligible)
* Exhibit uncontrolled hypertension ( \[greater than\] \>150/100 \[millimeters of mercury\] mm/Hg despite optimal medical therapy), or history of poor compliance with antihypertensive treatment
* Evidence of bleeding diathesis, National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 hemorrhage (less than) \<4 weeks of starting the study treatment, coagulopathy, or thromboembolic event
* Significant surgery (less than) \<4 weeks of starting study treatment or a minor surgical procedure (less than) \< 7 days prior to study treatment (Placement of a portacath or other venous access device does not require a waiting period)
* Suffer from medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
* Known or suspected allergy to any agent given in association with this trial
* Prior palliative radiotherapy to metastatic lesion(s) is/are permitted, provided there is at least 1 measurable lesion that has not been irradiated. Radiotherapy must have been completed (greater than) \>2 weeks prior to starting study treatment, and radiation-related side effects must have resolved
* Pregnant or lactating women
* Impairment of the gastrointestinal (GI) function or GI disease that may significantly alter the absorption of sunitinib
* Current or recent (within 10 days of first dose of study treatment) daily use of aspirin ( \[greater than\] \>325 \[milligram\] mg/day )
* Serious nonhealing wounds, acute or nonhealing ulcers, or bone fractures

Answer: C