Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 2, Randomized, Open-Label Study of Nivolumab Combined With Ipilimumab Versus Standard of Care in Subjects With Previously Untreated and Advanced (Unresectable or Metastatic) Non-clear Cell Renal Cell Carcinoma (nccRCC)
Brief Summary: SUNNIFORECAST (Standard of Care vs. Nivolumab + Ipilimumab as First line treatment of renal cell cancer of non-clear cell subtypes) is a Phase II, randomized, open-label investigator initiated trial (IIT) of Nivolumab (BMS-936558) combined with Ipilimumab vs standard of care in subjects with previously untreated and advanced (unresectable or metastatic) non-clear cell renal cell carcinoma (nccRCC).


Options:
A: 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
B: Inclusion Criteria:

1. Signed Written Informed Consent a) Subjects must have signed and dated an approved written informed consent form according to the Institutional Review Board (IRB) and in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care.

   b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
2. Target Population a) Histological confirmation of non-clear cell renal cell carcinoma (nccRCC) with at least 50% non-clear cell component according to actual World Health Organization (WHO) classification.

   b) Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) nccRCC c) Performance status: Karnofsky (KPS) \> 70% d) Measurable disease as per RECIST v 1.1 documented by an English radiology report e) Tumor tissue (FFPE archival or recent acquisition) must be available and sent to the central pathological reviewer (see Table 6) in order to confirm the diagnosis. (Note: Fine Needle Aspiration (FNA) and bone metastases samples are not acceptable for submission).

   f) Patients with all risk categories will be eligible for the study. Patients will be stratified for papillary or non-papillary non-clear cell histology and IMDC risk score Patients will be categorized according to favorable versus intermediate versus poor risk status at registration according to the International Metastatic RCC Database Consortium (IMDC) criteria: i. KPS equal to 70% ii. \< 1 year from diagnosis to randomization iii. Hemoglobin \< than the lower limit of normal (LLN) iv. Corrected calcium concentration greater than the upper limit of normal (ULN) v. Absolute neutrophil count greater than the ULN vi. Platelet count greater than the ULN If none of the above factors are present, subjects are only eligible for the favorable-risk cohort, if 1-2 factors are present subjects are categorized as intermediate risk and \> 3 factors as poor risk.
3. Age and Reproductive Status

   a) Males and Females, \> 18 years of age b) WOCBP 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 study drug.

   c) Women must not be breastfeeding d) WOCBP must agree to follow instructions for method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo five half-lives. The terminal half-lives of Nivolumab and Ipilimumab are up to 25 days and 18 days, respectively. The terminal half-life of the active metabolite of Sunitinib is up to 110 hours. The terminal half-life of other Standard of Care agents has to be derived from the product information.

   i. WOCBP randomized to receive Nivolumab + Ipilimumab 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 investigational drug.

   ii. WOCBP randomized to receive the Standard of Care agent should use an adequate method to avoid pregnancy for 8 weeks (30 days plus the time required for the active metabolite of the Standard of Care agent to undergo five half-lives) e) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo five half-lives. The terminal half lives of Nivolumab and Ipilimumab are up to 25 days and 18 days, respectively. The terminal half-life of the active metabolite of Sunitinib is up to 110 hours.

   i. Males randomized to receive Nivolumab combined with Ipilimumab who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for Nivolumab to undergo five half-lives) after the last dose of investigational drug.

   ii. Males randomized to receive Sunitinib who are sexually active and women of childbearing potential (WOCBP) must continue contraception for 16 weeks (90 days plus the time required for the active metabolite of Sunitinib to undergo five half-lives) after the last dose of investigational drug.

   f) Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in this section.

   Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of \< 1% when used consistently and correctly.

   At a minimum, subjects must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or uncertain effective as listed below:

   HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

   • Male condoms with spermicide

   • Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) by WOCBP subject or male subject's WOCBP partner

   • Female partners of male subjects participating in the study may use hormone based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug

   • Nonhormonal IUDs
   * Tubal ligation
   * Vasectomy
   * Complete Abstinence\*

     * Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs. Subjects who choose complete abstinence are not required to use a second method of contraception, but female subjects must continue to have pregnancy tests. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence.

   UNCERTAIN METHODS OF CONTRACEPTION

   • Diaphragm with spermicide

   • Cervical cap with spermicide

   • Vaginal sponge

   • Male Condom without spermicide

   • Progestin only pills by WOCBP subject or male subject's WOCBP partner

   • Female Condom\*.
   * A male and female condom must not be used together

   Exclusion Criteria:

1. Target Disease Exceptions

1. Any active brain metastases requiring systemic corticosteroids. Baseline imaging of the brain by MRI is required in patients with clinical signs of potential central nerve system (CNS) involvement within 28 days prior to randomization.
2. Tumors with a clear-cell component of \> 50%

   Medical History and Concurrent Diseases
3. 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) or prior treatment with an mTOR inhibitor or cytokines.
4. Prior treatment with an immune checkpoint inhibitor as anti-programmed cell death (PD)PD-1, anti-PD-L1, anti-PD-L2, 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.
5. 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 I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll.
6. 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.
7. Uncontrolled adrenal insufficiency.
8. 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
9. Poorly controlled hypertension (defined as systolic blood pressure (SBP) of \> 150 mmHg or diastolic blood pressure (DBP) of \> 90 mmHg), despite antihypertensive therapy.
10. 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.
11. History of cerebrovascular accident including transient ischemic attack within the past 12 months.
12. History of deep vein thrombosis (DVT) unless adequately treated with low molecular weight heparin
13. History of pulmonary embolism within the past 6 months unless stable, asymptomatic, and treated with low molecular weight heparin for at least 6 weeks.
14. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months.
15. Serious, non-healing wound or ulcer.
16. Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 30 days.
17. Any requirement for anti-coagulation, except for low molecular weight heparin.
18. 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.
19. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
20. Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
21. Known medical condition (eg, 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.
22. Major surgery (eg, nephrectomy) \< 28 days prior to the first dose of study drug.
23. Anti-cancer therapy \< 28 days prior to the first dose of study drug or palliative, focal radiation therapy \< 14 days prior to the first dose of study drug.
24. Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors (See Appendix 4, 14.4).
25. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the Standard of Care agent (eg, malabsorptive disorder, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or small bowel resection).
26. Hypersensitivity to the Standard of Care or any of the excipients aa) Patients who were vaccinated with a live vaccine 2 weeks prior to the start of the CT

    2. Physical and Laboratory Test Findings

a. Left ventricular ejection fraction (LVEF) less than the LLN as assessed by echocardiography or multigated acquisition (MUGA) scan. b. Any of the following laboratory test findings: 2. WBC \< 2,000/mm3 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. Total Bilirubin \> 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL) 7. Serum creatinine \> 2.5 x upper limit of normal (ULN) or creatinine clearance \< 20 mL/min (measured or calculated by Cockroft-

Gault formula):

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

3. Allergies and Adverse Drug Reaction

a) History of severe hypersensitivity reaction to any monoclonal antibody.

4. Other Exclusion Criteria

a) Subjects who are incompetent to understand and sign the informed consent.
C: Inclusion Criteria:

* 18 years or older
* Participants with metastatic RCC who have failed 2 or 3 prior systemic regimens, one of which includes a VEGFR TKI other than sorafenib or tivozanib.
* Histologically or cytologically confirmed RCC with a clear cell component (participants with pure papillary cell tumor or other non-clear cell histologies, including collecting duct, medullary, chromophobe, and unclassified RCC are excluded).
* Measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria Version 1.1.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Life expectancy ≥ 3 months.

Exclusion Criteria:

* Prior treatment with sorafenib or tivozanib.
* More than 3 prior regimens for metastatic RCC.
* Known central nervous system (CNS) metastases other than stable, treated brain metastases. Participants with previously treated brain metastasis will be allowed if the brain metastasis has been stable by neuroimaging without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery).
* Significant hematologic, gastrointestinal, thromboembolic, vascular, bleeding, or coagulation disorders.
* Significant serum chemistry abnormalities
* Significant cardiovascular disease, including: Active clinically symptomatic left ventricular failure, uncontrolled hypertension, myocardial infarction, severe angina, or unstable angina within 6 months prior to administration of first dose of study drug, history of serious ventricular arrhythmia, cardiac arrhythmias requiring anti-arrhythmic medications.
* Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug.
* Currently active second primary malignancy.
D: For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

* Histological confirmation of renal cell carcinoma (RCC) with a clear-cell component
* Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC
* No prior systemic therapy for RCC with the following exception:

  1. One prior adjuvant or neoadjuvant therapy for completely resectable RCC if such therapy did not include an agent that targets vascular endothelial growth factor (VEGF) or VEGF receptors and if recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy

     * Karnofsky Performance Status (KPS) of at least 70%
     * Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
     * Tumor tissue \[formalin-fixed paraffin-embedded (FFPE) archival or recent acquisition\] must be received by the central vendor (block or unstained slides) in order to randomize a subject to study treatment. (Note: Fine Needle Aspiration \[FNA\] and bone metastases samples are not acceptable for submission)

Exclusion Criteria:

* Any history of or current central nervous system (CNS) metastases. Baseline imaging of the brain is required within 28 days prior to randomization
* Prior systemic treatment with VEGF or VEGF receptor targeted therapy (including, but not limited to, Sunitinib, Pazopanib, Axitinib, Tivozanib, and Bevacizumab)
* Prior treatment with an anti-programmed death (PD)-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte antigen 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 I 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

Answer: B