Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 2 BIOmarker Driven Trial With Nivolumab and Ipilimumab or VEGFR tKi in Naïve Metastatic Kidney Cancer
Brief Summary: Disease and Stage: naïve metastatic kidney cancer.

A multicenter, randomized, a Phase 2 BIOmarker driven trial with Nivolumab and Ipilimumab or VEGFR tKi in naïve metastatic Kidney cancer


Options:
A: 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
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: 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.
D: Inclusion Criteria:

1. ≥ 18-years of age.
2. Subjects with recurrent or metastatic RCC.
3. Subjects must have undergone prior nephrectomy (complete or partial) for excision of the primary tumor.
4. Histologically or cytologically confirmed RCC with a clear cell component (subjects with pure papillary cell tumor or other non-clear cell histologies, including collecting duct, medullary, chromophobe, mixed tumor containing predominantly sarcomatoid cells, and unclassified RCC are excluded).
5. Measurable disease per the RECIST criteria Version 1.0.
6. Treatment naïve subjects or subjects who have received no more than one prior systemic treatment (immunotherapy, including interferon-alfa or interleukin-2 based therapy, chemotherapy, hormonal therapy or an investigational agent) for metastatic RCC. Postoperative or adjuvant systemic therapy will not be counted as a prior therapy unless recurrence is detected within 6 months of completion of treatment, in which case it will be counted as a prior therapy for metastatic disease.
7. ECOG performance status of 0 or 1, and life expectancy ≥ 3 months.
8. If female and of childbearing potential, documentation of negative pregnancy test prior to enrollment.
9. Ability to give written informed consent and comply with protocol requirements.

Exclusion Criteria:

1. Any prior VEGF-directed therapy including VEGF antibody (eg, bevacizumab), VEGF receptor tyrosine kinase inhibitor (eg, sunitinib, sorafenib, axitinib, pazopanib, etc.), VEGF trap (eg, aflibercept), or any other agent or investigational agent targeting the VEGF pathway.
2. Any prior therapy with an agent targeting the mTOR pathway (eg, temsirolimus, everolimus, etc)
3. Primary CNS malignancies or CNS metastases; subjects with previously treated brain metastasis will be allowed if the brain metastasis have been stable without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery).
4. Any hematologic abnormalities (as noted in the protocol).
5. Any serum chemistry abnormalities (as noted in the protocol).
6. Significant cardiovascular disease.
7. Non-healing wound, bone fracture, or skin ulcer.
8. Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal condition with increased risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to administration of first dose of study drug.
9. Serious/active infection or infection requiring parenteral antibiotics.
10. Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug.
11. Significant thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug.
12. Significant bleeding disorders within 6 months prior to administration of first dose of study drug.
13. Currently active second primary malignancy, including hematologic malignancies (leukemia, lymphoma, multiple myeloma, etc.), other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer and ductal or lobular carcinoma in situ of the breast. Subjects are not considered to have a currently active malignancy if they have completed anti-cancer therapy and have been disease free for \>2 years.
14. Pregnant or lactating females.
15. History of genetic or acquired immune suppression disease such as HIV; subjects on immune suppressive therapy for organ transplant.
16. Life-threatening illness or organ system dysfunction compromising safety evaluation.
17. Requirement for hemodialysis or peritoneal dialysis.
18. Inability to swallow pills, malabsorption syndrome or gastrointestinal disease that severely affects the absorption of tivozanib or sorafenib, major resection of the stomach or small bowel, or gastric bypass procedure.
19. Psychiatric disorder or altered mental status precluding informed consent or necessary testing.
20. Sexually active pre-menopausal female subjects (and female partners of male subjects) must use adequate contraceptive measures, while on study and for 50 days after the last dose of study drug. Sexually active male subjects must use adequate contraceptive measures, while on study for at least 90 days after the last dose of drug. All fertile male and female subjects and their partners must agree to use a highly effective method of contraception (including their partner). Effective birth control includes (a) IUD plus one barrier method; or (b) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). (Note: Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are not considered effective for this study.)

Answer: C