Conditions: Kidney Cancer
Keywords: Kidney cancer Renal Cell Carcinoma Poor-Risk Clear-Cell Renal Cell Carcinoma RCC Metastatic Locally advanced Complete response CR Partial Response PR Overall survival OS Time to progression TTP Pazopanib GW786034 Temsirolimus CCI-779 Torisel Benadryl Diphenhydramine TemPa
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 69
Healthy volunteers: no

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.

Detailed description:
Study Groups and Study Drug Administration:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups. You will have an equal chance of being assigned to either group.

* If you are assigned to Group 1, you will take pazopanib by mouth 1 time every day at about the same time each day on an empty stomach (at least 1 hour before or 2 hours after a meal).
* If you are assigned to Group 2, you will receive temsirolimus by vein 1 time every week over 30-60 minutes. About 30 minutes before you receive each dose of temsirolimus, you will receive Benadryl (diphenhydramine) by vein over 1-2 minutes to help lower the risk of side effects.

If you are assigned to Group 1, do not crush tablets and do not repeat missed doses if it is less than 12 hours until your next scheduled dose. You will be given a pill diary to record when you take each dose. You will return the diary to the study doctor at each study visit.

If you have any side effects, you should tell the study doctor right away. If the study doctor thinks it is in your best interest, your dose may be lowered.

If the disease gets worse while you are on study, you will have the option to change to the study group you were not originally assigned to and take the other study drug. The study drug dosing and study visit schedule will be the same, and the study doctor will discuss any important details with you at the time you change study groups.

Study Visits:

Every 4 weeks on this study is called a study cycle.

Every week during Cycle 1 (Group 1 only), your blood pressure will be checked (either at home, at the clinic, or by your local doctor). If you are checking your own blood pressure at home, you will need to write down your blood pressure in a blood pressure diary each time you check it and bring the diary with you to each clinic visit.

Every 2 weeks for the first 2 cycles (Group 1 only) , blood (about 3 tablespoons) will be drawn for routine tests.

Every week (Group 2 only), blood (about 1 tablespoon) will be drawn for routine tests.

Every cycle (Group 2 only) OR Every other cycle (Group 1 only):

* You will have a physical exam, including measurement of your weight and vital signs.
* You will be asked about any drugs or treatments you may be receiving.
* You will be asked about any side effects you may have had.
* Blood (about 3 tablespoons) will be collected for routine tests.

On Day 1 of Cycle 2, Day 1 of Cycle 4, and every 4 cycles after that (Group 1 only), you will have an ECG to check your heart function.

If you are in Group 2 only, on Day 1 of Cycles 2, 3, and every other cycle after that (Cycles 5, 7, 9, and so on), blood (about 3 tablespoons) will be drawn for routine tests. You will be asked to fast (eat nothing and drink only water) for at least 8 hours before those blood draws.

Every 2 cycles:

* You will have the same imaging scans that you had at screening. After 1 year on treatment, these imaging scans may only be done every 3 cycles (Cycles 5, 8, 11, and so on).
* You will fill out the quality-of-life questionnaires.
* Blood (about 2 teaspoons) will be drawn for tests to check your thyroid function (Group 1 only).
* Urine will be collected for routine tests.

Every 4 cycles, you will have an ECG (Group 2 only).

Every 6 cycles, you will have an ECHO or MUGA scan to check your heart function.

Length of Study:

You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take a study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

End-of-Treatment Follow- up:

About 30 days after you stop treatment, during a clinic visit or by phone, you will be asked about any drugs or treatments you may be receiving and any side effects you may have had.

Long-Term Follow-up:

After you stop taking the study drug, the study staff will check up on you to ask how you are doing about every 3 months from then on. The study staff will collect the information they need either from your medical records or by calling you. If you are contacted by phone, the call should only last about 5 minutes.

Arms:
arm 1: Pazopanib 800 mg by mouth daily. Quality of Life Assessment - Completion of full assessment battery at baseline, prior to treatment then every 8 weeks at clinical evaluation. arm 2: Temsirolimus 25 mg by vein infused over 30-60 minutes weekly. Benadryl 25 to 50 mg by vein approximately 30 minutes before the start of each dose of temsirolimus. Quality of Life Assessment - Completion of full assessment battery at baseline, prior to treatment then every 8 weeks at clinical evaluation.

Interventions: intervention 1: Pazopanib intervention 2: Temsirolimus intervention 3: Quality of Life Assessment intervention 4: Benadryl
Intervention descriptions: intervention 1: 800 mg by mouth daily in 4 week study cycle. intervention 2: 25 mg by vein infused over 30-60 minutes every week in 4 week study cycle. intervention 3: Completion of full assessment battery at baseline, prior to treatment then every 8 weeks at clinical evaluation. intervention 4: 25 to 50 mg by vein approximately 30 minutes before the start of each dose of temsirolimus.

Protocol document:
Prot_SAP_000.pdf: 
Protocol 2011-0358 
October 23, 2017 
A Randomized Phase 2 Trial of Pazopanib versus Temsirolimus in Poor-
Risk Clear-cell Renal Cell Carcinoma 
 
  
1.0 OBJECTIVES  
2.0 BACKGROUND AND RATIONALE  
3.0 BACKGROUND DRUG INFORMATION  
4.0 ELIGIBILITY CRITERIA  
5.0 TREATMENT PLAN  
6.0 DOSING DELAYS/DOSE MODIFICATIONS  
7.0 QUALITY OF LIFE ASSESSMENT  
8.0 CORRELATIVE STUDIES  
9.0 STUDY CALENDAR  
10.0 CRITERIA FOR RESPONSE AND PROGRESSION  
11.0 ADVERSE EVENTS: LISTING AND REPORTING REQUIREMENTS  
12.0 CRITERIA FOR REMOVAL FROM PROTOCOL TREATMENT  
13.0 STATISTICAL CONSIDERATIONS  
14.0 REPORTING AND EXCLUSIONS  
15.0 DATA AND PROTOCOL MANAGEMENT  
16.0 INVESTIGATOR OBLIGATIONS  
17.0 REFERENCES  
 
Protocol Version Tracking 
V00 for CRC submission 
04/26/2011 
V01 for resubmission 
05/12/2011 
V02 for resubmission 
06/27/2011 
V03 for resubmission 
01/26/2012 
V04 for resubmission 
06/27/2012 
V05 for resubmission 
09/07/2012 
V06 for resubmission 
02/13/2013 
V07 for resubmission 
04/24/2013 
V08 for resubmission 
07/26/2013 
V09 for resubmission 
10/28/2013 
V10 for resubmission 
03/28/2014 
V11 for resubmission 
12/16/2014 
V12 for resubmission 
06/12/2015 
V13 for resubmission 
12/03/2015 
V14 for resubmission 
03/07/2016 
V15 for resubmission 
04/19/2016 
V16 for resubmission 
08/10/2016 
V17 for resubmission 
11/09/2016 
V18 for resubmission 
10/23/2017 
 
 
 


 
 
 
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1.0 OBJECTIVES  
 
Primary:  
• 
To determine the progression-free survival (PFS) with pazopanib and temsirolimus in patients 
with advanced poor-risk clear-cell renal cell carcinoma (RCC).  
Secondary:  
• 
To determine the objective response rate (CR+PR) in patients with advanced poor-risk clear-cell 
RCC treated with pazopanib and temsirolimus.  
• 
To determine the overall survival (OS) in patients with advanced poor-risk clear-cell RCC treated 
with pazopanib and temsirolimus.  
• 
To determine the time to progression (TTP) in patients with advanced poor-risk clear-cell RCC 
treated with pazopanib and temsirolimus.  
• 
To determine the duration of response in patients with advanced poor-risk clear-cell RCC 
treated with pazopanib and temsirolimus.  
• 
To determine the safety associated with pazopanib and temsirolimus in patients with advanced 
poor-risk clear cell RCC.   
Tertiary:  
 
• 
To perform informative correlative studies in this disease state. 
• 
To determine the safety and patient reported outcomes.  
 
2.0 BACKGROUND AND RATIONALE 
2.1 Renal Cell Carcinoma (RCC) 
Renal cell carcinoma comprises more than 90% of kidney cancer cases and accounts for 
approximately 2-4 % of all adult malignancies. In 2008, approximately 54,000 people in the 
United States were diagnosed with kidney cancer (renal cell cancer and transitional cell 
carcinoma of the renal pelvis) and approximately 13,000 died secondary to metastatic disease. 
Approximately 25 % of patients with RCC present with metastasis at the time of initial diagnosis 
and up to 20-30 % of patients develop recurrent disease after nephrectomy. Surgical removal of 
the primary tumor is the only effective therapy in the non-metastatic setting. No adjuvant 
therapy has been shown yet to alter the clinical course even in patients at high-risk for 
developing metastatic disease. 
Metastatic RCC (mRCC) is a heterogeneous disease with variable clinical outcome. Two 
randomized phase III trials have provided support for performing cytoreductive nephrectomy in 
mRCC, although the most optimal timing of this procedure has not been determined. Some 
patients with solitary metastasis, who are candidates for complete metastasectomies, can 


 
 
 
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achieve a long-term survival; however, once metastases develop in multiple organs, systemic 
therapies, until recently, have had little effect on the clinical course for the majority of patients. 
Immunotherapy with interleukin-2, interferon-alfa, or a combination of these two cytokines, has 
been the main therapy in mRCC for two decades, but benefits only a small percentage of 
patients. In an effort to objectively compare different therapies in the same trial and similar 
therapies across trials, prognostic models have been developed to assign patients to different 
risk categories based on pretreatment clinical features. Cytokines (interleukin-2, interferon alfa) 
have recently been replaced by agents targeting the VEGF or the m-TOR pathways. 
2.2 Targeted Therapies in MRCC 
Advances in the understanding of the genetic mutation or silencing of the tumor suppressor 
gene, known as the von Hippel-Lindau (VHL) gene, have shown that this abnormal gene 
produces a deviant protein which causes the accumulation of hypoxia inducible factors (HIF), 
which in turn induce the production of products which are critical to the proliferation of clear-
cell RCC. Three of these products are vascular endothelial growth factor (VEGF), platelet derived 
growth factor (PDGF), and transforming growth factor-alpha (TGF-α). All four of these cellular 
products, i.e., HIF, VEGF, PDGF and TGF-α, have constituted rational targets of novel therapies. 
Pazopanib is a multi-tyrosine kinase inhibitor that selectively inhibits protein tyrosine kinase 
receptors including VEGFR1-3, PDGFRα/β, c-Kit, and Flt-3. Pazopanib demonstrated substantial 
anti-tumor activity in a phase II trial in mRCC with randomized discontinuation design (Hutson et 
al, 2009 ). A randomized phase III trial comparing pazopanib to placebo, either as first-line 
therapy in treatment-naïve patients, or after failure of one cytokine in 435 patients with 
advanced clear-cell RCC showed significant prolongation of median PFS in favor of pazopanib 
(9.2 months vs. 4.2 months for all patients, p<0.0000001;11.1 months vs.2.8 months for 
treatment-naïve patients, p<0.0000001;7.4 months vs. 4.2 months for cytokine-pretreated 
patients). 
Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds 
to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of 
mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in 
treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 
ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was 
blocked. In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the 
activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and 
HIF-2 alpha, and the vascular endothelial growth factor. The clinical benefit of temsirolimus for 
poor-risk, advanced RCC patients was demonstrated in a Phase III study comparing 
temsirolimus, with interferon alpha (IFN-alpha), or combined temsirolimus plus IFN-alpha as 
first-line treatment of advanced RCC.  It showed that treatment with temsirolimus alone 
significantly increased median overall survival in poor-risk, advanced RCC patients (10.9 vs 7.3 vs 


 
 
 
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8.4 months). This was the first Phase III trial to demonstrate an overall improvement in survival 
using an agent as "targeted therapy" for patients with advanced RCC. 
 
The targeted agents discussed above, although not curative, represent a significant progress in 
the management of mRCC. 
 
2.3 Rationale  
In the past few years, considerable progress has been made in the management of patients with 
metastatic renal cell carcinoma (RCC). There are now six (five in the first-line setting) FDA-
approved treatments for metastatic RCC, however most patients experience disease progression 
within a year or less. The vast majority of metastatic RCC patients who were enrolled on phase 3 
trials with anti-VEGF therapies, sorafenib, sunitinib, pazopanib and bevacizumab plus interferon 
alfa had good- or intermediate-risk disease. Temsirolimus is the standard of care for the 
treatment of patients with advanced poor-risk RCC, based on results from a phase 3 trial 
comparing single-agent temsirolimus versus single-agent interferon alfa versus the combination 
of temsirolimus and interferon alfa. The response rate of temsirolimus in this study was 8.4 %, 
and the median PFS and median OS were 3.8 months and 10.9 months, respectively. There is no 
data on the efficacy of multityrosine kinase inhibitors (TKI) in this disease state. Therefore, it is 
important to investigate agents with the oral convenience and tolerability of TKIs, such as 
pazopanib, in advanced poor-risk RCC.    
3.0 BACKGROUND DRUG INFORMATION 
3.1 Pazopanib 
3.1.1 Description 
Pazopanib is a tyrosine kinase inhibitor (TKI). Pazopanib is presented as the 
hydrochloride salt, with the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6-
yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide 
monohydrochloride. It has the molecular formula C21H23N7O2S•HCl and a molecular 
weight of 473.99. 
Pazopanib hydrochloride is a white to slightly yellow solid. It is very slightly soluble at pH 
1 and practically insoluble above pH 4 in aqueous media.  
Tablets of pazopanib are for oral administration and is supplied in a 200 mg film-coated 
tablet. Each film-coated tablet contains pazopanib hydrochloride equivalent to 200 mg 
of pazopanib free base.  The inactive ingredients of pazopanib are: Tablet Core: 
Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. 
Coating: Hypromellose, macrogol/polyethylene glycol 400 (PEG 400), polysorbate 80, 
titanium dioxide and may contain iron oxide black , yellow, or red depending on tablet 


 
 
 
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color. The 200 mg tablets of pazopanib are modified capsule-shaped, gray, film-coated 
with GS JT debossed on one side.  Pazopanib should be stored at 25°C (77°F); excursions 
permitted to 15° to 30°C (59° to 86°F).  Pazopanib is being provided by the study 
supporter, Novartis. 
3.1.2 Preclinical Studies 
Pazopanib is a potent, multi-targeted tyrosine kinase inhibitor (TKI) of VEGFR-1, -2, -3, 
PDGFR-α and -β and c-kit, with half-maximal inhibition (IC50) values of 10, 30, 47, 71, 84 
and 74nM, respectively. It inhibits VEGF-induced VEGFR-2 phosphorylation in human 
umbilical vein endothelial cells (HUVEC) as well as in mouse lungs in a dose-dependent 
manner. Data from preclinical studies show pazopanib has significant growth inhibition 
of a variety of human tumor xenografts in mice, and also inhibits basic fibroblast growth 
factor- (bFGF-) and VEGF-induced angiogenesis in two mouse models of angiogenesis, 
viz., the Matrigel plug assay and the cornea micropocket model. 
3.1.3 Clinical Studies 
Glaxo SmithKline (GSK) initiated the clinical development of pazopanib in December 
2002. As of September 2008, a total of 38 clinical studies (including some initiated by 
the United States National Cancer Institute) have been conducted or are in progress in 
adult subjects with cancer, including renal cell carcinoma, ovarian cancer, breast cancer, 
soft tissue sarcoma, cervical cancer, non-small cell lung cancer, multiple myeloma, 
glioma, colorectal cancer, and hepatocellular cancer. 
As of September 2008, approximately 1600 cancer subjects have received pazopanib in 
clinical studies. The most common adverse events (AEs) reported to date include 
diarrhea, fatigue, nausea, hypertension, hair color changes (hair depigmentation), 
anorexia, vomiting, dysgeusia, headache, abdominal pain, rash, aspartate 
aminontransferase (AST) and alanine aminontransferase (ALT) increases, constipation, 
cough, and arthralgia. Most of these events were Grade 1 or 2 using the NCI Common 
Terminology Criteria for Adverse Events Version 3.0 (NCI-CTCAE). The most frequent 
Grade 3 or 4 events were hypertension, fatigue, diarrhea, and AST and ALT increases. 
Less common AEs of note include hand-foot syndrome, mucositis/stomatitis, 
proteinuria, venous thrombotic events, and bleeding. Intestinal perforations and arterial 
thromboses were uncommon. The most common serious adverse events (SAEs) 
occurring in subjects enrolled in pazopanib studies as of September 2008, regardless of 
treatment assignment include diarrhea, abdominal pain, vomiting, dyspnea, 
hypertension (including one SAE of hypertensive crisis), pyrexia, anemia, dehydration, 
fatigue, pneumonia, pleural effusion, neutropenia, pulmonary embolism, ALT increased, 
and nausea. 


 
 
 
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3.1.4 Pharmacokinetics 
Absorption: Pazopanib is absorbed orally with median time to achieve peak 
concentrations of 2 to 4 hours after the dose. Daily dosing at 800 mg results in 
geometric mean AUC and Cmax of 1,037 hr microg/mL and 58.1 microg/mL (equivalent 
to 132 microM), respectively. There was no consistent increase in AUC or Cmax at 
pazopanib doses above 800 mg. 
Administration of a single pazopanib 400 mg crushed tablet increased AUC(0-72) by 46% 
and Cmax by approximately 2 fold and decreased tmax by approximately 2 hours 
compared to administration of the whole tablet. These results indicate that the 
bioavailability and the rate of pazopanib oral absorption are increased after 
administration of the crushed tablet relative to administration of the whole tablet. 
Therefore, due to this potential for increased exposure, tablets of pazopanib should not 
be crushed. 
Systemic exposure to pazopanib is increased when administered with food. 
Administration of pazopanib with a high-fat or low-fat meal results in an approximately 
2-fold increase in AUC and Cmax. Therefore, pazopanib should be administered at least 
1 hour before or 2 hours after a meal. 
Distribution: Binding of pazopanib to human plasma protein in vivo was greater than 
99% with no concentration dependence over the range of 10 to 100 mg/mL. In vitro 
studies suggest that pazopanib is a substrate for P-glycoprotein (Pgp) and breast cancer 
resistant protein (BCRP). 
Metabolism: In vitro studies demonstrated that pazopanib is metabolized by CYP3A4 
with a minor contribution from CYP1A2 and CYP2C8. 
Elimination: Pazopanib has a mean half-life of 30.9 hours after administration of the 
recommended dose of 800 mg. Elimination is primarily via feces with renal elimination 
accounting for <4% of the administered dose. 
Hepatic Impairment: Interim data from a dose escalation study assessed the influence of 
hepatic impairment on the safety and pharmacokinetics of pazopanib in cancer patients 
with normal hepatic function and in patients with mild, moderate, and severe hepatic 
impairment. The starting doses were 800, 400, 200, and 100 mg once daily for patients 
with normal hepatic function and patients with mild, moderate, and severe hepatic 
impairment, respectively. 
Pharmacokinetic data from patients with normal hepatic function (n = 12) and moderate 
(n = 7) hepatic impairment indicate that pazopanib clearance was decreased by 50% in 
those with moderate hepatic impairment. The maximum tolerated pazopanib dose in 


 
 
 
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patients with moderate hepatic impairment is 200 mg once daily. There are no data on 
patients with mild or severe hepatic impairment. 
Drug Interactions: Coadministration of oral pazopanib with CYP3A4 inhibitors has 
resulted in increased plasma pazopanib concentrations. Concurrent administration of a 
single dose of pazopanib eye drops with the strong CYP3A4 inhibitor and Pgp inhibitor, 
ketoconazole, in healthy volunteers resulted in 220% and 150% increase in mean AUC(0-
t) and Cmax values, respectively. 
Administration of 1,500 mg lapatinib, a substrate and weak inhibitor of CYP3A4, Pgp, 
and BCRP, with 800 mg pazopanib resulted in an approximately 50% to 60% increase in 
mean pazopanib AUC(0-24) and Cmax compared to administration of 800 mg pazopanib 
alone. 
In vitro studies with human liver microsomes showed that pazopanib inhibited the 
activities of CYP enzymes 1A2, 3A4, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1. Potential 
induction of human CYP3A4 was demonstrated in an in vitro human PXR assay. Clinical 
pharmacology studies, using pazopanib 800 mg once daily, have demonstrated that 
pazopanib does not have a clinically relevant effect on the pharmacokinetics of caffeine 
(CYP1A2 probe substrate), warfarin (CYP2C9 probe substrate), or omeprazole (CYP2C19 
probe substrate) in cancer patients. Pazopanib resulted in an increase of approximately 
30% in the mean AUC and Cmax of midazolam (CYP3A4 probe substrate) and increases 
of 33% to 64% in the ratio of dextromethorphan to dextrorphan concentrations in the 
urine after oral administration of dextromethorphan (CYP2D6 probe substrate). 
Coadministration of pazopanib 800 mg once daily and paclitaxel 80 mg/m2 (CYP3A4 and 
CYP2C8 substrate) once weekly resulted in a mean increase of 26% and 31% in paclitaxel 
AUC and Cmax, respectively. 
In vitro studies also showed that pazopanib inhibits UGT1A1 and OATP1B1 with IC50s of 
1.2 and 0.79 microM, respectively. Pazopanib may increase concentrations of drugs 
eliminated by UGT1A1 and OATP1B1. 
CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., 
ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations. A dose 
reduction for pazopanib should be considered when it must be coadministered with 
strong CYP3A4 inhibitors [see Section 6.1.1.3]. Grapefruit juice should be avoided as it 
inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. 
CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib 
concentrations. Pazopanib should not be used if chronic use of strong CYP3A4 inducers 
cannot be avoided. 


 
 
 
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A comprehensive list of cytochrome p450 3A4 inducers and inhibitors may be found at: 
http://www.medicine.iupui.edu/clinpharm/ddis/table.asp 
3.1.5 Pazopanib Drug Interactions  
 
Clinically relevant drug interactions: substrates, inducers, and inhibitors of isoenzyme 
CYP3A 
 
SUBSTRATES  
Antibiotics:  
Clarithromycin, erythromycin, 
telithromycin  
Calcium channel blockers:  
Amlodipine, diltiazem, felodipine, lercanidipine, 
nifedipine, nisoldipine, nitrendipine, verapamil  
Anti-arrhythmics:  
Quinidine  
HMG CoA reductase inhibitors:  
Cerivastatin, lovastatin, simvastatin  
Benzodiazepines:  
Alprazolam, diazepam, midazolam, 
triazolam  
Steroid 6beta-OH:  
estradiol, hydrocortisone, progesterone, testosterone  
Immune modulators:  
Cyclosporine, tacrolimus (FK506)  
Miscellaneous:  
Alfentanil, aprepitant, aripirazole, buspirone, cafergot, 
caffeine, cilostazol, cocaine, codeine-N-demethylation, 
dapsone, dexamethasone, dextromethorphan, 
docetaxel domperidone, eplerenone, fentanyl, 
finasteride, Gleevec/imatinib, haloperidol, irinotecan, 
LAAM, lidocaine, methadone, nateglinide, ondansetron, 
pimozide, propranolol, quetiapine, quinine, risperidone, 
salmeterol, sildenafil, sirolimus, sorafenib, sunitinib, 
tamoxifen, taxol, terfenadine, temsirolimus, trazodone, 
vincristine, zaleplon, ziprasidone, zolpidem  
HIV Antivirals:  
Indinavir, nelfinavir, ritonavir, 
saquinavir  
Prokinetic:  
Cisapride  
Antihistamines:  
Astemizole, chlorpheniramine, 
terfenadine  
INDUCERS  
Barbiturates, carbamazepine, glucocorticoids, modafinil, oxcarbazepine, phenobarbital, 
phenytoin, pioglitazone, rifabutin, rifampin, St. John’s wort, troglitazone, efavirenz, nevirapine  
INHIBITORS  
Strong inhibitors:  
indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, 
saquinavir, telithromycin,  
Posaconazole (Krishna et al, 2009)  
Moderate inhibitors:  
aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil 
 
Weak inhibitors:  
Cimetidine,  
Seville orange (Malhotra et al, 2001)  


 
 
 
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Unclassified as per the Indiana University DDI listing:  
Ciprofloxacin, delaviridine, troleandamycin, mibefradil, amiodarone, chloramphenicol, 
diethyldithiocarbamate, fluvoxamine, starfruit, gestodene, imatinib, mifepristone, norfloxacin, 
norfluoxetine, voriconazole 
 
 
Based on http://medicine.iupui.edu/clinpharm/ddis/table.asp as of December 01, 2009 * 
Voriconazole (unclassified as per the Indiana University DDI table)  
Strong inhibitor according to the following reference: 
(http://www.nature.com/clpt/journal/v80/n5/pdf/clpt2006438a.pdf)  
 
Clinically relevant drug interactions mediated by PgP 
PgP Substrates  
PgP Inhibitors in vivo  
PgP Inducers  
digoxin, fexofenadine, 
indinavir, vincristine, 
colchicine, topotecan, 
paclitaxel  
amiodarone, azithromycin, captopril, 
carvedilol, clarithromycin, conivaptan, 
cyclosporine, diltiazem, elacridar, 
erythromycin, felodipine, (GF120918), 
itraconazole, ketocoanzole, lopinavir, 
(LY335979), mibefradil, nifedipine, 
nitrendipine, (PSC833), quinidine, ranolazine, 
ritonavir, talinolol, valspodar, verapamil  
rifampin, St 
John’s wort  
 
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Dec. 2, 
2009, which summarizes DDI data from three sources including the FDA’s “Guidance for Industry, 
Drug Interaction Studies, the University of Washington’s Drug Interaction Database, and Indiana 
University School of Medicine's Drug Interaction Table.”  
 
NOTES: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM072101.pdf 
3.1.6 Clinical Safety: 
a. Hepatic Toxicity: 
In a controlled clinical study with pazopanib for the treatment of RCC, ALT >3 X ULN 
was reported in 18% and 3% of the pazopanib and placebo groups, respectively. ALT 
>10 X ULN was reported in 4% of patients who received pazopanib and in <1% of 
patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin 
>2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 
5/290 (2%) of patients on pazopanib and 2/145 (1%) on placebo. [See Dosage and 
Administration (2.2) and Warnings and Precautions (5.1).] 
b. QT Interval Prolongation and Torsade de Pointes 


 
 
 
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Pazopanib should be used with caution in patients with a history of QT interval 
prolongation, patients who are taking antiarrhythmics, or patients with relevant 
pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using 
pazopanib, periodic monitoring with on-treatment electrocardiograms and 
electrolytes (magnesium, potassium) should be considered. Concomitant treatment 
with strong CYP3A4 inhibitors, which may increase pazopanib plasma 
concentrations, should be used with caution and dose reduction of pazopanib 
should be considered. 
c. Hypertension 
Patients should be monitored for hypertension and treated as needed with standard 
anti-hypertensive therapy. In cases of severe hypertension, temporary suspension 
of pazopanib is recommended until hypertension is controlled. 
d. Hemorrhagic events 
Tumor-related hemorrhage has been observed in patients treated with pazopanib. 
These events may occur suddenly, and in the case of pulmonary tumors may 
present as severe and life-threatening hemoptysis or pulmonary hemorrhage. 
Serious, sometimes fatal gastrointestinal complications including gastrointestinal 
perforation have occurred rarely in patients with intra-abdominal malignancies 
treated with pazopanib. 
e. Hypothyroidism 
Baseline laboratory measurement of thyroid function is recommended and patients 
with hypothyroidism should be treated as per standard medical practice prior to the 
start of pazopanib treatment. All patients should be observed closely for signs and 
symptoms of hypothyroidism on pazopanib treatment. Patients with signs or 
symptoms suggestive of hypothyroidism should have laboratory monitoring of 
thyroid function performed and be treated as per standard medical practice. 
f. QT Prolonging Medications 
Certain medications that are associated with a risk for QTc prolongation, although 
not prohibited, should be avoided or replaced with medications that do not carry 
these risks, if possible.  
 
QTc prolongation is a rare but serious adverse event associated with 
pazopanib.  Caution should be exercised when administering pazopanib to subjects 
with a history of QTc interval prolongation, in subjects taking anti-arrhythmics or 


 
 
 
Protocol 2011-0358 
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other medications that may prolong the QTc interval, and those with relevant pre-
existing cardiac disease (i.e. amiodarone, clarithromycin, disopyramide, haloperidol, 
methadone, procainamide; some SSRIs such as citalopram, fluoxetine, venlafexine; 
and fluoroquinolones such as ciprofloxacin, levofloxacin, and moxifloxacin). See 
Appendix F for a more comprehensive list of drugs that may prolong Qt interval. 
 
*Note these medication lists are not all inclusive and are as only a reference of 
potential drug-drug interactions. A useful website for a more inclusive list may be 
found at: http://www.azcert.org/index.cfm 
See PAZOPANIB package insert for additional drug information. 
 
3.2  Temsirolimus 
 
3.2.1 Description 
Temsirolimus is a white to off-white powder with a molecular formula of C56H87NO16 
and a molecular weight of 1030.30. It is non-hygroscopic. Temsirolimus is practically 
insoluble in water and soluble in alcohol. It has no ionizable functional groups, and its 
solubility is independent of pH. 
The chemical name of temsirolimus is 
(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14, 
21,22,23,24, 25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-
[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-
6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4] 
oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone 4′- [2,2-
bis(hydroxymethyl) propionate]; or Rapamycin, 42-[3-hydroxy-2-(hydroxymethyl)- 2-
methylpropanoate]. 
Temsirolimus injection, 25 mg/mL, is a clear, colorless to light yellow, nonaqueous, 
ethanolic, sterile solution. Temsirolimus injection requires two dilutions prior to 
intravenous infusion. Temsirolimus injection should be diluted only with the supplied 
diluent.   
Supplied diluent is a sterile, non-aqueous solution that is supplied with temsirolimus 
injection, as a kit.  Active ingredient: temsirolimus (25 mg/mL).  Inactive ingredients: 
dehydrated alcohol (39.5% w/v), dl-alpha-tocopherol (0.075% w/v), propylene glycol 
(50.3% w/v), and anhydrous citric acid (0.0025% w/v).  Diluent inactive ingredients: 
polysorbate 80 (40.0% w/v), polyethylene glycol 400 (42.8% w/v) and dehydrated 
alcohol (19.9% w/v).   


 
 
 
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After the temsirolimus injection vial has been diluted with supplied diluent, in 
accordance with the instructions below, the solution contains 35.2% alcohol. 
Temsirolimus injection and supplied diluent are filled in clear glass vials with butyl 
rubber stoppers.  Each kit is supplied in a single carton containing one single-use vial of 
25 mg/mL of temsirolimus and one diluent vial which includes a deliverable volume of 
1.8 mL, and must be stored at 2°-8°C (36° 46°F). Protect from light. 
3.2.1.1  Preparation and Administration 
Temsirolimus must be stored under refrigeration at 2°-8°C (36°-46°F) and 
protected from light. During handling and preparation of admixtures, 
temsirolimus should be protected from excessive room light and sunlight. 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. 
In order to minimize the patient exposure to the plasticizer DEHP (di-2-
ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the 
final temsirolimus dilution for infusion should be stored in bottles (glass, 
polypropylene) or plastic bags (polypropylene, polyolefin) and administered 
through polyethylene-lined administration sets. 
Dilution: In preparing the temsirolimus administration solution, follow this two-
step dilution process in an aseptic manner. 
Step 1: Inject 1.8 mL of supplied diluent into the vial of temsirolimus 
injection(25 mg/ml). The temsirolimus vial contains an overfill of 0.2 mL (30 
mg/1.2 mL). 
Due to the intentional overfill in the temsirolimus injection vial, the drug 
concentration of the resulting solution will be 10 mg/mL. A total volume of 3 mL 
will be obtained including the overfill. Mix well by inversion of the vial. Allow 
sufficient time for air bubbles to subside. This 10 mg/mL drug solution/diluent 
mixture must be further diluted as described in Step 2 below. 
The solution is clear to slightly turbid, colorless to yellow, and free from visual 
particulates. The 10 mg/mL drug solution/diluent mixture is stable for up to 24 
hours at controlled room temperature. 
Step 2: Withdraw the required amount of temsirolimus from the 10 mg/mL drug 
solution/diluents mixture prepared in Step 1. Inject rapidly into a 250 mL 
container (glass, polyolefin, or polyethylene) of 0.9% sodium chloride injection. 


 
 
 
Protocol 2011-0358 
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Mix the admixture by inversion of the bag or bottle. Avoid excessive shaking as 
this may cause foaming. 
Administration: The sodium chloride injection container should be composed of 
non-DEHP containing materials, such as glass, polyolefin or polyethylene, and 
the administration set should consist of non-DEHP tubing to avoid extraction of 
di-(2-ethylhexyl) phthalate (DEHP). 
Temsirolimus contains polysorbate 80, which is known to increase the rate of di-
(2-ethylhexyl) phthalate (DEHP) extraction from PVC.  An in line 
polyethersulfone filter with a pore size of not greater than 5 microns is 
recommended for administration. 
The final diluted solution of temsirolimus is intravenously infused over a 30-60 
minute period once a week. The use of an infusion pump is the preferred 
method of administration to ensure accurate delivery of the drug. 
Administration of the final diluted infusion solution should be completed within 
six hours from the time that the drug solution/diluent mixture is added to the 
sodium chloride injection. 
3.2.1.2  Compatibilities and Incompatibilities 
Undiluted temsirolimus injection should not be added directly to aqueous 
infusion solutions.  Direct addition of temsirolimus injection to aqueous 
solutions will result in precipitation of drug. Always combine temsirolimus 
injection with supplied diluent before adding to infusion solutions. It is 
recommended that temsirolimus be administered in 0.9% sodium chloride 
injection after combining with supplied diluent. The stability of temsirolimus in 
other infusion solutions has not been evaluated. Addition of other drugs or 
nutritional agents to admixtures of temsirolimus in sodium chloride injection 
has not been evaluated and should be avoided. Temsirolimus is degraded by 
both acids and bases, and thus combinations of temsirolimus with agents 
capable of modifying solution pH should be avoided. 
3.2.2  Preclinical Studies  
Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus 
binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the 
activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 
growth arrest in treated tumor cells. When mTOR was inhibited, its ability to 
phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the 
PI3 kinase/AKT pathway was blocked. In in vitro studies using renal cell carcinoma cell 


 
 
 
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lines, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the 
hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth 
factor.  In other preclinical models, it appeared that the agent decreased proliferation of 
murine xenografts bearing various solid tumors, including glioma, breast and prostate 
cancer. 
 
3.2.3  Clinical Studies 
A phase 3, multi-center, three-arm, randomized, open-label study was conducted in 
previously untreated patients with advanced renal cell carcinoma (clear cell and non-
clear cell histologies).  The objectives were to compare Overall Survival (OS), 
Progression-Free Survival (PFS), Objective Response Rate (ORR), and safety in patients 
receiving IFN-α to those receiving temsirolimus and temsirolimus plus IFN-α. Patients in 
this study had 3 or more of 6 pre-selected prognostic risk factors (less than one year 
from time of initial RCC diagnosis to randomization, Karnofsky performance status of 60 
or 70, hemoglobin less than the lower limit of normal, corrected calcium of greater than 
10 mg/dL, lactate dehydrogenase > 1.5 times the upper limit of normal, more than one 
metastatic organ site). Patients were stratified for prior nephrectomy status within 
three geographic regions and were randomly assigned (1:1:1) to receive IFN-α alone 
(n=207), temsirolimus alone (25 mg weekly; n=209), or the combination arm (n=210). 
The ITT population for this interim analysis included 626 patients. Demographics were 
comparable between the three treatment arms with regard to age, gender, and race. 
The mean age of all groups was 59 years (range 23-86). Sixty-nine percent were male 
and 31% were female. The racial distribution for all groups was 91% White, 4% Black, 2% 
Asian, and 3% other. Sixty-seven percent of patients had a history of prior nephrectomy. 
The median duration of treatment in the temsirolimus arm was 17 weeks (range 1-126 
weeks). The median duration of treatment on the IFN arm was 8 weeks (range 1-124 
weeks). 
There was a statistically significant improvement in OS (time from randomization to 
death) in the temsirolimus 25 mg arm compared to IFN-α. The combination of 
temsirolimus 15 mg and IFN-α did not result in a significant increase in overall survival 
when compared with IFN-α alone. 
3.2.4  Pharmacokinetics 
Absorption: Following administration of a single 25 mg dose of temsirolimus in patients 
with cancer, mean temsirolimus Cmax in whole blood was 585 ng/mL (coefficient of 
variation, CV =14%), and mean AUC in blood was 1627 ng•h/mL (CV=26%). Typically 
Cmax occurred at the end of infusion. Over the dose range of 1 mg to 25 mg, 
temsirolimus exposure increased in a less than dose proportional manner while 


 
 
 
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sirolimus exposure increased proportionally with dose.  Following a single 25 mg 
intravenous dose in patients with cancer, sirolimus AUC was 2.7-fold that of 
temsirolimus AUC, due principally to the longer half-life of sirolimus. 
Distribution: Following a single 25 mg intravenous dose, mean steady-state volume of 
distribution of temsirolimus in whole blood of patients with cancer was 172 liters. Both 
temsirolimus and sirolimus are extensively partitioned into formed blood elements. 
Metabolism: Cytochrome P450 3A4 is the major isozyme responsible for the formation 
of five temsirolimus metabolites. Sirolimus, an active metabolite of temsirolimus, is the 
principal metabolite in humans following intravenous treatment. The remainder of the 
metabolites account for less than 10% of radioactivity in the plasma. In human liver 
microsomes temsirolimus was an inhibitor of CYP2D6 and 3A4. However, there was no 
effect observed in vivo when temsirolimus was administered with desipramine (a 
CYP2D6 substrate), and no effect is anticipated with substrates of CYP3A4 metabolism. 
Elimination: Elimination is primarily via the feces. After a single IV dose of [14C]-
temsirolimus approximately 82% of total radioactivity was eliminated within 14 days, 
with 4.6% and 78% of the administered radioactivity recovered in the urine and feces, 
respectively. Following a single25 mg dose of temsirolimus in patients with cancer, 
temsirolimus mean (CV) systemic clearance was 16.2 (22%) L/h. Temsirolimus exhibits a 
bi-exponential decline in whole blood concentrations and the mean half-lives of 
temsirolimus and sirolimus were 17.3 hr and 54.6 hr, respectively. 
Drug Interactions: Co-administration of temsirolimus with rifampin, a potent CYP3A4/5 
inducer, had no significant effect on temsirolimus Cmax (maximum concentration) and 
AUC (area under the concentration versus the time curve) after intravenous 
administration, but decreased sirolimus Cmax by 65% and AUC by 56% compared to 
temsirolimus treatment alone. If alternative treatment cannot be administered, a dose 
adjustment should be considered.  Co-administration of temsirolimus with 
ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus Cmax 
or AUC; however, sirolimus AUC increased 3.1-fold, and Cmax increased 2.2-fold 
compared to temsirolimus alone. If alternative treatment cannot be administered, a 
dose adjustment should be considered. The concentration of desipramine, a CYP2D6 
substrate, was unaffected when 25 mg of temsirolimus was co-administered. No 
clinically significant effect is anticipated when temsirolimus is co-administered with 
agents that are metabolized by CYP2D6 or CYP3A4. 
3.2.4.1 Temsirolimus Drug Interactions    
Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 
inhibitors should be avoided (e.g. ketoconazole, itraconazole, clarithromycin, 


 
 
 
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atazanavir, indinavir,nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
and voriconazole). Grapefruit juice may also increase plasma concentrations of 
sirolimus (a major metabolite of temsirolimus) and should be avoided. If 
patients must be co-administered a strong CYP3A4 inhibitor, based on 
pharmacokinetic studies, a temsirolimus dose reduction to 12.5 mg/week 
should be considered. This dose of temsirolimus is predicted to adjust the AUC 
to the range observed without inhibitors. 
However, there are no clinical data with this dose adjustment in patients 
receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a 
washout period of approximately 1 week should be allowed before the 
temsirolimus dose is adjusted back to the dose used prior to initiation of the 
strong CYP3A4 inhibitor.  (see previous table in 6.1.1.3)   
Concomitant Strong CYP3A4 Inducers: The use of concomitant strong CYP3A4 
inducers should be avoided (e.g. dexamethasone, phenytoin, carbamazepine, 
rifampin, rifabutin, rifampacin, phenobarbital). If patients must be co-
administered a strong CYP3A4 inducer, based on pharmacokinetic studies, a 
temsirolimus dose increase from 25 mg/week up to 50 mg/week should be 
considered. This dose of temsirolimus is predicted to adjust the AUC to the 
range observed without inducers. However, there are no clinical data with this 
dose adjustment in patients receiving strong CYP3A4 inducers. If the strong 
inducer is discontinued the temsirolimus dose should be returned to the dose 
used prior to initiation of the strong CYP3A4 inducer 
3.2.5  Clinical Safety  
Hypersensitivity Reactions 
Hypersensitivity reactions manifested by symptoms including, but not limited to, 
anaphylaxis, dyspnea, flushing, and chest pain have been observed with temsirolimus  
Temsirolimus should be used with caution in persons with known hypersensitivity to 
temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any other 
component (including the excipients) of temsirolimus. 
An H1 antihistamine should be administered to patients before the start of the 
intravenous temsirolimus infusion. Temsirolimus should be used with caution in patients 
with known hypersensitivity to an antihistamine, or patients who cannot receive an 
antihistamine for other medical reasons. 
If a patient develops a hypersensitivity reaction during the temsirolimus infusion, the 
infusion should be stopped and the patient should be observed for at least 30 to 60 
minutes (depending on the severity of the reaction). At the discretion of the physician, 
treatment may be resumed with the administration of an H1-receptor antagonist (such 


 
 
 
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as diphenhydramine), if not previously administered, and/or an H2-receptor antagonist 
(such as intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 
30 minutes before restarting the temsirolimus infusion. The infusion may then be 
resumed at a slower rate (up to 60 minutes). 
Hepatic Impairment 
The safety and pharmacokinetics of temsirolimus were evaluated in a dose escalation 
phase 1study in 110 patients with normal or varying degrees of hepatic impairment. 
Patients with baseline bilirubin >1.5 x ULN experienced greater toxicity than patients 
with baseline bilirubin ≤1.5 x ULN when treated with temsirolimus. The overall 
frequency of ≥ grade 3 adverse reactions and deaths, including deaths due to 
progressive disease, were greater in patients with baseline bilirubin >1.5 x ULN. 
temsirolimus is contraindicated in patients with bilirubin >1.5 x ULN due to increased 
risk of death. Use caution when treating patients with mild hepatic impairment. 
Concentrations of temsirolimus and its metabolite sirolimus were increased in patients 
with elevated AST or bilirubin levels. If temsirolimus must be given in patients with mild 
hepatic impairment (bilirubin >1 – 1.5 x ULN or AST >ULN but bilirubin ≤ULN), reduce 
the dose of temsirolimus to15 mg/week.   
 
Hyperglycemia/Glucose Intolerance 
The use of temsirolimus is likely to result in increases in serum glucose. In the phase 3 
trial, 89% of patients receiving temsirolimus had at least one elevated serum glucose 
while on treatment, and 26% of patients reported hyperglycemia as an adverse event. 
This may result in the need for an increase in the dose of, or initiation of, insulin and/or 
oral hypoglycemic agent therapy. Serum glucose should be tested before and during 
treatment with temsirolimus. Patients should be advised to report excessive thirst or 
any increase in the volume or frequency of urination. 
 
Infections 
The use of temsirolimus may result in immunosuppression. Patients should be carefully 
observed for the occurrence of infections, including opportunistic infections  
 
Interstitial Lung Disease 
Cases of interstitial lung disease, some resulting in death, occurred in patients who 
received temsirolimus. Some patients were asymptomatic with infiltrates detected on 
computed tomography scan or chest radiograph. Others presented with symptoms such 
as dyspnea, cough, hypoxia, and fever. Some patients required discontinuation of 
temsirolimus and/or treatment with corticosteroids and/or antibiotics, while some 
patients continued treatment without additional intervention. Patients should be 
advised to report promptly any new or worsening respiratory symptoms. 
 


 
 
 
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Hyperlipemia 
The use of temsirolimus is likely to result in increases in serum triglycerides and 
cholesterol. In the phase 3 trial, 87% of patients receiving temsirolimus had at least one 
elevated serum cholesterol value and 83% had at least one elevated serum triglyceride 
value. This may require initiation, or increase in the dose, of lipid-lowering agents. 
Serum cholesterol and triglycerides should be tested before and during treatment with 
temsirolimus. 
 
Bowel Perforation 
Cases of fatal bowel perforation occurred in patients who received temsirolimus. These 
patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, 
diarrhea, and/or acute abdomen. Patients should be advised to report promptly any 
new or worsening abdominal pain or blood in their stools. 
 
Renal Failure 
Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related 
to disease progression occurred in patients who received temsirolimus. Some of these 
cases were not responsive to dialysis. 
 
Wound Healing Complications 
Use of temsirolimus has been associated with abnormal wound healing. Therefore, 
caution should be exercised with the use of temsirolimus in the perioperative period. 
 
Intracerebral Hemorrhage 
Patients with central nervous system tumors (primary CNS tumor or metastases) and/or 
receiving anticoagulation therapy may be at an increased risk of developing 
intracerebral bleeding (including fatal outcomes) while receiving temsirolimus. 
 
Co-administration with Inducers or Inhibitors of CYP3A Metabolism 
Agents Inducing CYP3A Metabolism: 
Strong inducers of CYP3A4/5 such as dexamethasone, carbamazepine, phenytoin, 
phenobarbital, rifampin, rifabutin, and rifampacin may decrease exposure of the active 
metabolite, sirolimus. If alternative treatment cannot be administered, a dose 
adjustment should be considered. St. John’s Wort may decrease temsirolimus plasma 
concentrations unpredictably. Patients receiving temsirolimus should not take St. John’s 
Wort concomitantly.  
 
Agents Inhibiting CYP3A Metabolism: 
Strong CYP3A4 inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, 
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin may 


 
 
 
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increase blood concentrations of the active metabolite sirolimus. If alternative 
treatments cannot be administered, a dose adjustment should be considered. 
 
Vaccinations 
The use of live vaccines and close contact with those who have received live vaccines 
should be avoided during treatment with temsirolimus. Examples of live vaccines are: 
intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, 
and TY21a typhoid vaccines. 
 
Pregnancy 
Pregnancy Category D:  Temsirolimus administered daily as an oral formulation caused 
embryo-fetal and intrauterine toxicities in rats and rabbits at human sub-therapeutic 
exposures. Embryo-fetal adverse effects in rats consisted of reduced fetal weight and 
reduced ossifications, and in rabbits included reduced fetal weight, omphalocele, 
bifurcated sternabrae, notched ribs, and incomplete ossifications .In rats, the 
intrauterine and embryo-fetal adverse effects were observed at the oral dose of 2.7 
mg/m2/day (approximately 0.04-fold the AUC in cancer patients at the human 
recommended dose). In rabbits, the intrauterine and embryo-fetal adverse effects were 
observed at the oral dose of ≥7.2 mg/m2/day (approximately 0.12-fold the AUC in 
cancer patients at the recommended human dose). 
Women of childbearing potential should be advised to avoid becoming pregnant 
throughout treatment and for 3 months after temsirolimus therapy has stopped. 
Temsirolimus can cause fetal harm when administered to a pregnant woman. If this 
drug is used during pregnancy, or if the patient becomes pregnant while taking this 
drug, the patient should be apprised of the potential hazard to the fetus. 
Men should be counseled regarding the effects of temsirolimus on the fetus and sperm 
prior to starting treatment. Men with partners of childbearing potential should use 
reliable contraception throughout treatment and are recommended to continue this for 
3 months after the last dose of temsirolimus. 
4.0 ELIGIBILITY CRITERIA  
 
 
4.1 INCLUSION 
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  


 
 
 
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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:  
• 
Absolute neutrophil count ≥1,500/µL  
•  Platelets  ≥100,000/µL  
• 
Hgb  ≥ 9.0 g/dL (transfusion allowed)  
•  Renal:  serum creatinine ≤ 1.5 x ULN or calculated CrCl ≥40 cc/min and random urine 
protein:creatitine ratio (UPC) < 1 or 24-hr urine protein < 1g 
•  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 
•  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. 
4.2 EXCLUSION 
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. 
 


 
 
 
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4. Uncontrolled brain metastases and infections.   Patients with brain metastases treated 
with Gamma Knife (GK) or with 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. 
 
5.0 TREATMENT PLAN  
 


 
 
 
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5.1 Study Summary  
 
Patients with advanced poor-risk clear-cell RCC who have not had any prior systemic targeted 
therapy will be randomized fairly in a 1:1 ratio to receive pazopanib or temsirolimus as first-line 
therapy. Patients will be stratified upfront by nephrectomy status (yes/no) and prior 
cytokine/vaccine therapy (yes/no).  At the time of disease progression, patients will be offered 
the option of crossover to receive the agent they did not receive in the first-line. 
 
5.2 Administration 
After registration on the protocol, patients will be randomized to receive either pazopanib or 
temsirolimus treatment. Following randomization patients will begin treatment with the first 
assigned agent. At progression, if they have not suffered an adverse event that would preclude 
them from continuing with systemic therapy, after the applicable washout period, will begin 
treatment with the remaining treatment agent at the discretion of the physician.   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pazopanib will be taken at 800 mg PO daily without food (at least 1 hour before or 2 hours after 
a meal) until PD or prohibitive toxicity or withdrawal of consent.  Tablets will not be crushed due 
to the potential for increased rate of absorption which may affect systemic exposure. If a dose is 
missed, it should not be taken if it is less than 12 hours until the next dose. Patients will 
complete a pill diary for pazopanib to document compliance. 
Temsirolimus will be given at 25 mg IV infused over 30-60 minutes every week until PD or 
prohibitive toxicity or withdrawal of consent. Patients will receive prophylactic intravenous 
diphenhydramine 25 to 50 mg (or similar antihistamine) approximately 30 minutes before the 
start of each dose of temsirolimus.   
A cycle consists of 4 weeks of therapy.   Pazopanib will be self-administered at home and in the 
outpatient setting for patients who receive temsirolimus.    
R
A
N
D
O
M
I
Z
A
T
I
O
N 
Pazopanib 800 
mg PO qd 
Temsirolimus 
25 mg 1 x wk 
Pazopanib 800 
mg PO qd 
Temsirolimus
25 mg 1 x wk 
O
F
F 
S
T
U
D
Y 


 
 
 
Protocol 2011-0358 
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Page 23 
 
 
All patients will have a washout period of 2 weeks from the day of progressive disease tumor 
assessment before they start 2nd-line therapy.   
5.3 Evaluation before treatment  
 
Within 4 weeks of registration:  
* A standing window of allowance equal to +/- 3 days will be utilized.  
• All participants must sign a consent form agreeing to participate in the study  
• Baseline radiological studies should include CT scans of the chest (high-resolution) and 
abdomen and MRI of the brain. Additional studies (e.g., CT scan of pelvis, bone scan, plain 
films) should be obtained as appropriate. MRI of the abdomen and/or CT scan of the brain 
can be substituted at the physician’s discretion.  
• Cardiac evaluation with a 12-lead EKG and an echocardiogram or MUGA. The 
echocardiogram or MUGA scan may be obtained within 12 weeks of registration.  
• A minimum of 7 days must elapse between the diagnostic biopsy and treatment if tissue 
diagnosis was not previously made.  
• Optional:  Previously collected tissue will be requested from patients who consent, and will 
be stored for future research related to cancer.  Tissue will also be collected during 
procedures performed while patients are enrolled in this study. No new procedures will be 
required. This tissue will also be banked as described above.  
 
5.3.1 Within 14 days of registration:  
 
* A standing window of allowance equal to +/- 2 days will be utilized.  
 
• 
All patients must undergo a complete history and physical examination, 
including vital signs, ECOG performance status, height, current weight including 
recent weight loss, Concurrent non-malignant disease and medications must be 
documented. All prior surgical procedures or radiation treatments must be 
recorded in detail.  
 
• 
Laboratory studies should include CBC w/ platelet count and differential, 
chemistry panel (total protein, albumin, alkaline phosphatase, AST, ALT, 
calcium, LDH, total bilirubin, BUN, creatinine, phosphorus, glucose, sodium, 
potassium, chloride, carbon dioxide), fasting lipid panel, free T4, thyroid 
stimulating hormone (TSH), PT and PTT.  Serum amylase and lipase will be done 
only if clinically indicated. Patients will have a U/A.  Patients who have urine 
protein ≥ 300 on U/A should have a random UPC ratio at baseline. A pregnancy 
test (serum/plasma or urine betaHCG) in female patients of childbearing 
potential will also be included.  
 


 
 
 
Protocol 2011-0358 
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• 
All patients will complete a full Quality of Life assessment battery (see Section 7 
for additional details) 
 
• 
Optional baseline blood specimens for future correlative studies will be 
collected.  
5.4 Evaluation During Treatment (initial treatment or crossover)  
 
*Evaluations while on study will have a standing window of allowance equal to +/- 7 days.  
 
Treatment evaluations will consist of the following study activities (a cycle is 4 weeks):  
• Interim medical history and physical examination, including vital signs, height, current weight 
including recent weight loss every 4 weeks for temsirolimus patients.  (May be done by local 
physician every other cycle for temsirolimus patients only).  Interim medical history and 
physical examination, including vital signs, current weight including recent weight loss every 
8 weeks for pazopanib patients.   
 
• All patients will complete a follow-up Quality of Life assessment battery (see Section 7 for 
additional details) 
• Weekly blood pressure monitoring for the first four weeks for patients receiving pazopanib, 
and then with each history and physical every 8 weeks. Monitoring may be performed at 
doctor's office or by the patient at home using an electronic blood pressure device.  Blood 
pressure measurements performed outside of the office of the treating physician should be 
recorded by the patient and submitted to the treating physician during cycle one. An 
increase in blood pressure to > 160 systolic or > 100 diastolic should be reported to the 
treating physician immediately.  
• Urinalysis (U/A) every 8 weeks. Patients who have urine protein ≥ 300 on U/A should have a 
random UPC ratio checked for pazopanib patients only.  
• Patients on Pazopanib will have serum chemistry and electrolytes including total protein, 
albumin, alkaline phosphatase, AST, ALT, calcium, LDH, total bilirubin, BUN, creatinine, 
phosphorus, glucose, sodium, potassium, chloride, and carbon dioxide will be done every 2 
weeks for the first 8 weeks and 8 weeks x 2, and every 16 weeks therafter.  Pazopanib patients 
will have CBC with platelet count and differential every 2 weeks for the first 8 weeks, every 8 
weeks x 2, and every 16 weeks thereafter.   
• Patients on temsirolimus will have serum chemistry and electrolytes including total protein, 
albumin, alkaline phosphatase, AST, ALT, calcium, LDH, total bilirubin, BUN, creatinine, 
phosphorus, glucose, sodium, potassium, chloride, and carbon dioxide will be done every 2 
weeks for the first 8 weeks and every 4 weeks thereafter. Fasting lipid panel every 4 weeks 
for the first 8 weeks, every 8 weeks x 2, and every 16 weeks thereafter.  CBC with platelet 
count and differential will be done every week for patients on temsirolimus.   


 
 
 
Protocol 2011-0358 
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• Record concomitant medications with each history and physical.  
• Reconcile the medication diary provided during treatment with each history and physical for 
those on pazopanib.   
• Adverse events will be assessed at each visit and monitored throughout the study.  
• 12-Lead Electrocardiogram will be repeated at Cycle 2 Day 1, 12 weeks later, and every 16 
weeks after that for patients on Pazopanib. (see Section 6.1.1.4 for additional details of QT 
interval monitoring) Patients receiving temsirolimus will have an ECG done every 16 weeks. 
• Optional blood specimens for future correlative studies will be obtained every 8 weeks and 
at progression.  
• Serum amylase and lipase will be obtained only as clinically indicated.  
• Serum T4 and TSH will be obtained every 8 weeks for patients receiving pazopanib.  
• 
Repeat radiological studies (CT, MRI as indicated) to evaluate response every 8 weeks. 
Studies to confirm a complete response or document progressive disease will be 
performed as needed.  Patients who are progression free after 1 year can have their 
imaging studies obtained every 16 weeks. 
• Echocardiogram or MUGA scan (echocardiogram preferred) will be repeated every 24 weeks 
and as clinically indicated.  
Outside Physician Participation During Treatment (Temsirolimus Patients may have interim 
infusions with local MD) 
 
1. MDACC Physician communication with the outside physician is required prior to the patient 
returning to the local physician. This will be documented in the patient record 
2. A letter to the local physician outlining the patient's participation in a clinical trial will 
request local physician agreement to supervise the patient's care (Appendix J); A copy of the 
protocol abstract and evaluation during treatment will be provided to the local physician 
with the letter. 
3. Protocol required evaluations outside MDACC will be documented by telephone, fax or e-
mail.  Fax and/or e-mail will be dated and signed by the MDACC physician, indicating that 
they have reviewed it. 
4. Changes in drug dose and/or schedule must be discussed with and approved by the MDACC 
physician investigator, or their representative prior to initiation, and will be documented in 
the patient record. 
5. Documentation to be provided by the local physician will include drug administration 
records, progress notes, reports of protocol required laboratory and diagnostic studies and 
documentation of any hospitalizations. 
6. The home physician will be requested to report to the MDACC physician investigator all life 
threatening events within 24 hours of documented occurrence. 
7. Patients will return to MDACC every 8 weeks for evaluation. 


 
 
 
Protocol 2011-0358 
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8.  Patients on pazopanib/torisel who have reached 12 months without progression may see 
their local physician and will return to MDACC every 8-16 weeks for evaluation and 
restaging. 
 
5.5  Off Treatment Follow-up (30 days after stopping therapy) 
 
Attempts will be made to follow-up with the patient in 30 days after the last dose of study 
drug.  If a patient cannot return for the 30-day assessment and contact cannot be made 
due to disease progression, inability to return, hospice care, death, etc, this will not be 
considered a protocol deviation.  Reporting to the IRB for deaths and other serious adverse 
events will be performed. 
 
• Record concomitant medications.  
• Adverse events will be assessed 
• Optional blood draw for correlative studies 
 
5.6   Crossover Phase  
 
• 
At progression by RECIST, if they have not suffered an adverse event that would preclude 
them from continuing with systemic therapy and after the applicable washout period, of 2 
weeks, patients who continue to meet the eligibility criteria will begin treatment with the 
remaining agent.   
Note:  
• 
At the discretion of the treating physician, the patient may continue on their 1st-
line agent if the treating physician believes the patient is benefitting, despite 
progression by RECIST.  
• 
Patient may start their 2nd-line therapy within 2 weeks from the last dose of the 
agent given in 1st-line, if felt indicated by the treating physician. 
• 
Patients who develop progressive disease while receiving the 1st-line agent may 
receive radiation therapy or undergo surgery if indicated and continue to receive 
treatment on protocol, as long as the 2nd-line agent is commenced within 8 weeks 
from discontinuation of the 1st-line agent. 
• 
For the cross-over stage of the study, patients will repeat the schedule of assessments as 
provided in the study calendar and section 5.4.  Cardiovascular assessments will only be 
repeated if more than 24 weeks from the previous exams and only for those who’ll be 
receiving pazopanib.  A MRI/CT of the brain will be performed at crossover to rule out any 
progression before the start of crossover therapy at the discretion of the physician. 
 
• 
Screening blood work must have been performed within the past 14 days before starting 
the new treatment.  
 
• 
Optional blood draws will continue the same schedule as indicated in the study calendar.   
 
5.7  Long-Term Follow-up 


 
 
 
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Patients will be followed for overall survival every 3 months after removal from final study 
therapy.  Follow-up will consist of a phone call, e-mail correspondence or medical record review. 
 
5.8  Supportive Care  
 
The use of concurrent medications and blood products will be left to the discretion of the treating 
physician and should follow established guidelines.  
 
5.9  Duration of Therapy  
 
Patients may continue therapy until progressive disease by RECIST criteria or until other criteria 
for removal (Section 12) has been met. 
 
6.0 DOSING DELAYS/DOSE MODIFICATIONS 
6.1 General Guidelines 
Doses will be delayed or reduced for clinically significant hematologic, renal, and other toxicities 
that are related to pazopanib or temsirolimus, as determined by the investigators at MD 
Anderson. All toxicity will be assessed using the NCI CTC version 4.0.  Recovery from any toxicity 
to at least grade 1 or baseline as outlined below must occur prior to re-initiating therapy with 
agent responsible for the toxicity. Treatment with the same agent will resume as soon as 
possible with the appropriate dose reductions. Patients receiving treatment who experience an 
adverse event that necessitates its interruption and a delay of ≥ 6 weeks in its re-initiation will 
discontinue it and come off protocol.  In all cases, patients, who are withdrawn from the study 
due to adverse event(s), must be followed until resolution of the adverse event(s) or start of 
new treatment.  If a patient experiences several toxicities leading to conflicting 
recommendations, the recommended dose adjustment reducing the dose to the lowest level 
will be used. The dose of any study drug may be re-escalated to a higher level following 
discussion with the principal investigator. All dose modifications will follow predefined dose 
levels. 
Patients who require any emergency intervention (e.g. for appendectomy or cholecystectomy 
because of trauma complications) or who require a procedure (e.g. Kyphoplasty/vertebroplasty) 
may remain on trial, even if administration of the targeted agent is interrupted, as long as the 
targeted agent is resumed within 6 weeks from date of interruption. 
Pulmonary Embolism 
Patients who are incidentally discovered on CT scan imaging to have pulmonary embolism may 
receive anticoagulation and continue treatment on protocol at the discretion of the treating 
physician. 


 
 
 
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6.1.1 Pazopanib Dose Modifications  
 
Dose Modifications for Pazopanib Associated Toxicity 
 
Toxicity  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Non-hematological  
Continue at the 
same dose level  
Continue at the same 
dose level  
Withhold dose until 
toxicity is grade ≤ 1 
or has returned to 
baseline, then 
resume treatment  
with the dose 
reduced   by 1 level 
Withhold dose until 
toxicity is grade ≤ 1 
or has returned to 
baseline, then 
resume treatment  
with the dose 
reduced by 1 level  
Hematological  
Continue at the 
same dose level  
Continue at the same 
dose level  
Withhold dose until 
toxicity is grade ≤ 1 
or has returned to 
baseline, then 
resume treatment at 
the same dose level  
Withhold dose until 
toxicity is grade ≤ 1 
or has returned to 
baseline, then 
resume treatment at 
the same dose level  
 
 
 
 
 
 
6.1.1.1 Guidelines for Management of Treatment Emergent Hepatotoxicity  
In the event of treatment emergent hepatotoxicity, potential contributing factors 
such as concomitant medications, viral hepatitis, choledocholithiasis, and hepatic 
metastases should be investigated. Concomitant medications known to be 
hepatotoxic which may be contributing to liver dysfunction should be discontinued 
or replaced with alternative medications to allow for recovery of liver function. As 
generally understood, ALT >3x ULN and concomitant bilirubin ≥2.0xULN (>35% 
direct bilirubin), in the absence of elevated alkaline phosphatase or biliary injury, 
suggests significant liver injury. The table below provides guidelines for 
hepatotoxicity monitoring.  
Event  
Dose Modification Algorithms  
(A). ALT ≤ 3.0 x ULN  
Continue study treatment at current dose with LFTs monitored 
as per protocol.  
Dose Level 
Pazopanib 
0 
800 mg oral Daily 
-1 
600 mg oral Daily 
-2 
400 mg oral Daiily 


 
 
 
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(B). ALT >3.0 x ULN to 
≤8.0 x ULN without 
bilirubin elevation 
(defined as total bilirubin 
<2.0 x ULN or direct 
bilirubin ≤35%) and 
without hypersensitivity 
symptoms (e.g., fever, 
rash)  
Liver Event Monitoring Criteria:  
(1) Continue study treatment at current dose levels.  
(2) Monitor subject closely for clinical signs and symptoms; 
perform full panel LFTs once weekly or more frequently if 
clinically indicated until ALT/AST is reduced to Grade 1.  
(C). ALT >8.0 x ULN 
without bilirubin 
elevation (defined as total 
bilirubin <2.0 x ULN or 
direct bilirubin ≤35%) and 
without hypersensitivity 
symptoms (e.g., fever, 
rash)  
1st occurrence – Liver Event Interruption Criteria:  
(1) Interrupt treatment until toxicity resolves to ≤Grade 1 or 
baseline. Repeat liver chemistries within 24 to 72 hours.  
(2) Monitor subject closely for clinical signs and symptoms; 
perform full panel LFTs once weekly or more frequently if 
clinically indicated until ALT is reduced to Grade 1.  
(4) If the subject is benefiting from the study treatment, 
consider re-challenge. Re-treatment may be considered at a 
dose of 400 mg once daily and with weekly serum liver tests x 8 
weeks, if ALL following criteria are met:  
- ALT reduced to Grade 1  
- Total bilirubin <1.5 x ULN or direct bilirubin ≤35%  
- No hypersensitivity signs or symptoms  
- Subject is benefiting from therapy.  
Recurrence – Liver Event Stopping Criteria:  
Discontinue pazopanib permanently and monitor subject 
closely for clinical signs and symptoms; perform full panel LFTs 
once weekly or more frequently if clinically indicated until ALT 
is reduced to Grade 1.  
(D). ALT >3.0 x ULN with 
concomitant elevation in 
bilirubin2 (defined as total 
bilirubin ≥2.0 x ULN; with 
direct bilirubin >35%) or 
with hypersensitivity 
symptoms (e.g., fever, rash)
Liver Event Stopping Criteria:  
(1) Discontinue treatment immediately, and report the event 
to Novartis as an SAE within 24 hours of learning of its 
occurrence. Repeat LFTs within 24 hours.  
(2) Consult a gastroenterologist / hepatologist, and perform 
the following assessments to identify potential co-factors:  
- Eosinophil count  
- Viral serology for hepatitis A, B, C and E, cytomegalovirus, 
Epstein-Barr virus (IgM antibody, heterophile antibody, or 
monospot testing)  
- Anti-nuclear antibody, anti-smooth muscle antibody, anti-
mitochondrial antibody  
- Serum creatinine phosphokinase for possible muscle injury 
caused LFT elevation  


 
 
 
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- Liver imaging  
(3) Monitor subject closely for clinical signs and symptoms; 
record the appearance or worsening of clinical symptoms of 
hepatitis, or hypersensitivity, such as fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever rash or 
eosinophilia as relevant on the AE report form. Perform full 
panel LFTs weekly or more frequently if clinically indicated until 
LFTs are reduced to Grade 1.  
For isolated total bilirubin 
elevation without 
concurrent ALT increases 
(defined as ALT <3 X ULN).  
(1) Isolated hyperbilirubinemia (i.e., in the absence of elevated 
ALT or other signs/symptoms of liver injury) does not require 
dose modification. Pazopanib inhibits UGT1A1 and OATP1B1, 
which can cause elevation of indirect (unconjugated) bilirubin 
in the absence of liver injury.  
(2) If bilirubin is >2 x ULN in the absence of ALT elevation, 
fractionation of bilirubin elevation should be performed. If the 
bilirubin is predominantly indirect (unconjugated), continue 
pazopanib at the same dose. If bilirubin is >35% direct 
(conjugated), further evaluation for underlying cause of 
cholestasis should be performed.  
 
1. Full panel LFTs include: AST, ALT, alkaline phosphatase, , and total bilirubin.  
2. Serum bilirubin fractionation should be performed if testing is available. If testing is 
unavailable and a subject meets the criterion of total bilirubin ≥2.0 x ULN, then the event 
should be promptly reported as defined.  
3. When a liver chemistry event meets the Liver Event Interruption Criteria, or Liver Event 
Stopping Criteria, blood samples should be obtained for clinical laboratory testing.  
 
Abbreviations: ALT alanine aminotransferase; AST aspartate aminotransferase; LFT liver 
function tests; SAE serious adverse event; ULN upper limit of normal. 
6.1.1.2 Guidelines for Management of Treatment Emergent Hypertension  
 
 
Hypertension Grade of 
Event per MDACC 
guidelines  
Management/ Next Dose  
Grade 1  
Consider increased BP monitoring  
Grade 2 asymptomatic and 
diastolic BP < 110 mm Hg 
Begin anti-hypertensive therapy and continue 
agent  


 
 
 
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requiring more than 3 
antihypertensive medications. 
Grade 2 symptomatic/ 
persistent OR diastolic BP ≥ 110 
mm Hg OR grade 3  
1. Agent should be held until symptoms resolve 
and diastolic BP ≤ 100 mm Hg; also treat patient 
with anti-hypertensives and when agent is 
restarted, reduce by 1 dose level. Following 
discussion with the PI, determination to continue 
with same dose or reduce by 1 level may be 
made. 2. If diastolic BP not controlled (≤ 100) on 
maximal medical therapy (as defined as more 
than 3 antihypertensive medications), reduce 
one dose level  
Grade 4  
Discontinue the offending agent and remove 
patient from  
 
MDACC Hypertension definitions:  
Grade 1: asymptomatic, transient (< 24 hours) increase > 20 mmHg (diastolic) or to 
>140/90 if previously WNL; intervention not indicated  
Grade 2: recurrent or persistent (>24 hours) or symptomatic increase > 20 mmHg 
(diastolic) or to >140/90 if previously WNL; monotherapy may be indicated.  
Grade 3: requiring multiple antihypertensive agents or more intensive therapy than 
previously  
Grade 4: life-threatening (e.g., hypertensive crisis)  
 
6.1.1.3 Concomitant Strong CYP3A4 Inhibitors:  
The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, 
clarithromycin) may increase pazopanib concentrations and should be avoided. If 
coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of 
pazopanib to 400 mg. Further dose reductions may be needed if adverse effects 
occur during therapy. This dose is predicted to adjust the pazopanib AUC to the 
range observed without inhibitors. However, there are no clinical data with this 
dose adjustment in patients receiving strong CYP3A4 inhibitors. 
6.1.1.4  12-Lead Electrocardiogram 
 
In clinical studies with pazopanib, events of QTcB prolongation have occurred.  For 
patients receiving pazopanib a 12-lead ECG will be obtained at Screening/Baseline 
and again at Cycle 2 Day 1.  If QTcB is normal, patients will have an ECG every 16 
weeks thereafter.  Prior to each ECG test, the subject should be at rest for 
approximately 10 minutes.  
If the QTcB interval at any ECG during treatment is ≥ 500 msec, study drug will be 
held and the ECG should be repeated within 7 days and, if the QTcB interval remains 


 
 
 
Protocol 2011-0358 
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≥ 500 msec, the subject should be removed from the study.  The ECG can be 
performed at an outside facility with results sent to MDACC. 
Additionally, if the QTcB interval is increased by 60 msec or more from baseline, but 
the QTcB interval remains at < 500 msec, an ECG should be repeated within 7 
days.  If the repeat ECG again shows a ≥ 60 msec increase in the QTcB interval from 
baseline, consideration should be given to removing the subject from the study or 
increasing monitoring, after discussion with the principal investigator.  
NOTE: If the QTcB prolongation > 500 msec is clearly and causally associated with an 
underlying situation that is clearly reversible (e.g., a subject with severe diarrhea 
and hypokalemia with QTcB prolongation that resolves once the diarrhea improves 
and potassium is corrected), then the subject may restart study drug once the 
underlying situation has been corrected (e.g., electrolytes supplemented), the QTcB 
interval prolongation has resolved.   
6.1.2 Temsirolimus Dose Modifications 
 
6.1.2.1. Hepatic Impairment: Use caution when treating patients with hepatic 
impairment. If temsirolimus must be given in patients with mild hepatic impairment 
(bilirubin >1 – 1.5 x ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of 
temsirolimus to 15 mg/week. Temsirolimus is contraindicated in patients with 
bilirubin >1.5 x ULN .  
6.1.2.2. Hypertriglyceridemia  
Patients who have persistently elevated serum triglycerides (> 1000mg/dL) for ≥ 4 
weeks,  despite treatment with lipid-lowering agents, or patients who develop 
pancreatitis (regardless of the duration of the preceding triglyceride elevation) 
should discontinue temsirolimus and come off protocol.  
 
 
Temsirolimus should be held for absolute neutrophil count (ANC) < 1,000/mm3, 
platelet count< 75,000/mm3, or NCI CTCAE grade 3 or greater adverse reactions. 
Once toxicities have resolved to grade 1 or less, temsirolimus may be restarted with 
the dose reduced by 5 mg/week to a dose no lower than 15 mg/week. 
 
 
 
6.2 Concomitant Drugs 
Patients receiving both pazopanib and temsirolimus will be instructed not to take any additional 
medications (including over-the-counter products) during the course of the study without prior 
consultation with the investigator. At each visit, the investigator will ask the patient about any 
new medications he/she is or has taken after the start of the study drug.  All concomitant 


 
 
 
Protocol 2011-0358 
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medications/significant non-drug therapies taken ≤ 30 days prior to start and after start of study 
drug, including physical therapy and blood transfusions, should be recorded.  Please reference 
the Warnings and Precautions section for CYP3A4-related drugs in the temsirolimus label and 
the Dose Modification Guidelines section in the pazopanib label for further detail. 
 
The following restrictions apply during the entire duration of the study:  
• 
No other investigational therapy should be given to patients.  
• 
No anticancer agents other than the study medication should be given to patients. If such 
agents are required for a patient then the patient must first be withdrawn from the study.  
• 
It is highly recommended that patients with positive HBV-DNA or HBsAg are treated 
prophylactically with an antiviral for 1-2 weeks prior to receiving study drug.  
• 
The antiviral treatment should continue throughout the entire study period and for at least 
4 weeks after the last dose of study drug.  
• 
Patients on antiviral prophylaxis treatment or positive HBV antibodies should be tested for 
HBV-DNA according to study visit schedule.  
 
Seville orange, star fruit, grapefruit and their juices affect P450 and PgP activity. Concomitant 
use should be avoided  
No chronic treatment with systemic steroids (at a dose equivalent of greater than 20 mg 
prednisone per day) or other immunosuppressive agents. Topical or inhaled corticosteroids are 
allowed.  
The use of live vaccines and close contact with those who have received live vaccines should be 
avoided during treatment with temsirolimus. Examples of live vaccines include intranasal 
influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid 
vaccines.  
7.0 QUALITY OF LIFE ASSESSMENT  
 
Measuring quality of life (QOL) outcomes in cancer patients has become an important mandate for 
clinical trials.  It is especially important to assess QOL in phase II cancer clinical trials that are likely to 
move into the phase III setting.  The extent to which treatment impairs QOL is information the patients 
need when making treatment decisions.   
Patients will experience somewhat different symptoms when they receive the different therapies.  In 
order to assess the effects of these treatments, we will assess multidimensional aspects of QOL over 
the treatment course. 
 
Assessment Schedule 


 
 
 
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All patients will complete a full assessment battery at baseline, prior to treatment.  Patients will then 
complete an assessment battery every 8 weeks when they come in for their clinical evaluation (see 
Table 1). 
Table 1:  Data collection sessions for psychosocial measures 
BASELINE 
FOLLOW-UP   
(EVERY 8 WEEKS) 
•  FACT-G 
•  FKSI-15 
•  Depression (CES-D) 
• 
FACT-G 
• 
FKSI-15 
• 
CES-D 
 
Instruments 
Several measures used previously in our work on chronic stress and QOL will be used in the proposed 
study.  In all cases, they have proven to be useful and sensitive measures of stress and QOL, have 
proven to be stable, reliable, and valid with groups of people who are and are not suffering from major 
depression or other psychiatric disorders. 
Quality of Life  
The Functional Assessment of Cancer Therapy (FACT) is a cancer-specific measure of health-related 
quality of life. This instrument was able to discriminate between individuals with metastatic and non-
metastatic disease, as well as between patients at different stages of illness.  The scale has been found 
to have good concurrent validity, high internal consistency (0.89), and good test re-test reliability (0.82 
to 0.88).  The FACT will be completed at each assessment.  Kidney cancer specific QOL symptoms will be 
assessed with the FKSI-15 from the FACT group. 
Depression:   
 Depression will be assessed using the Centers for Epidemiologic Studies - Depression (CES-D).  The CES-
D is a well-validated 20-item self-report measure of depression that focuses on affective components of 
depression.  Cut-off scores of 16 for screening clinical depression have been recommended.  Internal 
consistency is high in the general population and in patient populations.  It also has been demonstrated 
to possess adequate convergent validity with other measures of depression.  The CES-D will be 
completed at baseline and at each subsequent clinical visit (every 8 weeks). 
 
8.0 CORRELATIVE STUDIES 
Optional blood will be collected on day 1 of cycle 1, day 1 of every other cycle, and at the end of 
treatment.  Blood will be stored in the GU Biorepository and tissue will be stored in the MD Anderson 
institutional tissue bank.     
 
We plan to identify and quantify circulating endothelial cells (CECs) in peripheral blood. We hypothesize 
that CECs correlate with tumor angiogenesis in mRCC and may thus be useful for the monitoring of 
disease progression. Moreover, we expect to find treatment-related effects on CECs, which could 
contribute to the assessment of response in future studies with anti-angiogenic therapies. The presence 


 
 
 
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of a dynamic number of CECs in the circulation of cancer patients is already well established. Recent 
reports suggest a role for CECs as biomarkers of cancer progression and response to targeted therapies.  
Two distinct populations of CECs have been identified: Circulating endothelial progenitor cells, mainly 
derived from bone marrow, which may contribute to the formation of new blood vessels in the tumor; 
and mature CECs, thought to be derived from established vasculature. In addition to immunophenotypic 
markers like CD146, CD133, VEGFR2 and CD31, both populations can be distinguished by a distinctive 
ability for proliferation. We will obtain a mononuclear cell fraction from each blood specimen and detect 
CECs by fluorescence-activated cell sorting analysis. We will systematically examine changes in the 
plasma and serum angiogenic profiles consisting of a panel of pro-angiogenic cytokines, targeted 
receptors, and potential biomarkers of endothelial damage. 
 
The analysis of plasma- and serum-based biomarkers will focus on two groups of proteins. First, factors 
known to be modulated by VEGFR antagonists or by endothelial injury will be assessed. Such biomarkers 
include plasma VEGF and soluble VEGFR-2, as well as soluble VEGFR-1 and E-selectin.  
The second set of factors will be pro-angiogenic cytokines that may contribute to resistance to VEGF 
inhibitors by promoting the proliferation and survival of tumor endothelial cells even in the presence of 
VEGF blockade. These cytokines will be assessed in two ways. First, several selected pro-angiogenic 
cytokines known to play a role in angiogenesis in renal cell cancer, including VEGF, basic fibroblast 
growth factor (bFGF), transforming growth factor α (TGFα), and interleukin-8 (IL-8), will be assessed 
quantitatively by validated enzyme-linked immunosorbent assay (ELISA). Second, we will broadly screen 
a set of approximately 100 known angiogenic factors by using an established cytokine array capable of 
detecting angiogenic factors. Candidate cytokines identified using the array will then be assayed 
individually. 
Plasma VEGF levels will be measured using commercially available ELISA kits. VEGF levels can be 
accurately detected at a level of 6–20,000 pg/ml with a coefficient of variance of less than 10% by this 
method. TGFα, bFGF, IL-8, and other soluble factors will be analyzed using similar methodologies. 
Together with the cytokine array, these assays will form an angiogenic profile that will be monitored 
during treatment and at time of disease progression.  
We will also use these assays to find correlations with adverse events. Our hypothetis is that 
cardiovascular toxicity may be related to baseline levels and/or changes of inflammatory cytokines, 
angiogenic factors, or markers of endothelial damage or repair.   
Immunological studies will be conducted to define changes in effector and regulatory T cell populations 
and/or function and changes in cytokine profiles that occur after patients have started treatment. 
Laboratory techniques will follow previously published methods and will include flow cytometry, ELISA 
assays, ELISPOT assays, Affymatrix analyses, microRNA analyses, Western blot and reverse-phase 
protein array analyses. 90 cc of blood will be collected pre-therapy at baseline, at 8 weeks and 16 weeks, 
and at progression. Blood will be processed by standard ficoll methods and immunological studies will 
be conducted on obtained PBMCs and plasma.   
When feasible, pre-treatment tissue samples leftover from routine diagnostic procedures will be 
collected for the proposed correlative studies.  In addition, residual pathological material may be 
collected for patients who undergo procedures while on therapy.   Specific biological markers will be 


 
 
 
Protocol 2011-0358 
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assayed, focusing on factors associated with angiogenic signaling, and the activity and viability of specific 
cell types within the tumor, including the MAP kinase pathway, and the PI3K pathway with a focus on 
signaling molecules downstream of mTOR.  A tissue microarray will be generated from nephrectomy or 
metastasectomy blocks from patients enrolled on the trial. For patients where blocks are not available 
selected staining may be performed on biopsy material where indicated. Specifically, to evaluate the 
MAP kinase and PI3K pathways, ERK, phospho ERK, p38, phospho p38, Akt phospho Akt, S6 kinase, 
phospho S6 kinase S6, phospho S6 and EIF4E and VEGF isoforms will be assayed using 
immunohistochemical techniques.  In addition, p27 levels and its subcellular localization, Ki67 levels, and 
the TUNEL assay will be performed to evaluate the effect of temsirolimus and pazopanib on cell cycle, 
proliferation and apoptosis in endothelial, stromal and tumor cells. Other biomarkers may be added as 
appropriate to contextualize the information gathered from the above assays. To assess the effect of 
temsirolimus and pazopanib on angiogenesis, endothelial FGFR, VEGFR2, Tie-2 and PDGFR levels and 
phosphorylation states will be assayed using coimmunofluorescence techniques. In addition, we will also 
evaluate the potential effect of temsirolimus, and pazopanib on the expression of TGF-α, which has 
been suggested to be a prognostic factor in RCC patients, and may increase RCC growth via an autocrine 
loop.  Oligonucleotide array analysis will also be performed to detect global patterns in pre-treatment 
tumor samples. Since chromosome copy number alterations have been shown to be associated with 
outcomes of clear-cell RCC, we will determine whether chromosomal imbalances identified with SNP 
arrays could be used as predictors of response to these agents. We will obtain archival FFPE tumor 
samples and extract DNA from the FFPE tissue sections for analysis with Affymetrix 250K Nsp SNP 
microarrays to identify genomic imbalances and loss of heterozygosity (LOH) (Samples will be sent to Dr. 
Federico Monzon at Baylor College of Medicine for SNP Analysis, please see Appendix G for procedural 
details).  
By performing these studies, we aim to generate correlative information that will permit improved 
therapeutic applications in the future.   
We also aim to evaluate the loss of SETD2 histone methyltransferase activity, its effect on the decreases 
of H3K36 trimethylation (H3K36Me3) and the possible promotion of tumorigenesis in RCC. (Samples will 
be sent to Dr. Thai Ho at Mayo Clinic – Scottsdale, AZ for analysis, please see Appendix H for procedural 
details.) 
 
 
 
9.0 STUDY CALENDAR  
 
In the event that the patient’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy. All evaluations will have a standing 
window of allowance equal to +/- 3 days.  


 
 
 
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Screening 
Weekly  
Every 4 
Weeks 
Every 8 
Weeks 
Every 16 
Weeks 
Off Treatment q,r 
History & Physical Exam 
xa 
 
xp 
xh 
 
 
Concomitant Meds 
xa 
 
xp 
xh 
 
x 
Vital Signs incl. Weight 
xa 
xb 
xp 
xh 
 
 
Height 
xa 
 
 
 
 
 
Performance Status 
xa 
 
 
 
 
 
CBC w/ Dif & Plts. 
xa 
xe,p 
xe 
xe 
 
 
Serum Chemistryd 
xa 
xs 
xs 
xh,s 
xh,s 
 
Lipid Panel 
xa 
 
xe 
xe 
xe 
 
Amylase 
xa, f 
 
xf 
 
 
 
Lipase 
xa, f 
 
xf 
 
 
 
PT/PTT 
xa 
 
 
 
 
 
ßHCGg 
xa 
 
 
 
 
 
Free T4 & TSH h 
xa 
 
 
xh 
 
 
Urinalysis 
xa 
 
 
Xh,i 
 
 
Radiological Evaluationj 
xk 
 
 
x 
Xt 
 
Electrocardiogram 
xk 
 
xf,n 
 
xp 
 
Echocardiogram or MUGA 
scan 
xm 
 
Repeated every 24 weeks 
 
 
Screening 
                      Every 8  weeks               off treatment 
Adverse Event Monitoring 
 
Adverse Events will be monitored throughout 
Quality of Life battery 
xa 
 
 
x 
 
 
Optional Blood Collectionl 
xa 
 
 
x 
 
x 


 
 
 
Protocol 2011-0358 
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Page 38 
 
 
Optional Tissue 
Collectionc,o 
-------------------------------------------------------------- 
 
a. Within 14 days of registration 
b. Only the blood pressure must be monitored weekly for the 1st 4 weeks on study in patients receiving 
pazopanib. This may be performed at a doctor's office or using any calibrated electronic device.   
c. 
Previously collected tissue, will be requested from patients who consent. This tissue may come from MD 
Anderson or an outside institution. Tissue will be requested, once the study is closed to new patient entry, to 
allow for batch analysis. No new procedures will be required. This tissue will also be banked for future 
research related to immunologic response. 
d. Serum chemistry consists of total protein, albumin, alkaline phosphatase, AST and ALT, calcium, LDH, total 
bilirubin, BUN, creatinine, phosphorus, glucose, sodium, potassium, chloride, carbon dioxide. 
e. CBC with platelet count and differential will be done every 2 weeks for the first 8 weeks,every 8 weeks x 2, 
and every 16 weeks thereafter, for patients on pazopanib. For patients on temsirolimus, a CBC with platelet 
count and differential will be done weekly.   Fasting lipid panel will be done every 4 weeks for the first 8 
weeks, every 8 weeks x 2, and every 16 weeks thereafter, for those patients receiving temsirolimus . 
f. 
As clinically indicated 
g. Female patients of child-bearing age must have a negative pregnancy test within 7 days of beginning 
treatment. 
h. Patients receiving pazopanib only 
i. 
Urinalysis. If patient has urine protein ≥ 300 on UA, a random UPC ratio should be ordered. 
j. 
CT Chest, abdomen and pelvis. MRI of the brain (bone scan, plain films) should be obtained as appropriate. 
MRI of the abdomen and/or CT scan of the brain can be substituted at the physician’s discretion.). 
k. 
Within 4 weeks of study entry  
l. 
Optional blood collection for future correlative studies will be drawn at baseline, every 8 weeks, and at Off 
Treatment Visit. 
m. Within 12 weeks of study entry 
n. Patients receiving pazopanib will have a follow-up ECG at C2D1, 12 weeks later, and every 16 weeks 
thereafter.  
o. Tissue will also be collected during procedures performed, at any time point, while patients are enrolled in 
this study. No new procedures will be required. This tissue will also be banked for future research related to 
immunologic response. 
p. Patients receiving temsirolimus 
q. In 30 days after stopping therapy 
r. 
Long-Term Follow-Up for survival will occur every 3 months from final study therapy.  Follow-up will consist 
of a phone call, e-mail correspondence or medical record review. 
s. 
Every 2 weeks for the first 8 weeks (both arms). Temsirolimus patients  every 4 weeks thereafter.  Pazopanib 
patients every 8 weeks x 2 and every 16 weeks thereafter. 
t. 
Patients who are progression free after 1 year can have their imaging studies obtained every 16 weeks. 
 
10.0 CRITERIA FOR RESPONSE AND PROGRESSION  
10.1 Definitions  
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee. Changes in 
only the largest diameter (unidimensional measurement) of the tumor lesions are used in the 


 
 
 
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RECIST criteria. Note: Lesions are either measurable or non-measurable using the criteria 
provided below. The term “evaluable” in reference to measurability will not be used because it 
does not provide additional meaning or accuracy.  
 
10.1.1 Measurable disease  
 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm with conventional techniques 
(CT, MRI, x-ray) or as >10 mm with spiral CT scan. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). In patients with primary 
tumor in place, the primary tumor will not be considered a site of measurable disease.  
10.1.2 Non-measurable disease  
 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm 
with conventional techniques or <10 mm using spiral CT scan), are considered non-
measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses 
(not followed by CT or MRI), and cystic lesions are all non-measurable.  
10.1.3 Target Lesions  
 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically). A sum of the longest 
diameter (LD) for all target lesions will be calculated and reported as the baseline sum 
LD. The baseline sum LD will be used as reference by which to characterize the objective 
tumor response.  
10.1.4 Non-Target Lesions  
 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Non-target lesions include measurable lesions that 
exceed the maximum numbers per organ or total of all involved organs as well as non-
measurable lesions. Measurements of these lesions are not required, but the presence 
or absence of each should be noted throughout follow-up.  
10.2 Guidelines for Evaluation of Measurable Disease  
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment.  


 
 
 
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The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumor effect of a treatment.  
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
Conventional CT and MRI: These techniques should be performed with cuts of 10 mm or less in 
slice thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. This applies to tumors of the chest, abdomen, and pelvis. Head and 
neck tumors and those of extremities usually require specific protocols.  
Ultrasound (US): When the primary endpoint of the study is objective response evaluation, US 
should not be used to measure tumor lesions. It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules. 
US might also be useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination.  
Endoscopy/Laparoscopy: The utilization of these techniques for objective tumor evaluation has 
not yet been fully and widely validated. Their uses in this specific context require sophisticated 
equipment and a high level of expertise that may only be available in some centers. Therefore, 
the utilization of such techniques for objective tumor response should be restricted to validation 
purposes in reference centers. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained.  
Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. Specific additional criteria for standardized usage of prostate-specific antigen 
(PSA) and CA-125 response in support of clinical trials are being developed.  
Cytology/Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain).  
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease.  
10.3 Response Criteria  
 


 
 
 
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10.3.1 Evaluation of Target Lesions  
 
Complete Response (CR): Disappearance of all target lesions  
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of 
target lesions, taking as reference the baseline sum LD  
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the treatment started or the 
appearance of one or more new lesions  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the treatment started  
10.3.2 Evaluation of Non-Target Lesions  
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level  
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits  
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Although a clear progression of “non-target” 
lesions only is exceptional, in such circumstances the opinion of the treating physician 
should prevail, and the progression status should be confirmed at a later time by the 
review panel (or study chair).  
Note: If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response.  
10.3.3 Evaluation of Best Overall Response  
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria.  
 
Target Lesions  
Non-Target Lesions  New 
Lesions  
Overall Response  
CR  
CR  
No  
CR  
CR  
Incomplete  
No  
PR  
response/SD  
PR  
Non-PD  
No  
PR  
SD  
Non-PD  
No  
SD  
PD  
Any  
Yes or No  
PD  


 
 
 
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Any  
PD  
Yes or No  
PD  
Any  
Any  
Yes  
PD  
Note:  
 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration.” Every effort should be made to 
document the objective progression, even after discontinuation of treatment.  
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) 
before confirming the complete response status.  
 
10.4 Confirmatory Measurement/Duration of Response 
10.4.1 Duration of overall response  
 
The duration of overall response is measured from the time measurement criteria are 
met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented.  
10.4.2 Duration of Stable Disease  
 
Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the 
treatment started.  
 
 
 
 
11.0 Serious Adverse Event Reporting (SAE)    
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
• 
Death 
• 
A life-threatening adverse drug experience – any adverse experience that places the patient, in the 
view of the initial reporter, at immediate risk of death from the adverse experience as it occurred. It 
does not include an adverse experience that, had it occurred in a more severe form, might have 
caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is for: 


 
 
 
Protocol 2011-0358 
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• 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• 
elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication 
under study and has not worsened since the start of study drug 
• 
treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of 
a SAE given above and not resulting in hospital admission 
• 
social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
• 
Important medical events as defined above, may also be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the 
Principal Investigator. All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the timeframes and procedures 
outlined in “The University of Texas M. D. Anderson Cancer Center Institutional Review Board (IRB) 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices”.  For this 
protocol adverse events will be captured according to the Recommended Adverse Event Recording 
Guideline for Phase II protocols (below). 
 
 
Recommended Adverse Event Recording Guidelines 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
 
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase I 
Phase II   


 
 
 
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Phase III 
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II  
 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
 
The Investigator or physician designee is responsible for verifying and providing source documentation 
for all adverse events and assigning the attribution for each event for all subjects enrolled on the trial 
•   Serious adverse events will be captured from the time of the first protocol-specific intervention, 
until 30 days after the last study treatment/intervention, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or there has 
been acceptable resolution of the event. 
• 
Additionally, any serious adverse events that occur after the 30 day time period that are related 
to the study treatment must be reported In accordance with the IRB policy. This may include the 
development of a secondary malignancy. 
 
Reporting to FDA: 
• 
 SAE’s will be reported per regulatory (local and federal) guidelines. 
 
It is the responsibility of the PI and the research team to ensure that serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the supporter guidelines, and Institutional Review Board policy. 
Investigator Communication with Supporting Companies: 
Reporting to Novartis for patients taking Pazopanib 


 
 
 
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All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A 
(MedWatch Form).  
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
• 
after the patient has provided informed consent and until at least 30 days after the patient 
has stopped study treatment/participation 
• 
after protocol-specified procedures begin (e.g., placebo run-in, washout period, double-
blind treatment, etc.) and 30 days after the patient has stopped study treatment 
• 
after the start of any period in which the study protocol interferes with the standard 
medical treatment given to a patient (e.g., treatment withdrawal during washout period, 
change in treatment to a fixed dose of concomitant medication) and until 30 days after the 
patient has stopped study treatment 
All Events must be reported to Novartis within 24 hours of learning of its occurrence  
Information about all SAEs is collected and recorded on a Serious Adverse Event Report Form; all 
applicable sections of the form must be completed in order to provide a clinically thorough 
report. The investigator must assess and record the relationship of each SAE to each specific 
study treatment (if there is more than one study treatment), complete the SAE Report Form in 
English, and send the completed, signed form by fax to (fax: 877-778-9739) within 24 hours to 
the oncology Novartis DS&E department with the provided FAX cover sheets. 
This includes serious, related, labeled (expected) and serious, related, unlabeled (unexpected) 
adverse experiences. All deaths during treatment or within 30 days following completion of 
active protocol therapy must be reported within 5 working days. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. Recurrent episodes, complications, 
or progression of the initial SAE must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. A SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event.  The end date of the first event must be provided. 
The original copy of the SAE Report and the fax confirmation sheet must be kept within the Trial 
Master File at the study site. 
Follow-up information is sent to the same fax number as the original SAE Report Form was sent, 
using a new fax cover sheet, stating that this is a follow-up to the previously reported SAE, and 
giving the date of the original report. Each re-occurrence, complication, or progression of the 
original event should be reported as a follow-up to that event regardless of when it occurs. The 


 
 
 
Protocol 2011-0358 
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follow-up information should describe whether the event has resolved or continues, if and how 
it was treated, whether the blind was broken or not (if applicable), and whether the patient 
continued or withdrew from study participation. 
If the SAE is not previously documented in the Pazopanib Investigator Brochure or Package 
Insert (new occurrence) and is thought to be related to the Novartis study drug, a DS&E 
associate may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN), to inform all investigators 
involved in any study with the same drug that this SAE has been reported. Suspected 
Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC 
or as per national regulatory requirements in participating countries. 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. 
 
 
12.0 CRITERIA FOR REMOVAL FROM PROTOCOL TREATMENT  
 
Subjects who meet the following criteria should be discontinued from study treatment:  
• 
Progressive disease: Patients, who develop rapidly progressive disease before the scheduled 
evaluation, may be taken off study at the discretion of the investigator, if they are not felt to 
be candidates to begin treatment with the second agent.  
• 
Intercurrent illness that, in the opinion of the treating physician/investigator, prevents 
continuation of treatment.  
• 
Decision of the patient to withdraw from the study, or patient non-compliance with therapy.  
• 
Grade ≥ 2 pulmonary or CNS hemorrhage; any Grade 4 hemorrhage  
• 
Any grade arterial thromboembolic event  
• 
Grade 4 congestive heart failure  
• 
Gastrointestinal perforation  
• 
Wound dehiscence requiring surgical intervention  
 


 
 
 
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13.0 STATISTICAL CONSIDERATIONS 
This is a randomized, two-arm, parallel group, phase II trial enrolling advanced, poor-risk, clear-cell RCC.  
Patients will be fairly randomized to either temsirolimus (control arm) or pazopanib (experimental arm).  
The maximum sample size to be accrued is 90 patients (45 in each treatment arm).  The primary 
measure of efficacy and primary endpoint is progression free survival (PFS).  PFS will be monitored on an 
interim basis and we will use stopping rules for futility to serve as guidelines for early termination.  The 
stopping rules are ad-hoc in nature but are selected in a manner such that the overall type 1 error is 
controlled at a one-sided 10% with 80% power. 
Descriptive and inferential statistics will be used to summarize treatment effects.  The mean, standard 
deviation, median, 25% percentile, 75% percentile, minimum, and maximum will be reported for 
continuous variables.  For discrete variables, descriptive analyses will be based on the distribution of 
discrete outcomes and will be reported as percentages and patient counts. Time to event endpoints will 
be descriptively summarized by Kaplan-Meier curves.  Point and interval estimates of treatment effect 
will be based on maximum likelihood methods.  For binomially distributed variables, we will report 
differences in proportions between treatment groups and the 95% confidence interval associated with 
those differences.  We will estimate treatment effects for time to event variables via hazard ratios using 
Wald scores from Cox proportional hazard regression models.  Unless stated otherwise, all statistical 
tests will be assessed using a two-sided a= 0.05 alpha significance level and confidence intervals will be 
constructed using two-sided 95% and will be based on the normal approximation.  Although multiple 
secondary endpoints will be evaluated we will make no adjustment for multiplicities associated with 
these multiple tests. 
Estimation of Sample Size 
The clinical hypothesis we are assessing in this trial is whether patients receiving the experimental 
therapy have a lower hazard of progression or death relative to patients receiving the control therapy.  
The statistical hypothesis is stated as: 
H0: 
log(HR)=0 
HA: 
log(HR)<0 
Where HR is the hazard ratio (experimental:control).  For sample size calculation purposes we assume 
that the median PFS in the temsirolimus arm is 60% that of the pazopanib arm (3.8 months versus 6.1 
months).  The sample size estimate is based on a one-sided log-rank test with type one error equal to 
0.10 and power of 0.80.   
We will conduct an interim analysis for futility after 42 events have been observed.  If the p-value used 
to assess futility at the interim analysis is greater than 0.4798 we will stop the trial early for futility.   


 
 
 
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Secondary Objectives 
 
Overall survival: Overall survival is calculated from day of therapy initiation to the date of death.  
Patients who are lost to follow-up will be censored at date of last contact.   
We will use the Kaplan-Meier estimator to estimate the OS for each group of patients (control, 
experimental), and the log-rank statistic will be used to test for treatment differences.  We will also use 
the Cox proportional hazards regression model to estimate the hazard ratio (experimental:control) for 
OS with a 95% confidence interval. 
We will also assess the response rate and report 95% confidence intervals. 
 
Additional analyses: 
 
Demographics   
For each treatment group (control, experimental), summary statistics will be provided for age, 
weight, baseline disease status and prior treatments. 
 
Toxicities 
 Toxicities and side effects that will be evaluated include, but are not limited to infections, renal 
toxicity, hepatic toxicity, and pulmonary toxicity.  Methods of assessment will include 
monitoring blood counts, and performing laboratory tests as indicated by clinical signs and 
symptoms. Evidence of toxicities or adverse events will be recorded at all clinic visits.  All 
observed toxicities and side effects will be graded (NCI CTC-AE v. 4.0) for all patients and the 
degree of association of each with pazopanib or temsirolimus assessed.  The incidence and 
severity of toxicities will be compared between the two treatment arms with Fisher’s exact test. 
 
Stratification Factors 
The Pocock-Simon Minimization Method will be used to randomize patients according to the 
following stratification factors: 
− Prior nephrectomy status (yes or no) 
− Prior cytokine/vaccine therapy (yes or no) 
The randomization program based on this method will be developed in the Department of 
Biostatistics and Applied Mathematics, and the program will be available via an intranet web 
site of MD Anderson Cancer Center.  
Data Analyses for Quality of Life Measures  
Prior to inferential procedures, extensive descriptive analyses will be conducted for each of the 
measures obtained at each session.  Descriptive statistics (e.g., means, ranges, standard 
deviations) will be computed, together with ninety-five percent confidence intervals for the 
means.  Proportions of subjects falling outside normative ranges for the stress and QOL 
measures will also be calculated.  Values for the standardized scales will be compared to 
normative data and patients receiving other types of cancer therapy.  Graphical methods (e.g., 
boxplots and histograms) will be employed to more closely examine the distributions of the 


 
 
 
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measures at each time point.  Change scores for the stress and QOL measures will be computed 
as the simple differences between the baseline measure and subsequent evaluations.  Bivariate 
associations between the raw scores, the change scores, optimism, social support, and 
demographic variables will be evaluated using Pearson’s product moment correlation 
coefficients together with scatterplots where appropriate.  These procedures will allow us to 
thoroughly characterize the stress and QOL profiles of this patient population across the 
sessions. 
In this study, numerous models will be constructed to analyze the data and, therefore, the 
results will be treated as hypothesis generating and interpreted with caution.  Inferential 
statistics will comprise paired t-tests of the stress and QOL measures.  Significant test results (p 
< .05) will be interpreted as indicating significant changes in depression and QOL associated with 
the treatment.    The association between depression and survival and TTP will also be 
examined. 
14.0 REPORTING AND EXCLUSIONS  
14.1 Evaluation of toxicity:  
 
Patients will be evaluable for toxicity related to the targeted therapy given in the first stage and 
in the second stage.  
 
14.2 Evaluation of response:  
 
All patients who are registered and assigned to treatment will be assessed for response.  
All patients who met the eligibility criteria (with the possible exception of those who received no 
study medication) should be included in the main analysis of the response rate. Patients with an 
incorrect treatment schedule or drug administration does not result in exclusion from the 
analysis of the response rate. Precise definitions for categories 4-8 will be protocol specific.  
All conclusions should be based on all eligible patients. Sub-analyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.). However, these sub-analyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported. Data analysis will be performed using SAS or S-Plus, as 
appropriate. Patients who die of unrelated cause during therapy or are lost to follow-up shall be 
censored. 
 
15.0 DATA AND PROTOCOL MANAGEMENT  
15.1 Protocol Compliance  
 
The attending physician or designee will see each patient for evaluation of tumor response and 
toxicity every 8 weeks. All required interim and pretreatment data should be available, and the 
physician must make a designation as to tumor response and must provide a detailed description 


 
 
 
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of toxicity, when appropriate. If dose modifications or treatment interruptions are necessary, the 
details must be carefully documented.  
 
15.2 Data Entry  
 
Data will be entered into the GURU database at MD Anderson Cancer Center. GURU is a password 
protected database with an audit trail. Data can be collated with a unique GURU identification in 
order to de-link information.  
 
15.3 Accuracy of Data Collection  
At an appropriate time, an independent panel of hired radiologists will review all imaging 
studies to assess progressive disease and response in each patient, but the principal investigator 
at each institution will be responsible for decision regarding the treatment phases of each 
patient on this trial. 
15.4 Study Drug Destruction  
The institution will destroy any supplies of investigational product and other study medications 
that expire during this trial, as well as all supplies that remain unused at the termination of this 
trial. Institution will destroy these materials in accordance with all applicable regulations, 
governmental guidelines, and institutional policies. 
16.0 INVESTIGATOR OBLIGATIONS  
 
16.1 Review for institutional review as set forth in 21 CFR, Part 56 will be followed. Requirements 
for informed consent as set forth in 21 CFR, Part 50, will be followed. The investigator will keep 
the IRB informed as to the progress of the study as well as to any serious or unusual adverse 
events.  
 
16.2 All protocol amendments and consent form revisions will be reviewed and approved by the 
MDACC IRB prior to implementation. Any change to the protocol intended to eliminate any 
immediate risk to patients may be implemented immediately, but IRB must be notified at the 
time and a protocol amendment must subsequently submitted for approval.  
 
   Prior to initiation of therapy, the investigator will obtain a written informed consent from each 
patient, or their authorized representative, participating in the study. The consent form must be 
signed, witnessed and dated. The consent will contain all the essential elements of informed 
consent set forth in 21 CFR, Part 50.  
 
16.3 Detailed case summaries will be generated for every patient from the database.  
 
16.4 Patient Confidentiality: In order to maintain patient privacy, all database generated case 
report forms, study drug accountability records, study reports and communications will identify 
the patient by initials and the assigned patient number. The patient’s confidentiality will be 


 
 
 
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maintained and will not be made publicly available to the extent permitted by the applicable 
laws and regulations (21CFR312.63, 21CFR312.68). don’t we have a better paragraph? 
 
16.5 Record Retention: Study records include IRB approved protocol and informed consent, 
including historical copies of both, investigational drug brochure, signed informed consent 
forms, documentation of IRB approval, study forms, database-generated case report forms and 
source documents which allow verification of the case report forms. NO this needs to be more 
departmentally oriented. 
17.0 REFERENCES  
1. Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, et al. Randomized 
phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin 
kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 
2004;22:909-18. 
2. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, 
interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-81. 
3. Hurwitz HI, Dowlati A, Saini S et al. Phase I trial of pazopanib (GW786034), an oral 
multikinase angiogenesis inhibitor, in patients with advanced cancer: results of safety, 
pharmacokinetics, and clinical activity. Clin. Cancer Res. 15, 4220–4227 (2009). 
4. Hutson TE, Davis ID, Machiels JH et al. Efficacy and safety of pazopanib in patients with 
metastatic renal cell carcinoma. J. Clin. Oncol. 27, 475–480 (2010).  
5. Pavlakis N. Drug treatment of renal cancer. Aust Prescr 2006;29:151-3. 
6. Sternberg CN et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results 
of a randomized phase III trial. J Clin Oncol. 2010;28:1061–8.