Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised, Double-blind, Placebo Controlled, Multi-center Phase III Study to Evaluate the Efficacy and Safety of Pazopanib (GW786034) Compared to Placebo in Patients With Locally Advanced and/or Metastatic Renal Cell Carcinoma
Brief Summary: To evaluate efficacy and safety of pazopanib compared to placebo in patients with locally advanced and/ or metastatic renal cell carcinoma (RCC). Approximately 350-400 eligible patients will be stratified and randomized in a 2:1 ratio to receive either 800 mg pazopanib once daily or matching placebo. The study treatment will continue until patients experience disease progression, unacceptable toxicity or death. Primary objective of the study is to evaluate and compare the two treatment arms for progression-free survival. Principal secondary objective is to evaluate and compare the two treatment arms with respect to overall survival. Other objectives are overall response rate \[complete response (CR) + partial response (PR)\], rate of CR + PR + 6 months stable disease, and the incidence, severity and causality of adverse events and serious adverse events. Safety and efficacy assessments will be regularly performed on all patients. An Independent Data Monitoring Committee will be established to monitor safety during the course of the study and to evaluate interim efficacy data on overall survival.


Options:
A: Inclusion Criteria:

* Histologically and/or cytologically confirmed to have advanced renal cell carcinoma (RCC)
* Majority component of conventional clear-cell type is mandatory
* At least 1 measurable lesion (per RECIST)

Exclusion Criteria:

* Prior systemic treatment for RCC
* Evidence of current or prior central nervous system (CNS) metastases
* Cardiovascular disease
* Pregnant or nursing women
* Additional criteria applies
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:

* Cohort A only: Patients with microsatellite instability (MSI) positive colorectal cancer
* Cohort B only: Patients with MSI negative colorectal cancer
* Cohort C only: Patients with MSI positive non-colorectal cancer -
* Have measurable disease
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1
* Adequate organ function as defined by study-specified laboratory tests
* Must use acceptable form of birth control through the study and for 28 days after final dose of study drug
* Signed informed consent form
* Willing and able to comply with study procedures
* Agree to have a biopsy of participants' cancer
* Patients with colon cancer must have received at least two prior cancer therapy regimens.
* Patients with other cancer types must have received at least one prior cancer therapy
* Progressive disease

Exclusion Criteria:

* Patients with uncontrolled intercurrent illness, including but not limited to ongoing or active infection, systematic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric condition that would limit compliance with study requirements.
* Patients who have had chemotherapy or biological cancer therapy within 2 weeks prior to the first dose of study drug
* Patients who have had radiation within 2 weeks prior to the first dose of study drug
* Patients who have undergone major surgery within 4 weeks of dosing of investigational agent
* Patients who have received another investigational product or investigational device within 4 weeks prior to receiving study drug
* Patients who have received any of the following concomitant therapy: Interleukin-2 (IL-2), interferon, or other non-study immunotherapy regimens, immunosuppressive agents, other investigational therapies or chronic use of systemic corticosteroids within one week prior to first dose of study drug
* Patients who have received a live vaccine within 4 weeks prior to or after any dose of MK-3475 (exception: inactivated flu vaccines)
* Patients who have received growth factors, including but not limited to granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), erythropoietin, etc. within 2 weeks of study drug administration
* Patient who have had prior treatment with anti-PD-1 (anti-programmed cell death protein 1), anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-CD40, or anti-CTLA-4 antibodies
* Patients with history of any autoimmune disease:inflammatory bowel disease, (including ulcerative colitis and Crohn's Disease), rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus (SLE) autoimmune vasculitis, central nervous system (CNS) or motor neuropathy considered to be of autoimmune origin.
* Patients who have known history of infection with HIV, hepatitis B, or hepatitis C
* Patients with evidence of interstitial lung disease
* Systemically active steroid use
* Patients on home oxygen
* Patients with oxygen saturation of \<92% on room air by pulse oximetry
* Pregnant or lactating
* Conditions, including alcohol or drug dependence, or intercurrent illness that would affect the patient's ability to comply with study visits and procedures
* Patient with known active central nervous system metastases and/or carcinomatous meningitis.
* Patients with primary brain tumors.
* Requires any other form of systemic or localized antineoplastic therapy while on study
* Has any tissue or organ allograft
* Patients with history of allogeneic hematopoeitic stem cell transplant
D: Inclusion Criteria:

A patient will be considered for inclusion in this study only if all of the following criteria apply:

* Signed written informed consent.
* Diagnosis of clear cell RCC that is predominantly clear cell histology. Note: cytology cannot be the only pathologic criteria to confirm clear cell RCC. Patients with tumor types that are interpreted as non-clear cell, e.g. papillary, are excluded.
* Locally advanced RCC (defined as disease not amenable to curative surgery or radiation therapy) or metastatic RCC (equivalent to Stage IV RCC according to American Joint Committee on Cancer (AJCC) staging.
* Note: If the metastatic disease is restricted to a solitary lesion, its neoplastic nature must be confirmed by histology or cytology. Cytology cannot be the only pathologic criteria to confirm clear cell RCC, but can be used in a patient with histologically confirmed clear cell RCC to confirm that metastatic disease is neoplastic in nature.
* Must have measurable disease, i.e. presenting with at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST). A measurable lesion is defined as a lesion that can be accurately measured in at least one dimension with the longest diameter ≥ 20 mm using conventional techniques, or ≥ 10 mm with spiral CT scan.
* Note: Patient should be excluded if all baseline measurable lesions are within previously irradiated areas.
* Note: A patient must complete all the baseline disease assessments in order to be eligible. Baseline head, chest, abdominal and pelvic CT or MRI scans must be performed within 2 weeks prior to the first dose of study medication; baseline bone scan must be performed within 3 weeks of the first dose of study medication.
* Patients who have received only one prior systemic treatment for locally advanced or metastatic RCC with documented disease progression or documented treatment discontinuation due to unacceptable toxicity. This first-line systemic treatment must be cytokine based.
* Note: The first-line cytokine-based treatment can be interleukin-2 (IL-2) or interferon-α (INFα) monotherapy, IL-2 in combination with INF-α, IL-2 and/or INF-α in combination with chemotherapy, hormonal or other therapies excluding agents targeting angiogenesis pathways. Agents in a combination regimen can be given sequentially if the treatment sequence is pre-determined and the patient does not fail one agent prior to starting another.
* Note: Prior adjuvant or neo-adjuvant therapies are permitted excluding any agents that target vascular endothelial growth factor (VEGF) or VEGF receptors. The adjuvant/neo-adjuvant therapies should not be considered as first-line systemic treatment for advanced RCC.

Or,

* Patients who have received no prior systemic therapy for advanced/metastatic RCC can be enrolled if under any of the following circumstances:
* Patients who live in countries or regions where there is no established standard first-line therapy for advanced/metastatic RCC or where there are barriers to the access of established therapies such as sunitinib, sorafenib, IFNα or IL-2.
* Patients who live in countries or regions where IL-2 or INF-α has been approved for the treatment of advanced/metastatic RCC, however, these agents are generally not recognized by the local clinical community as a standard treatment for advanced/metastatic RCC, or where the physician and the patient have determined that the available cytokine therapies are not an acceptable therapeutic option.
* Patients who have recurred following prior adjuvant or neo-adjuvant cytokine therapy for RCC are eligible to participate without receiving a first-line systemic treatment for locally advanced or metastatic RCC. These patients should be stratified as the first-line population.
* Male or female ≥ 18 years of age.
* A woman is eligible to participate in the study if she is of:
* Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who:
* Has had a hysterectomy,
* Has had a bilateral oophorectomy (ovariectomy),
* Has had a bilateral tubal ligation,
* Is post-menopausal (total cessation of menses for ≥1 year).
* Childbearing potential, has a negative serum pregnancy test within 2 weeks of the first dose of study medication, and agrees to use adequate contraception. GSK acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows:
* An intrauterine device with a documented failure rate of less than 1% per year.
* Vasectomized partner who is sterile prior to the female patient's entry and is the sole sexual partner for that female.
* Complete abstinence from sexual intercourse for 14 days before exposure to investigation product, through the clinical trial, and for at least 21 days after the last dose of investigational product.
* Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide).
* Oral contraceptives are not reliable due to the potential for drug-drug interactions.
* A man with a female partner of childbearing potential is eligible to enter and participate in the study if he is abstinent or uses a barrier method of contraception during the study.
* Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1
* Adequate baseline organ function defined as:
* Hematologic function:

Absolute Neutrophil Count (ANC) ≥1 x 10\^9/L Hemoglobin ≥ 9 g/dL Platelet ≥75 x 10\^9/L

* Hepatic function:

Total bilirubin ≥ 1.5 x Upper Limit of Normal (ULN) Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≥ 2 x ULN

* Renal function:

Calculated creatinine clearance≥30 mL/min \[See Section 14.6 Appendix 6\] and

≥Urine protein is 0, trace, or +1 determined by dipstick urinalysis, or \< 1.0 gram determined by 24-hour urine protein analysis.

* Note: A patient should first be screened with dipstick urinalysis. If urine protein is ≥2+, then a 24-hour urine protein must be assessed and patient will be excluded if 24-hour urine protein is≥ 1.0 gram.
* Corrected serum calcium level within normal range per local clinical laboratory standard.

Note: Patients with hypercalcemia should be treated until the corrected serum calcium level reaches the normal range.

* At least 4 weeks must have elapsed since the last surgery and 2 weeks must have elapsed since radiotherapy or the last systemic cytokine therapy.
* Complete recovery from prior surgery, and/or reduction of all AEs to Grade 1 from prior systemic therapy or radiotherapy.
* Note: In patients with prior radiotherapy, the steroid doses should be stable or decreasing for at least 2 weeks.

Exclusion Criteria:

A patient will not be eligible for inclusion in this study if any of the following criteria apply:

* Pregnant or lactating female.
* History of another malignancy.
* Note: Patients who have had another malignancy and have been disease-free for 5 years, or patients with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible.
* History or presence of central nervous system (CNS) metastasis or leptomeningeal tumors as documented by CT or MRI scan, analysis of cerebrospinal fluid or neurological exam.

Note: A baseline brain CT or MRI scan must be obtained in all patients within 2 weeks of the first dose of study medication.

* Malabsorption syndrome or disease that significantly affects gastrointestinal function, or major resection of the stomach or small bowel that could affect the absorption of pazopanib.
* Unable to swallow and retain orally administered medication.
* 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 4 weeks prior to beginning study treatment.
* History of human immunodeficiency virus infection.
* Presence of uncontrolled infection.
* Corrected QT interval (QTc) prolongation defined as QTc interval \> 470 msecs.
* History of Class III or IV congestive heart failure according to New York Heart Association (NYHA) classification.
* History of any one of the following cardiac conditions within the past 6 months:
* Cardiac angioplasty or stenting, or
* Myocardial infarction, or
* Unstable angina.
* History of cerebrovascular accident within the past 6 months.
* Poorly controlled hypertension \[defined as systolic blood pressure (SBP) of ≥140mmHg, or diastolic blood pressure (DBP) of ≥ 90mmHg\].
* Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. The blood pressure must be re-assessed on two occasions that are separated by a minimum of 24 hours. The mean SBP / DBP values from both blood pressure assessments must be \< 140/90mmHg in order for a patient to be eligible for the study.
* History of untreated deep venous thrombosis (DVT) within the past 6 months (e.g. a calf vein thrombosis that is not treated).

Note: Patients with recent DVT who are treated with therapeutic anti-coagulating agents (excluding therapeutic warfarin) for at least 2 weeks are eligible.

* Presence of any non-healing wound, fracture, or ulcer, or presence of symptomatic peripheral vascular disease.
* Evidence of bleeding diathesis or coagulopathy.
* Any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with patient's safety, obtaining informed consent or compliance to the study.
* Has taken any prohibited medications within 14 days of the first dose of study medication.
* Current or prior use of an investigational anti-cancer drug within 4 weeks of start of study.
* Prior use of an investigational or licensed drug that targets VEGF or VEGF receptors (eg. bevacizumab, sunitinib, sorafenib, etc).

Answer: D