Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase 2 Trial of Pazopanib Versus Temsirolimus in Poor-Risk Clear-Cell Renal Cell Carcinoma
Brief Summary: The goal of this clinical research study is to compare pazopanib to temsirolimus in the treatment of advanced clear-cell renal cell carcinoma. The safety of each drug will also be studied.

Pazopanib is designed to block the growth of blood vessels that supply nutrients needed for tumor growth. This may prevent or slow the growth of cancer cells.

Temsirolimus is designed to block the growth of cancer cells, which may cause cancer cells to die.

This is an investigational study. Pazopanib and temsirolimus are both FDA approved and commercially available for the treatment of kidney cancer. It is investigational to compare the 2 drugs.

Up to 90 patients will be enrolled in this study. All will be enrolled at MD Anderson.


Options:
A: Inclusion Criteria:

1. Pathologic confirmation of metastatic or locally advanced RCC with a major clear cell component.
2. Measurable disease by RECIST criteria.
3. Age \>/= 18 years
4. ECOG performance status 0-2 or Karnofsky Performance Status \>/= 60%
5. Meets criteria for poor-risk defined as 3 or more of the following: ECOG performance status 2, anemia (hemoglobin lower than reference range), elevated serum LDH \> 1.5x upper limit of normal (ULN), hypercalcemia (corrected serum calcium level \> upper limit of normal), time from initial RCC diagnosis to registration on this trial \< 1 year, and \> 1 metastatic organ sites.
6. Adequate organ and marrow function within 14 days of registration as defined below: a) Absolute neutrophil count \>/=1,500/µL b) Platelets \>/=100,000/µL c) Hgb \>/= 9.0 g/dL (transfusion allowed) d) Renal: serum creatinine \</= 1.5 x ULN or calculated CrCl \>/= 40 cc/min and random urine protein:creatinine ratio (UPC) \< 1 or 24-hr urine protein \< 1g e) Liver: total bilirubin \</= 1.5 mg/dl; AST (SGOT) and ALT (SGPT) \</= 2.5 x ULN for subjects without evidence of liver metastases, \</= 5 x ULN for subjects with documented liver metastases f) INR \</= 1.2 x ULN; PTT \</= 1.5 x ULN. Therapeutic anticoagulation with warfarin is allowed if target INR \</= 3 on a stable dose of warfarin or on a stable dose of LMW heparin for \> 2 weeks (14 days) at time of randomization.
7. Female patients of childbearing potential (not postmenopausal for at least 12 months and not surgically sterile) must have a negative serum or urine pregnancy test within 14 days of study registration. Pregnancy test must be repeated if performed \> 14 days before starting study drug.

Exclusion Criteria:

1. Prior malignancy, except for non-melanoma skin cancer, in situ carcinoma of any site, or other cancers for which the patient has been adequately treated and disease free for 2 years
2. Prior targeted therapy (anti-VEGF agents or mTOR inhibitors) including adjuvant therapy, and prior chemotherapy for mRCC. However, prior immunotherapy (cytokines or vaccines) is allowed.
3. Any experimental drug while on this study; however, concomitant bone targeted therapy (bisphosphonates or the anti-RANK ligand denosumab) is allowed.
4. Uncontrolled brain metastases and infections. Patients with brain metastases treated with Gamma Knife (GK) or whole brain radiation within 24 hours of registration.
5. History of stroke within 6 months of registration
6. Clinically significant cardiovascular disease, defined as myocardial infarction (or unstable angina) within 6 months of registration, New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac dysrhythmia refractory to medical management. However, treated and controlled or stable/not clinically significant cardiovascular disease is allowed per evaluation by cardiologist.
7. Uncontrolled hypertension (home blood pressure readings are permitted) or prior history of hypertensive crisis or hypertensive encephalopathy; however, treatment of hypertension with medications is permitted.
8. History of uncontrolled hemoptysis (\>/= 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1
9. Significant vascular disease including aortic aneurysm, aortic dissection.
10. Symptomatic peripheral vascular disease
11. Pregnancy
12. HIV-positive patients receiving combination anti-retroviral therapy
13. Coagulopathy or bleeding diathesis
14. Concomitant treatment with rifampin, St. John's wort, or the cytochrome p450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or Phenobarbital)
15. Major surgery within 28 days prior to registration
16. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device within 7 days prior to starting drug
17. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study registration
18. Serious non-healing wound
19. Baseline QTcB \>/= 470 msec.
B: Inclusion Criteria:

* Histologically confirmed renal cell carcinoma of clear cell histology with metastases
* Evidence of measurable disease by radiographic technique
* Eastern Cooperative Oncology Group \[ECOG\] performance status of 0 or 1

Exclusion Criteria:

* Prior systemic (including adjuvant or neoadjuvant) therapy of any kind for RCC
* History of or known brain metastases
* Serious acute or chronic illness or recent history of significant cardiac abnormality
C: Inclusion Criteria:

* Written informed consent
* Diagnosis of renal cell carcinoma with clear-cell component histology.
* Received no prior systemic therapy (interleukin-2, interferon-alpha, chemotherapy, bevacizumab, mTOR inhibitor, sunitinib, sorafenib or other VEGF TKI) for advanced or metastatic RCC
* Locally advanced or metastatic renal cell carcinoma
* Measurable disease by CT or MRI
* Karnofsky performance scale status of \>=70
* Age \>=18 years
* A female is eligible to enter and participate in this study if she is of: non-childbearing or agrees to use adequate contraception.
* Adequate organ system function
* Total serum calcium concentration \<12.0mg/dL
* Left ventricular ejection fraction \>= lower limit of institutional normal.

Exclusion Criteria:

* Pregnant or lactating female (unless agrees to refrain from nursing throughout the treatment period and for 14 days following the last dose of study)
* History of another malignancy (unless have been disease-free for 3 years)
* History or clinical evidence of central nervous system (CNS) metastases (unless have previously-treated CNS metastases and meet all 3 of the following criteria are: are asymptomatic, have had no evidence of active CNS metastases for \>=6 months prior to enrolment, and have no requirement for steroids or enzyme-inducing anticonvulsants)
* 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, known intraluminal metastatic lesion/s with suspected bleeding, 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.
* Presence of uncontrolled infection.
* Prolongation of corrected QT interval (QTc) \> 480 milliseconds
* History of any one or more of the following cardiovascular conditions within the past 12 months: 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 pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months (unless had recent DVT and have been treated with therapeutic anti-coagulating agents for at least 6 weeks)
* Poorly controlled hypertension (defined as systolic blood pressure of \>=150mmHg or diastolic blood pressure of \>=90mmHg). Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry
* Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer.
* Evidence of active bleeding or bleeding susceptibility
* Spitting/coughing up blood within 6 weeks of first dose of study drug
* Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels
* 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.
* Use any prohibited medications within 14 days of the first dose of study medication.
* Use of an investigational agent, including an investigational anti-cancer agent, within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study drug.
* Prior use of an investigational or licensed drug that targets VEGF or VEGF receptors (eg. bevacizumab, sunitinib, sorafenib, etc), or are mTOR inhibitors (eg. temsirolimus, everolimus, etc).
* Is now undergoing and/or has undergone in the 14 days immediately prior to first dose of study drug, any cancer therapy (surgery, tumor embolization, chemotherapy, radiation therapy, immunotherapy, biological therapy, or hormonal therapy)
* Any ongoing toxicity from prior anti-cancer therapy that is \>Grade 1 and/or that is progressing in severity.
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or sunitinib.
D: Inclusion Criteria:

* Patients must provide written informed consent prior to performance of any study-specific procedures or assessments and must be willing to comply with treatment and follow up. Procedures conducted as part of the patient's routine clinical management (e.g. blood count, imaging study) and obtained prior to signing of informed consent may be utilised for screening or baseline purposes provided these procedures are conducted as specified in the protocol.
* Received no prior systemic therapy (including interleukin-2, interferon-alpha, chemotherapy, bevacizumab, mTOR inhibitor, sunitinib, sorafenib or other VEGF TKI) for advanced or metastatic RCC. Patients who received adjuvant treatment with a cancer vaccine are eligible.
* Locally advanced (defined as disease not amenable to curative surgery or radiation therapy) or metastatic renal cell carcinoma of any histology (equivalent to Stage IV RCC according to AJCC staging). Patients with non-measurable disease are allowed if metastatic disease can be confirmed.
* ECOG PS of 0 or 1
* Age \>= 18 years
* A female is eligible to enter and participate in this study if she is of:

Non-childbearing potential (i.e. physiologically incapable of becoming pregnant) Childbearing potential, including any female who has had a negative serum pregnancy test within two weeks prior to the first dose of study treatment, preferably as close to the first dose as possible and agrees to use adequate contraception.

* Adequate organ system functions
* Total serum calcium concentration \<12.0mg/dL
* Left ventricular ejection fraction (LVEF) \>=lower limit of institutional normal (LLN) as assessed by echocardiography (ECHO) or multigated acquisition (MUGA) scan. The same modality used at baseline must be applied for subsequent evaluations.
* Patient is able to swallow and retain oral tablets

Exclusion Criteria:

* Poor MSKCC risk group
* History of another malignancy. Note: Patients who have had another malignancy and have been disease-free for 3 years or patients with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible.
* History or clinical evidence of central nervous system (CNS) metastases.

Note: Patients who have previously-treated CNS metastases (surgery +/- radiotherapy, radiosurgery, or gamma knife) and meet all 3 of the following criteria are eligible:

* Are asymptomatic,
* Have had no evidence of active CNS metastases for \>=6 months prior to enrolment ,
* Have no requirement for steroids or enzyme-inducing anticonvulsants (EIAC).
* Any clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding or affect absorption of investigational product 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.
* Presence of uncontrolled infection.
* Corrected QT interval (QTc) \>480 msecs using Bazett's formula
* History of one or more of the following cardiovascular conditions within the past 6 months:
* Cardiac angioplasty or stenting
* Myocardial infarction
* Unstable angina
* Coronary artery bypass graft surgery
* Symptomatic peripheral vascular disease
* Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)
* Poorly controlled hypertension (defined as systolic blood pressure (SBP) of \> 150mmHg or diastolic blood pressure (DBP) of \> 90mmHg) at baseline.

Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Blood pressure must be re-assessed on two occasions that are separated by a minimum of 1 hour within a visit. The mean SBP/DBP values from each blood pressure assessment must be \<=150/90mmHg in order for a patient to be eligible for the study.

- History of cerebrovascular accident (CVA) including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

Note: Patients with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.

* Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major).
* Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
* Evidence of active bleeding or bleeding diathesis.
* Significant haemoptysis within 6 weeks prior to first dose of study drug.
* 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.
* Use any prohibited medications within 14 days of the first dose of study medication.
* Use of an investigational agent, including an investigational anti-cancer agent, within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study drug.
* Radiation therapy, surgery or tumour embolisation within 14 days prior to the first dose of study treatment.
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or sunitinib.
* Pregnant or lactating female Female patients who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.

Answer: A