Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III Randomized Study of BAY43-9006 in Patients With Unresectable and/or Metastatic Renal Cell Cancer.
Brief Summary: The purpose of this study is to evaluate safety, efficacy (including quality of life), and pharmacokinetics of BAY43-9006 when added to Best Supportive Care in patients with unresectable and/or metastatic renal cell cancer, who have received one prior systemic regimen for advanced disease.


Options:
A: Inclusion Criteria:

* Histologically confirmed advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) renal cell carcinoma with a clear-cell component.
* Intermediate- or poor-risk RCC as defined by International Metastatic RCC Database Consortium (IMDC) criteria.
* Measurable disease per RECIST 1.1 as determined by the Investigator. Measurable disease must be outside the radiation field if radiation therapy was previously administered.
* Karnofsky Performance Status (KPS) ≥ 70%.
* Adequate organ and marrow function.

Exclusion Criteria:

* Prior systemic anticancer therapy for unresectable locally advanced or metastatic RCC including investigational agents.
* Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks prior to randomization.
* Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and stable for at least 4 weeks prior to randomization.
* Concomitant anticoagulation with oral anticoagulants or platelet inhibitors.
* Administration of a live, attenuated vaccine within 30 days prior to randomization.
* Uncontrolled, significant intercurrent or recent illness including, but not limited to serious cardiovascular disorders (including uncontrolled hypertension defined as sustained blood pressure (BP) \> 150 mm Hg systolic or \> 90 mm Hg diastolic despite optimal antihypertensive treatment), GI disorders associated with high risk for perforation or fistula formation, tumors invading GI tract, bowel obstruction, intra-abdominal abscess, clinically significant bleeding events, cavitating pulmonary lesions, or lesions invading major pulmonary blood vessels.
* Other clinically significant disorders such as:

  * Autoimmune disease that has been symptomatic or required treatment within the past two years from the date of randomization.
  * Any condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization.
  * Active infection requiring systemic treatment. Acute or chronic hepatitis B or C infection, known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or known positive test for tuberculosis infection where there is clinical or radiographic evidence of active myobacterial infection.
  * Known history of COVID-19 unless the subject has clinically recovered from the disease at least 30 days prior to randomization.
* Major surgery (eg, nephrectomy, GI surgery, removal or biopsy of brain metastasis) within 4 weeks prior to randomization. Minor surgeries within 10 days prior to randomization. Subjects must have complete wound healing from major or minor surgery before randomization.
* Any other active malignancy at time of randomization or diagnosis of another malignancy within 3 years prior to randomization that requires active treatment, 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.
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:

Patients must have histologically confirmed alveolar soft part sarcoma. Pathology should be confirmed at the Laboratory of Pathology, National Institutes of Health.

Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal to 20 millimeters with conventional techniques or as greater than or equal to 10 millimeters with spiral computed tomography (CT) scan.

Patients must have metastatic alveolar soft part sarcoma that is not curable by surgery. Patients who have surgically resectable tumors with metastasis will be considered on a case by- case basis.

Any prior therapy must have been completed greater than or equal to 4 weeks prior to enrollment on protocol and the participant must have recovered to eligibility levels from prior toxicity. Patients should be at least 6 weeks out from nitrosoureas and mitomycin C. Prior radiation should have been completed greater than or equal to 4 weeks prior to study enrollment and all associated toxicities resolved to eligibility levels. Patients must be greater than or equal to 2 weeks since any investigational agent administered as part of a Phase 0 study (also referred to as an early Phase I study or pre-Phase I study where a sub-therapeutic dose of drug is administered) at the principal investigator's (PI's) discretion, and should haverecovered to eligibility levels from any toxicities.

Any degree of prior treatment is allowed, including other anti-angiogenic treatments (e.g., vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors or bevacizumab). Patients with no prior therapy are eligible, provided they have metastatic disease that is not curable by surgery.

Body surface area (BSA) greater than or equal to 1.04 square meter.

Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 for adults, Karnofsky performance status greater than or equal to 50% for pediatric patients greater than 10 years of age, and Lansky performance status greater than or equal to 50 for pediatric patients less than or equal to 10 years of age.

Life expectancy of greater than 8 weeks.

Patients must have normal organ and marrow function as defined below:

* absolute neutrophil count greater than or equal to 1,500/microliter
* platelets greater than or equal to 100,000/microliter
* total bilirubin less than 1.5 times institutional upper limit of normal
* Aspartate aminotransferase (AST)(Serum glutamic Oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (SGPT)) less than or equal to 2.5 times institutional upper limit of normal
* creatinine within normal limits based on age as follows:

Age (Years) Maximum Serum Creatinine (milligrams per deciliter)

less than or equal to 5 0.8

5 less than age less than or equal to 10 1.0

10 less than age less than or equal to 15 1.2

greater than 15 1.5

OR

creatinine clearance greater than or equal to 60 milliliter/min for adults or greater than or equal to 60 milliliter/min/1.73m\^2 for children with creatinine levels above institutional upper limit of normal.

Corrected QT interval (QTc) must be less than 500 msec.

Pediatric patients: Normal left ventricular function with ejection fraction greater than 55% or shortening fraction greater than or equal to 27%.

At present, the potential of Cediranib (AZD2171) for clinically significant drug interactions involving the cytochrome P450 (CYP) isozymes is unknown. However, studies of the agent in rats indicated possible suppression of cytochrome P450, family 1, subfamily A (CYP1A) that may be of biological significance. Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity of pharmacokinetics (PK) of AZD2171 will be determined following review of their case by the Principal Investigator. Efforts should be made to switch patients with brain metastases who are taking enzyme-inducing anticonvulsant agents to other medications one week prior to starting therapy.

AZD2171 has been shown to terminate fetal development in the rat, as expected for a process dependent on vascular endothelial growth factor (VEGF) signaling. For this reason, women of child-bearing potential must have a negative pregnancy test prior to study entry. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

Ability to understand and the willingness to sign a written informed consent document.

Patients should not be receiving any other investigational agents.

Prior therapy with anti-angiogenic agents is permitted.

EXCLUSION CRITERIA:

Patients with clinically significant illnesses which would compromise participation in the study, including, but not limited to: active or uncontrolled infection, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements.

Patients may not be receiving any medication that may markedly affect renal function (e.g., vancomycin, amphotericin, ibuprofen, pentamidine).

Patients who are unable to swallow tablets.

Mean QTc greater than 500 msec (with Bazett's correction) in screening electrocardiogram or history of familial long Q wave, T wave (QT) syndrome.

Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart.

Pregnant women are excluded from this study because AZD2171 is a VEGF inhibitor with known abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD2171, breastfeeding should be discontinued if the mother is treated with AZD2171.

Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions with AZD2171.

Adult patients with hypertension not controlled by medical therapy (hypertension defined as systolic blood pressure greater than 150 millimeters of mercury or diastolic pressure greater than 90 millimeters of mercury despite optimal medical management). Pediatric patients must have blood pressure (BP) within normal limits (WNL) for age. NOTE: blood pressure within the upper limit of normal is defined as: blood pressure less than or equal to the 95th percentile for age, height, and gender, and measured, and not be receiving medication for treatment of hypertension.
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: B