Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Open-Label, Multicenter, Phase 1b/2 Study of E7080 Alone, and in Combination With Everolimus in Subjects With Unresectable Advanced or Metastatic Renal Cell Carcinoma Following One Prior VEGF-Targeted Treatment
Brief Summary: This is an open-label, multicenter, Phase 1b/2 study of lenvatinib alone and in combination with everolimus in subjects with unresectable advanced or metastatic renal cell carcinoma following one prior VEGF-targeted treatment.


Options:
A: 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.
B: Inclusion Criteria:

* Patients with unresectable and/or metastatic, measurable renal cell carcinoma histologically or cytologically documented
* Patients must have had one prior systemic therapy for advanced disease, which was completed at least 30 days but no longer than 8 months prior to randomization
* Patients who have at least one uni-dimensional measurable lesion by CT-scan or MRI according to Response Evaluation Criteria in Solid Tumors (RECIST)
* Patients who have an Eastern Co-operative Oncology Group (ECOG) performance status of 0 or 1
* Patients who have adequate coagulation, liver and kidney functions

Exclusion Criteria:

* Patients with rare subtypes of renal cell carcinoma (RCC) such as pure papillary cell tumors, mixed tumor containing predominantly sarcomatoid cells, Bellini carcinoma, medullary carcinoma, or chromophobe oncocytic tumors
* Previous malignancy (except for cervical carcinoma in situ, adequately treated basal cell carcinoma,or superficial bladder tumors, or other malignancies curatively treated \> 2 years prior to entry
* Cardiac arrhythmias requiring anti-arrhythmics, symptomatic coronary artery disease or ischemia or congestive heart failure
* Patients with a history of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C
* Patients with a history or presence of metastatic brain or meningeal tumors
* Patients with seizure disorder requiring medication (such as anti-epileptics)
* History of organ allograft or bone marrow transplant of stem cell rescue
* Patients who are pregnant or breast-feeding Women of childbearing potential must have a negative pregnancy test prior to drug administration. Both men and women enrolled in this trial must use adequate birth control
* Patients who have three or more of the following:

  * ECOG performance status greater than or equal to 2,
  * Abnormally high lactate dehydrogenase,
  * Abnormally high serum hemoglobin,
  * Abnormally high corrected serum calcium,
  * Absence of prior nephrectomy
* Excluded therapies and medications, previous and concomitant:

  * Concurrent anti-cancer chemotherapy, immunotherapy or hormonal therapy except biphosphonates
  * Significant surgery with 4 weeks of start of study
  * Investigational drug therapy during or within 30 days
  * Concomitant treatment with rifampin or St. John's Wort
  * Prior use of Raf-kinase inhibitors (RKI), MEK or Farnesyl transferase inhibitors
  * Prior use of Bevacizumab, and all other drugs (investigational or licensed) that target VEGF/VEGF receptors
C: Inclusion Criteria:

1. Patients with advanced renal cell carcinoma.
2. Patients with at least one measurable lesion.
3. Patients with a Karnofsky Performance Status ≥70%.
4. Adequate bone marrow function.
5. Adequate liver function.
6. Adequate renal function.
7. Left ventricular ejection fraction (LVEF) ≥ lower limit of institutional normal (LLN)
8. Women of childbearing potential must have had a negative serum pregnancy test within 14 days prior to the administration of the study medication. Adequate contraception must be used while on study.

Exclusion Criteria:

1. Less than 4 weeks post-major surgery
2. Patients who had radiation therapy within 4 weeks prior to start of study treatment (palliative radiotherapy to bone lesions allowed within 2 weeks prior to study treatment start).
3. Patients in need for major surgical procedure during the course of the study
4. Patients with a serious non-healing wound, ulcer, or bone fracture
5. Patients with a history of seizure(s) not controlled with standard medical therapy
6. Patients who have received prior systemic treatment for their metastatic RCC
7. Patients who have previously received systemic mTOR inhibitors (sirolimus, temsirolimus, everolimus) or VEGF inhibitors. Note: History of adjuvant immunotherapy, vaccines or adjuvant sorafenib following localized surgical nephrectomy is acceptable.
8. Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins or to its excipients
9. Patients with a known hypersensitivity to sunitinib or its excipients
10. History or clinical evidence of central nervous system (CNS) metastases. Note: Subjects who have previously-treated CNS metastases (surgery plus or minus radiotherapy, radiosurgery, or gamma knife) and meet all 3 of the following criteria are eligible:

    * Are asymptomatic and,
    * have had no evidence of active CNS metastases for ≥ 6 months prior to enrollment and,
    * have no requirement for steroids or enzyme-inducing anticonvulsants (EIAC)
11. Clinically significant gastrointestinal abnormalities including, but not limited to:

    * Malabsorption syndrome
    * Major resection of the stomach or small bowel that could affect the absorption of study drug
    * Active peptic ulcer disease
    * Inflammatory bowel disease
    * Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation
    * History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.
12. Poorly controlled hypertension \[defined as systolic blood pressure (SBP) of ≥160mmHg or diastolic blood pressure (DBP) of ≥ 95mmHg\]
13. Patients receiving chronic systemic treatment with corticosteroids or another immunosuppressive agent
14. Patients with a known history of HIV seropositivity.
15. Patients with active bleeding.
16. Patients who have any severe and/or uncontrolled medical conditions or other conditions within the past 12 months that could affect their participation in the study such as:

    * Cardiac angioplasty or stenting, unstable angina pectoris, symptomatic peripheral vascular disease, symptomatic congestive heart failure (NYHA II, III, IV), myocardial infarction ≤ 6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia, cerebrovascular accidents ≤ 6 months before study treatment start.
    * Prolongation of corrected QT interval (QTc) \> 500 milliseconds (msecs).
    * Severally impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 0\^2 saturation that is 88% or less at rest on room air.
    * Poorly controlled diabetes as defined by fasting serum glucose \>2.0 x ULN.
    * Any active (acute or chronic) or uncontrolled infection/disorders that impair the ability to evaluate the patient or for the patient to complete the study.
    * Liver disease such as chronic active hepatitis or chronic persistent hepatitis.
17. History of cerebrovascular accident (CVA) including transient ischemic attack (TIA).
18. History of pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.
19. Patients who have a history of another primary malignancy and off treatment for ≤ 3 years
20. Female patients of child-bearing potential who are not using adequate birth control methods, or who are pregnant or breast feeding.
21. Patients who are using other investigational agents or who had received investigational drugs ≤ 2 weeks prior to study treatment start.
22. Patients unwilling or unable to comply with the protocol.
D: 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.

Answer: D