Conditions: Carcinoma, Renal Cell
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 16
Healthy volunteers: no

Brief summary:
Pazopanib is an orally administered multi-kinase inhibitor targeting VEGFR (vascular endothelial growth factor receptor), PDGFR (platelet derived growth factor) and c-kit, which are critical to growth and proliferation of neoplastic cells. Pazopanib has been FDA approved for advanced renal cell carcinoma (RCC) with a clear cell component. Conventional Pazopanib dosing WITHOUT FOOD is with an initial dose of 800 mg by mouth daily. Investigators hypothesize that administration of pazopanib with low fat meal would be safe and feasible with secondary implications of higher pazopanib levels; potentially translating into greater anti-tumor efficacy in advanced renal cell cancer, with significant cost savings. In the proposed pilot study, investigators seek to test the feasibility and practicality of this approach and gather preliminary data on adverse effects and the safety profile. Investigators hope to ameliorate any potential for greater toxicities with a dynamic dosing design that incorporates adverse events from each cycle into dosing for the next cycle and a structured symptom specific plan.

Detailed description:

Arms:
arm 1: Registered subjects will take pazopanib by mouth with a low-fat meal (containing less than 400 calories and less than 10% fat or 10 grams per meal) approximately, some sample meals are described in appendix 1) every day in 14 day cycles, with a starting dose of 400 mg and adjusted for the next cycle (dose level +1:600 mg; dose level +2: 800 mg; dose level -1: 200 mg) based on toxicity assessment during or at the end of each cycle.

Interventions: intervention 1: Pazopanib intervention 2: Low Fat Diet
Intervention descriptions: intervention 1: None intervention 2: Registered subjects will take pazopanib by mouth with a low-fat meal (containing less than 400 calories and less than 10% fat or 10 grams per meal.

Protocol document:
Prot_SAP_000.pdf: 
i. 
 
 
PROTOCOL UMCC 2016.013 
Pilot Study of Pazopanib with Low Fat Meal (PALM) in advanced renal cell carcinoma 
 
Principal Investigator:  
Ajjai Alva, MD  
 
 
 
 
University of Michigan  
 
 
 
 
7316 Cancer Center 
 
 
 
 
1500 E. Medical Center Drive 
 
 
 
 
Ann Arbor, MI 48109 
 
 
 
 
Phone: (734) 936-0091 
 
 
 
 
Fax:     (734) 615-2719 
 
 
 
 
Email: ajjai@med.umich.edu 
 
Sub-Investigator(s): 
 
Maryann Shango, MD  
 
 
 
 
Hematology/Oncology  
 
 
 
 
University of Michigan  
 
 
 
 
 
Bruce Redman, DO 
 
 
 
 
Hematology/Oncology  
 
 
 
 
University of Michigan  
 
 
 
 
 
Sarah Yentz, MD 
 
 
 
 
Hematology/Oncology 
 
 
 
 
University of Michigan 
 
 
 
 
 
Shawna Kraft, Pharmacist  
 
 
 
 
Pharmacy  
 
 
 
 
University of Michigan 
 
Research Staff: 
 
Danielle Karsies, MS, RD, CSO 
 
 
 
 
Lead Dietitian Senior 
 
 
 
 
C435 Med Inn Building, Box 5843 
 
 
 
 
Phone: (734) 232-1643 
 
Research Staff: 
 
Bo Wen, Manager 
 
 
 
 
Pharmacokinetics Core, College of Pharmacy 
 
 
 
 
University of Michigan 
 
 
 
 
Room 3400 of Building 520,  
 
 
 
 
North Campus Research Complex 
 
 
 
 
1600 Huron Parkway 
 
 
 
 
Ann Arbor, MI 48109. 
 
 
 
 
Phone: (734) 615-3470 
 
 
 
 
 
Biostatistician: 
 
Stephanie Daignault, MS  
 
Statistician Senior 
 
 Center for Cancer Biostatistics  
 
 
 
 
M2180 SPH II, University of Michigan 
 
 
 
 
Ann Arbor MI 48109-2029 
 
 
 
 
 
 
 
 
Phone: (734) 647-3271 
 
 
 
 
Email: sfaruzzi@med.umich.edu 
 
 
 
 
 
 
 
 
 
 
Study Drug: 
 
 
Pazopanib, sold under the brand name Votrient 
 
 


Protocol UMCC 2016.013 
 
 
Page ii of v 
 
 
Initial version:  
 
7/16/15 
Amendment One version: 
6/10/16 
Amendment Two version 
8/16/16 
Amendment Three version 
10/3/16 
 
IND: 
 
 
Exempt 
 
Funding Support: 
 
CTRAC 
 
Drug Supply: 
 
 
Commercially Available 
 
 
 


Protocol UMCC 2016.013 
 
 
Page iii of v 
 
 
TABLE OF CONTENTS 
ABBREVIATIONS ........................................................................................................................... 1 
STUDY SYNOPSIS .......................................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE ...................................................................................... 5 
1.1 
Disease Background........................................................................................................ 5 
1.2 
Rationale .......................................................................................................................... 6 
1.3 
Schema ............................................................................................................................ 7 
2.0 
STUDY OBJECTIVES ........................................................................................................... 8 
2.1 
Primary Objectives ........................................................................................................... 8 
2.2 
Secondary Objectives ...................................................................................................... 8 
2.4 
Endpoints ......................................................................................................................... 8 
3.0 
PATIENT ELIGIBILITY .......................................................................................................... 8 
3.1 
Inclusion Criteria .............................................................................................................. 8 
3.2 
Exclusion Criteria ............................................................................................................. 9 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES ........................................ 9 
5.0 
TREATMENT PLAN ............................................................................................................ 10 
5.1 
Treatment Dosage and Administration .......................................................................... 10 
5.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 10 
5.3 
Concomitant Medications/Treatments ........................................................................... 13 
5.4 
Duration of Therapy ....................................................................................................... 13 
5.5 
Off Treatment Criteria .................................................................................................... 13 
5.6 
Duration of Follow-Up .................................................................................................... 13 
5.7 
Off Study Criteria ........................................................................................................... 14 
5.8 
Patient Replacement ..................................................................................................... 15 
6.0 
STUDY PROCEDURES ....................................................................................................... 15 


Protocol UMCC 2016.013 
 
 
Page iv of v 
 
 
6.1 
Pharmacokinetic assesment …………………………………………………………………15 
6.2  
Screning/Baseline Procedures ...................................................................................... 15 
6.3 
Procedures During Treatment ....................................................................................... 16 
 
 
6.4 
Time and Events Table/Study Calendar ........................................................................ 17 
7.0 
MEASUREMENT OF EFFECT ............................................................................................ 19 
7.1 
Antitumor Effect- Solid Tumors ...................................................................................... 19 
7.2 
Safety/Tolerability .......................................................................................................... 23 
8.0 
ADVERSE EVENTS ............................................................................................................. 23 
8.1 
Experimental Therapy.................................................................................................... 23 
8.2 
Adverse Event Reporting Requirements ....................................................................... 23 
8.3 
Definitions ...................................................................................................................... 24 
8.4 
Adverse Event Characteristics ...................................................................................... 25 
8.5 
Serious Adverse Event Reporting Guidelines ............................................................... 26 
8.6 
Routine Reporting .......................................................................................................... 26 
8.7 
Reporting of Unanticipated Problems ............................................................................ 26 
8.9 
Stopping Rules .............................................................................................................. 27 
9.0 
DRUG INFORMATION ........................................................................................................ 27 
9.1 
Agent Pazopanib  .......................................................................................................... 27 
10.0 CORRELATIVES/SPECIAL STUDIES ................................................................................ 29 
11.0 
STATISTICAL CONSIDERATIONS .................................................................................. 30 
11.1 
Study Design/Study Endpoints ...................................................................................... 30 
11.2 
Sample Size and Accrual .............................................................................................. 30 
12.0 DATA AND SAFETY MONITORING ................................................................................... 31 
13.0 
REFERENCES ................................................................................................................... 31 


Protocol UMCC 2016.013 
 
 
Page ii of v 
 
 
 
APPENDICES .................................................................................................................... 32 


Protocol UMCC 2016.013 
 
Page 1 of 34 
 
ABBREVIATIONS: 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure  
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTO 
Clinical Trials Office 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECG  
Electrocardiogram  
EF 
Ejection fraction  
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
HTN 
Hypertension  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
LFTs 
Aspartate aminotransferase, alanine aminotransferase and total bilirubin  
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
RCC 
Renal Cell Carcinoma  
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PO 
per os/by mouth/orally 
PR 
Partial Response 
PRC 
Protocol Review Committee 
PPI  
Proton Pump Inhibitor  
SAE 
Serious Adverse Event 
SD 
Stable Disease 
TTE  
Transthoracic echocardiogram  
UaP 
Unanticipated Problem 
ULN 
Upper Limit Normal  
UMCCC 
University of Michigan Comprehensive Cancer Center 


Protocol UMCC 2016.013 
 
Page 2 of 34 
 
UPC 
Urine protein to creatinine 
VEGF/VEGFR 
Vascular endothelial growth factor/vascular endothelial growth factor receptor  
WBC 
White Blood Cells 
 
 
STUDY SYNOPSIS 
 
Title 
Pilot Study of PAzopanib with Low Fat Meal (PALM) in advanced renal 
cell carcinoma. 
Phase 
Feasibility pilot study  
Methodology 
Open-label  
Study Duration 
1 year of accrual. 
Study Center(s) 
Single-center   
Objectives 
 
Primary Objectives 
• 
To determine the safety and feasibility of pazopanib given with a 
low fat meal for therapy of metastatic renal cell carcinoma. 
 
Secondary Objectives 
• 
To determine the overall response rate to pazopanib given with 
a low fat diet in first-line therapy of metastatic renal cell 
carcinoma. 
• 
To explore PK characteristics (Cmax) of pazopanib taken with a 
low fat meal. 
 
Number of Subjects 
 
16 with interim analysis for safety after 8 subjects have been treated with 
pazopanib for at least 4 weeks. 
 
Inclusion Criteria 
1. Adult (>18 years old) patient with unresectable locally advanced or 
metastatic RCC with a clear cell component 
2. Measurable disease per RECIST 1.1 criteria  
3. No prior pazopanib therapy  
4. Subject must have ECOG PS of ≤2 
5. Subject must be willing to take pazopanib with a low-fat meal per 
protocol  
6. Subjects are permitted to have had up to 3 prior VEGF or VEGFR 
targeted therapies, plus any number of prior cytokine therapies 
(e.g.IL-2) or checkpoint inhibitor therapy (e.g. anti-PD1/PDL1, anti-
CTLA4) or mTOR  inhibitor therapy(e.g. everolimus, temsirolimus) 
7. Platelets > 100,000 mm3, ANC > 1000 mm3 and AST/ALN < 1.5 X 
ULN; Total Bilirubin < 1.5 times ULN  
8. Subject must be willing to discontinue any proton pump inhibitors/ 
strong CYP34A4 inducers or inhibitors (section 9.1)  
9. Agree to use effective contraception and stop simvastatin if on it. 
 


Protocol UMCC 2016.013 
 
Page 3 of 34 
 
Exclusion Criteria 
1. Any concurrent health condition that in the view of the treating 
physician would pose excessive risk to the subject if he/she is 
enrolled in the study.  
2. Subjects with a history of hemoptysis, cerebral hemorrhage or 
clinically significant GI hemorrhage or myocardial infarction (MI) 
within the past 6 months.  
3. Patients at significant risk for GI perforation or fistula.  
4. Pregnant or nursing mothers. 
5. Untreated CNS metastasis. If treated CNS metastasis/es, such 
treatment must have been completed at least 30 days prior to 
registration. 
6. Subjects with Cirrhosis, HIV, Hepatitis B or C 
7. Averaged QTc baseline in 3 ECGs at least 5 minutes apart of ≥450 
ms. 
8. Congestive Heart Failure (NYHA Class III/IV), LVEF <50% at 
baseline. 
 
Study Product(s), Dose, 
Route, Regimen 
 
Pazopanib 400mg (starting dose) PO daily with low-fat meal (LFM) in 14 
day cycles.  
Pazopanib may be increased to 600 mg and subsequently to 800 mg PO 
with low-fat meal daily starting with second cycle if the prior dose is 
tolerated.  
Pazopanib may be decreased to 200 mg PO with low-fat meal daily 
starting with second cycle if the starting dose is NOT tolerated. 
Pazopanib dose may be adjusted every 2 weeks based on toxicities. No 
re-escalation of dose is allowed. 
 
Duration of Administration 
 
Until progression of disease or unacceptable toxicity or withdrawal from 
protocol therapy or after 6 cycles (12 weeks) of Pazopanib treatment.   
 
Statistical Methodology 
 
The feasibility and safety of Pazopanib with low-fat meal will be 
assessed based on the following statistics with a 95% confidence 
interval around the reported statistic: frequency of toxicity, severity of 
toxicities (according to CTCAE version 4.03 criteria), frequency of dose-
reductions, duration of therapy, and mean or median total dose taken.  
 
 
 
 


Protocol UMCC 2016.013 
 
Page 4 of 34 
 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Background 
Pazopanib is an orally administered multi-kinase inhibitor targeting VEGFR (vascular 
endothelial growth factor receptor), PDGFR (platelet derived growth factor) and c-kit, 
which are critical to growth and proliferation of neoplastic cells. Pazopanib has been FDA 
approved for advanced renal cell carcinoma (RCC) with a clear cell component. This 
approval was based on phase 3 clinical trial results in adult patients with measurable, 
locally advanced, and/or metastatic RCC with either no prior therapy or one prior cytokine 
therapy randomly assigned 2:1 to receive oral pazopanib (800 mg once daily on an 
empty stomach) or placebo1. The primary end point was progression-free survival (PFS). 
Secondary end points included overall survival, objective tumor response rate (RECIST 
criteria) and safety. Of the 435 patients enrolled, 233 were treatment naive (54%) and 
202 were cytokine pretreated (46%). Progression free survival was significantly 
prolonged with pazopanib compared with placebo in the overall study population 
(median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001). 
In pre-planned subset analyses, pazopanib prolonged PFS in both treatment-naive 
subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < 
.0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 
0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% 
with pazopanib compared with 3% with placebo (P < .001), with a median duration of 
response longer than 12 months on pazopanib1.  
 
In a subsequent non-inferiority trial, pazopanib was compared to sunitinib in therapy of 
clear cell metastatic renal-cell carcinoma, in 1110 patients who were randomized in a 1:1 
manner to receive continuous pazopanib (800 mg once daily on an empty stomach; 557 
patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 
weeks without treatment; 553 patients)2. The primary end point was progression-free 
survival as assessed by independent review, and the study was powered to show non-
inferiority of pazopanib versus sunitinib. Secondary end points included overall survival, 
safety, and quality of life. Pazopanib was shown to be non-inferior to sunitinib with 
respect to progression-free survival (hazard ratio for progression of disease or death from 
any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined non-
inferiority margin (upper bound of the 95% confidence interval, <1.25). Overall survival 
was also similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). 
Patients treated with sunitinib, as compared with those treated with pazopanib, had a 
higher incidence of fatigue (63% vs. 55%), hand-foot syndrome (50% vs. 29%), and 
thrombocytopenia (78% vs. 41%). Patients treated with pazopanib had a higher incidence 
of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean 
change from baseline in 11 of 14 health-related quality-of-life domains, particularly those 
related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 
months of treatment favored pazopanib (P<0.05 for all 11 comparisons)2 
 
Pazopanib has since become one of the standard first line therapies in metastatic RCC3. 
If other agents are chosen in the first line setting, pazopanib is often used in subsequent 
lines of therapy.  
 
 
Pazopanib Dosing 
Conventional Pazopanib dosing WITHOUT FOOD is with an initial dose of 800 mg PO 
qday, with subsequent dose-reduction to 400mg or 600 mg daily as needed for toxicities.  
Pazopanib is routinely administered by mouth at least 1 hour before or at least 2 hours 
after food per the FDA approved package insert. These instructions are primarily to keep 
absorption of the medication fairly constant from one day to the next. When given as 
specified in the package insert, absolute bioavailability of the drug is only 21%. It is well 
known that fat in a meal co-administered with pazopanib results in higher absorption of 
the drug. Administration of pazopanib with a low or high fat meal has been studied in an 


Protocol UMCC 2016.013 
 
Page 5 of 34 
 
open-label, randomized, crossover, phase I study that evaluated the effect of low- and 
high-fat meals on the pharmacokinetics (PK) of pazopanib in patients with advanced solid 
tumors 4. Pazopanib is highly lipophilic, and therefore high fat meals can either potentiate 
the absorption of pazopanib, or reduce its solubility by stimulating gastric acid synthesis4. 
Six subjects were enrolled in a lead-in cohort. They received a single dose of pazopanib 
400 mg with a high-fat meal and were then monitored for safety for 8 days. Twenty-nine 
patients were then enrolled in the food-effect cohort and then randomized to receive two 
single doses of pazopanib 800 mg in either the fed condition (high- or low-fat meal) or 
fasting condition, in random sequence 14 days apart. After completion of the study, 
patients were given the opportunity to continue treatment with daily pazopanib 800 mg in 
the fasting state. Administration of pazopanib with either low- or high-fat meals had 
resulted in a similar magnitude of increase in the maximum observed plasma 
concentration (Cmax) and area under the plasma concentration-time curve (AUC) of 
approximately twofold as compared with the corresponding values when administered to 
patients in the fasted condition4.  
 
Pharmacokinetic studies have shown that pazopanib doses greater than 800mg daily in 
the fasting state did not increase systemic exposure of pazopanib at steady state, likely 
due to saturation of absorption in the gut4. Therefore, it is unclear at this time whether the 
increased Cmax and AUC of pazopanib when given with food will correlate with higher 
systemic exposure when these doses are given repeatedly daily with food. Furthermore, 
although Cmax and AUC were increased, the half-life of the drug was the same in 
patients who received pazopanib fasting or with food, indicating that administering 
pazopanib with food primarily affects its bioavailability4. This study did not control for the 
content and volume of meals the participants ate, and did not perform pharmacokinetic 
studies on continued dosing of pazopanib with food.  
 
Administration of pazopanib with food in the context of varying day to day diets could 
indeed result in excessive variability of absorption and systemic levels of the drug. But if 
pazopanib could be taken with meals of similar fat content daily, higher and fairly 
consistent absorption of the drug may possibly be achieved safely, potentially translating 
into equivalent or improved efficacy of pazopanib with smaller quantities of the drug 
compared to standard administration without food and with an acceptable safety profile.  
 
 
1.2 
Study Rationale 
1) Increased efficacy: Administration of pazopanib with a consistent meal containing a 
standard low quantity of fat every day could result in higher systemic levels of the 
drug with low intra-patient variability, translating into higher efficacy against advanced 
renal cell cancer. 
 
2) Lower cost: A similar strategy with abiraterone acetate in castration resistant prostate 
cancer was recently reported and sets a precedent for our approach 5. If our 
approach is shown to be feasible and safe, future strategies could allow intake of 
similar amounts of the drug to achieve similar or greater efficacy as in the fasting 
state, resulting in substantial cost savings given its high cost of the medication. For 
example, abiraterone when taken with food could result in savings of $3,750 per 
month per patient at current prices. Assuming patients would only need 
approximately half the quantity of drug as currently used (given the 2-fold increase in 
Cmax and AUC), the potential for cost savings with pazopanib given with low fat diet 
could be approximately $3,890 per month per patient at current prices. 
 
3) Convenience: Intake of the drug with food also minimizes the practical inconvenience 
of taking pazopanib in the fasting state.  
 


Protocol UMCC 2016.013 
 
Page 6 of 34 
 
We hypothesize that administration of pazopanib with low fat meal would be safe and 
feasible with secondary implications of higher pazopanib levels; potentially translating 
into greater anti-tumor efficacy in advanced renal cell cancer, with significant cost 
savings. In the proposed pilot study, we seek to test the feasibility and practicality of this 
approach and gather preliminary data on adverse effects and the safety profile. We hope 
to ameliorate any potential for greater toxicities with a dynamic dosing design that 
incorporates adverse events from each cycle into dosing for the next cycle and a 
structured symptom specific plan. 
1.3 
Study Design/Schema 
Registered subjects will take pazopanib by mouth with a low-fat meal (containing less than 400 
calories and less than 20% fat or 10 grams per meal) approximately, some sample meals are 
described in appendix 1) every day in 14 day cycles, for a total of 6 cycles, with a starting dose of 
400 mg and adjusted for the next cycle (dose level +1:600 mg; dose level +2: 800 mg; dose level 
-1: 200 mg) based on toxicity assessment during or at the end of each cycle. No dose re-
escalations are permitted. Imaging will be performed post 12 weeks of treatment. 
 
An interim analysis for safety will be performed after 8 subjects have completed at least 2 cycles 
(4 weeks) of therapy. 
 
 
 
 


Protocol UMCC 2016.013 
 
Page 7 of 34 
 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
To assess the safety and feasibility of pazopanib administered with a low fat 
meal in therapy of advanced renal cell carcinoma  
2.2 
Secondary Objectives 
 
2.2.1 
To estimate the efficacy of pazopanib administered with a low fat meal in therapy 
of advanced renal cell carcinoma. 
 
2.2.2 
To explore PK characteristics (Cmax) of pazopanib taken with a low fat meal.  
2.3 
Endpoints 
2.4  
Primary Endpoint:  
2.4.1 
To assess the frequency of grade 3 or 4 adverse events associated with 
pazopanib administered with a low fat meal by CTCAE ver 4.0. 
 
2.5  
Secondary endpoints: 
2.5.1 
To estimate the overall response proportion to pazopanib administered with a low 
fat meal by RECIST 1.1 criteria. 
 
2.5.2 
To explore Cmax in subjects treated with pazopanib administered with a low fat 
meal and its potential correlation with toxicity as assessed by CTCAE ver 4.0 
 
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be enrolled on the study. Study 
treatment may not begin until a subject is registered. 
3.1 
Inclusion Criteria 
3.1.1 
Adult (>18 years of age) with unresectable locally advanced or metastatic renal 
cell carcinoma with a clear cell component.  
 
3.1.2 
Subjects must have measurable disease per RECIST 1.1 criteria.  
 
3.1.3 
Subjects must not have had prior pazopanib therapy.  
 
3.1.4 
Subjects must have an ECOG PS of < 2.  
 
3.1.5 
Up to 3 lines of prior VEGF or VEGFR targeted therapy are permitted. Any prior 
therapy should have been completed ≥ 2 weeks prior to start of study therapy. 
 
3.1.6 
Subjects may have received any number of the following therapies: cytokine 
therapy (e.g. high dose interleukin-2) or checkpoint inhibitor therapy (e.g. anti-
PD1/PDL1, anti-CTLA4) or mTOR inhibitor therapy (e.g. everolimus, 
temsirolimus). 
 
 
 
 


Protocol UMCC 2016.013 
 
Page 8 of 34 
 
3.1.7 
Adequate organ and marrow function as defined below: 
 
ANC  
> 1000/mm3  
Platelets  
> 100,000/mm3  
AST, ALT, 
Total 
bilirubin 
< 1.5 X ULN. Patients with Gilbert’s disease are exempt 
from this criteria (please see dose-adjustment for Gilbert’s 
as per table 3). 
 
3.1.8 
Subject must be willing and able to take pazopanib with a low-fat meal every day 
as specified in the protocol.  
 
3.1.9 
Subjects must be willing and able to come off any PPI/other strong CYP3A4 
inhibitors or inducers/simvastatin.  
 
3.1.10 Ability to understand and the willingness to sign a written informed consent. 
 
3.1.11 All subjects, including those who are surgically sterilized, must be willing to use 
an effective method of contraception (barrier method of birth control or 
abstinence) from the time informed consent is signed until 6 months after 
completion of protocol therapy.  
3.2 
Exclusion Criteria 
3.2.1 
Any concurrent health condition that in the view of the treating physician would 
pose excessive risk to the patient if enrolled in the study. 
 
3.2.2 
Subjects with a history of significant hemoptysis per the treating physician’s 
judgment, cerebral hemorrhage or clinically significant GI hemorrhage or 
myocardial infarction (MI) within the past 6 months.  
 
3.2.3 
Patients at significant risk for GI perforation or fistula.  
 
3.2.4 
Pregnant or nursing mothers. 
 
3.2.5 
Untreated CNS metastasis. If treated CNS metastasis/es, treatment of CNS 
disease (surgery or radiation) must have been completed at least 30 days prior to 
registration. Patients could still be on steroids. 
 
3.2.6 
Subjects with known history of Cirrhosis, HIV, Hepatitis B or C. 
 
3.2.7 
Averaged QTc baseline in 3 ECGs at least 5 minutes apart of ≥450 ms. 
 
3.2.8 
Congestive Heart Failure (NYHA Class III/IV) or LVEF <50% at baseline. 
 
3.2.9 
Uncontrolled hypertension (HTN) despite medical management (Blood pressure 
(BP) ≥ 160/100. 
 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
Subjects will be recruited from the routine clinical practice of the treating oncologists. After 
informed consent is obtained and PRIOR to the initiation of protocol therapy all patients satisfying 
the inclusion/exclusion criteria must have eligibility confirmed by the Clinical Trials Office. The 
patient will not be considered registered and enrolled in the study until all information is confirmed 
by the Clinical Trials Office Data Manager.  
  


Protocol UMCC 2016.013 
 
Page 9 of 34 
 
5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
Protocol treatment must start within seven business days of registration to the study.  
 
Subjects will take starting dose of pazopanib 400 mg PO once a day with a low-fat meal 
as specified in the protocol once daily in every 14 days cycles, for a maximum of 12 
weeks.  
 
Consecutive doses should be taken approximately 24 hours (± 4 hours) apart. 
 
If the subject does not develop significant toxicities as described in Section 5.2 after the 
first cycle, then the pazopanib dose will be escalated to 600 mg PO once daily with low-
fat meal for the next cycle. If the subject does not develop significant toxicities as 
described in Section 5.2 at 600 mg, then the pazopanib dose will be escalated to 800 mg 
PO once daily with low-fat meal for the next cycle. 
 
Subject will be assessed for significant toxicities as described in section 5.2 at the end of 
each cycle by clinical exam and laboratory values including liver function tests. Any grade 
3 or 4 pazopanib-related (as assessed by treating investigator) non-hematological 
toxicities (except specific toxicities listed in table 2, 3 and 4) will necessitate dose 
reduction by 1 dose level for the next cycle.  
 
No dose re-escalations are permitted.  
 
 
Table 1 Pazopanib Dose Levels in Study 
 
Dose Level 
Pazopanib with low fat meal 
 +2 
800 mg daily 
 +1 
600 mg daily 
  0 
400 mg daily (starting dose) 
 -1 
200 mg daily 
 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives at least 1 dose of pazopanib on this protocol will be evaluable 
for toxicity. Each patient will be assessed for the development of toxicity according to the 
Time and Events Table (Section 6.5). Toxicity will be assessed according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.  
 
Dose adjustments should be made according to the system showing the greatest degree 
of toxicity. Please see tables 2, 3, 4, 5 for dose adjustment criteria.  
 
Note:  
• 
Subjects will be removed from the trial if treatment is held for 4 weeks or longer 
continuously.  
 
• 
To avoid potential wound healing complications, Pazopanib should be 
discontinued 5 days prior to any surgery and restarted based on the clinical 
judgment of the primary physician caring for the wound post-operatively.  
 
 
 
Any pregnancies occurring up to 6 months after completion of protocol therapy   
 
 
will be reported to IRBMED. 
 


Protocol UMCC 2016.013 
 
Page 10 of 34 
 
Table 2: Dose-adjustment of pazopanib for hematological toxicities. 
 
 Hematological Toxicity Dose Reductions for Pazopanib 
ANC1 
Platelets 
Action 
≥ 1,000/µL or 
≥50,000/µL 
None. 
 
<1,000/µL or 
 
<50,000/µL 
Hold drug until ANC ≥ 1,000/µL and 
platelets ≥ 50,000/µL. Restart at one dose 
level lower. If already at lowest dose level 
(-1), discontinue pazopanib. 
 
 
 
Table 3: Dose–reductions of pazopanib for specific non-hematological toxicities.  
 
Example of  Non-Hematological Toxicity Dose Reductions 
Event 
Action 
Liver toxicity  
Normal 
total 
bilirubin with any 
degree 
of 
ALT 
elevation or total 
bilirubin 
<1.5x 
ULN  
None 
Isolated AST/ALT 
elevations 
between 
3-8 
x 
ULN 
with 
total 
bilirubin ≤ 2x ULN 
Continue pazopanib without dose reduction, but monitor AST/ALT weekly 
until ALT returns to grade 1 (NCI CTCAE version 4) or baseline.  
Isolated ALT >8x 
ULN 
with 
total 
bilirubin less than 
or equal to 2x ULN 
Hold pazopanib and monitor ALT/AST weekly until ALT returns to grade 1 
(NCI CTCAE version 4) or baseline. At this time, can restart pazopanib at 
400mg daily. Continue measuring AST/ALT levels weekly for at least 8 
more weeks. If hepatotoxicity is to recur during this period, discontinue 
pazopanib permanently and remove the subject from trial.  
 
ALT ≥ 3x ULN 
AND total bilirubin 
>2x ULN 
Discontinue pazopanib permanently and monitor LFTs weekly until they 
return to grade 1 (NCI CTCAE version 4) or baseline.  
ALT/AST >3x ULN 
with 
known 
or 
suspected Gilbert 
with mild indirect 
hyperbilirubinemia 
(total bilirubin ≤ 
6mg/dL and direct 
bilirubin <35% of 
total). 
Continue pazopanib without dose reduction, but monitor AST/ALT weekly 
until ALT returns to grade 1 (NCI CTCAE version 4) or baseline.  
 
Hypertension 
Grade 
1: 
(pre-
hypertension with 
systolic BP 120-
139 
mmHg 
or 
diastolic BP 80-89 
mmHg) 
None. Blood pressure should be monitored as recommended by the 
treating physician.  


Protocol UMCC 2016.013 
 
Page 11 of 34 
 
Grade 
2: 
Persistent 
(>24 
hours) 
or 
recurrent 
HTN 
(systolic BP 140-
159 
mmHg 
or 
diastolic BP 90-99 
mmHg) 
or 
symptomatic 
BP 
increase by >20 
mmHg diastolic or 
>140/90 mmHg if 
previously within 
normal limits. 
Initiate monotherapy with anti-hypertensive agent of treating physician’s 
choice belonging to the Calcium channel blocker (CCB) or ACE I/ARB class 
to lower BP back down to goal of systolic less than 140 mmHg and diastolic 
less than 90 mmHg. Blood pressure should be monitored as recommended 
by the treating physician and dose adjustment of pazopanib as per 
judgment of treating physician but is not mandated.  
Grade 3: Systolic 
BP > 160mmHg or 
diastolic 
>100mmHg 
or 
medical 
intervention 
indicated 
Initiate more anti-hypertensive medications or intensive anti-hypertensive 
therapy with agents of treating physician’s choice to bring subject’s BP back 
to goal of systolic < 140 mmHg and diastolic < 90 mmHg. Blood pressure 
should be monitored as recommended by the treating physician and dose 
adjustment or discontinuation of pazopanib as per judgment of treating 
physician.  
Grade 
4: 
life-
threatening HTN 
(i.e. 
malignant 
HTN or posterior 
reversible 
encephalopathy 
syndrome 
(PRES)) 
Discontinue Pazopanib permanently.  
 
QTc Prolongation 
QTc interval ≥ 500msec or > 60msec from 
baseline QTc interval on averaged 3 ECGs 
taken at least 5 minutes apart  
Check concurrent medications for causes of 
QTc 
prolongation 
and 
if 
considered 
contributing, discontinue them. 
 
Check electrolyte levels in serum including 
magnesium, potassium and calcium. 
 
Continue study drug at 1 dose level lower and 
recheck ECG x 3 five minutes apart on next 
visit. If already at -1 dose level, then 
discontinue pazopanib. 
 
 
Proteinuria  
Urine Protein Creatinine ratio (UPC ratio) >1 
but <3  
Obtain 24 hour urine protein and if <3g, 
continue at current dose and monitor as 
clinically indicated.  
Urine protein UPC ratio ≥ 3 and/or urine protein 
in 24 hr urine protein ≥ 3g/dL/1.73 m2 
Discontinue pazopanib and obtain weekly 
UPC or 24 urine protein until UPC ratio <3 or 
24 hour urine protein is <3g/dL/1.73 m2 BSA. 
Then, can restart pazopanib with a one level 
dose reduction.  
If no further dose reductions in pazopanib can 
be made, then discontinue pazopanib.  


Protocol UMCC 2016.013 
 
Page 12 of 34 
 
Nephrotic syndrome  
Discontinue pazopanib  
 
LV dysfunction or CHF  
Grade 1 and 2  
None  
Decline in LVEF greater ≥15% or EF is <50%.  
Stop pazopanib, repeat TTE in 8 weeks and if 
either of these (decline in LVEF greater ≥15% 
or EF is <50%) are confirmed, refer to 
cardiology to institute CHF measures such as 
beta-blocker, ACEI/ARB etc.  
 
Symptomatic heart disease or CHF  
Refer to cardiology and discontinue pazopanib 
permanently if alternative causes are not 
found.  
 
 
Table 4. Management of other specific adverse events. 
 
Event 
Action 
Hemorrhage/bleeding 
Grade 1  
None, except if hemoptysis, in which case the PI should be contacted to 
determine whether continuation of therapy is appropriate.  
Grade 2 
If non-pulmonary, hold pazopanib until resolves to grade 1 or less. Then can 
restart pazopanib with a one dose level dose-reduction. If already at (-1 dose 
level), discontinue pazopanib permanently.  
If pulmonary, the PI should be contacted to determine whether continuation of 
therapy is appropriate. 
Grade 3 or 4 
Discontinue pazopanib permanently  
Arterial thrombosis  
All grades  
Discontinue pazopanib permanently 
GI fistula or perforation 
All events 
Discontinue pazopanib permanently 
 
Table 5: Pazopanib dose-adjustments based on other unspecified non-hematological 
toxicity grade per NCI CTCAE version 4.0. 
 
NCI CTCAE 
Grade 
Pazopanib 
0-2 
No change from original starting dose (except liver toxicity as described 
in Table 3) 
3 -4 
Hold until resolved to < Grade 2, then resume with 1 dose level reduction.  
5.3 
Concomitant Medications/Treatments 
Patients should avoid PPI or other drugs that inhibit (i.e. itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, voriconazole) or induce (i.e. rifampin) 
CYP3A4. Specifically, taking pazopanib with simvastatin has showed to increase the risk 
of hepatotoxicity. So, simvastatin has to be stopped prior to/at subject registration. 
5.4 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until 
one of the following criteria apply: 
• 
Disease progression as defined in Section 7.0 
• 
Inter-current illness that prevents further administration of treatment as deemed 
appropriate by treating physician.  
• 
Unacceptable adverse event(s) as defined in Section 8.0 


Protocol UMCC 2016.013 
 
Page 13 of 34 
 
• 
Patient voluntarily withdraws from treatment OR changes in the patient’s condition 
render the patient unacceptable for further treatment in the judgment of the 
investigator. 
• 
Completion of therapy with pazopanib with low fat meal for 12 weeks. Patients could 
then go onto standard therapies, including pazopanib given without food/low fat meal. 
 
5.5 
Off Treatment Criteria  
Patients will be removed from protocol therapy when any of the criteria listed in Section 
5.4 apply. Document in the source the reason for ending protocol therapy and the date 
the patient was removed from treatment. All patients who discontinue treatment should 
comply with protocol specific follow-up procedures as outlined in Section 5.6. The only 
exception to this requirement is when a subject withdraws consent for all study 
procedures or loses the ability to consent freely. 
5.6 
Duration of Follow-Up 
Patients will be followed for 28 days after removal from treatment or until death, 
whichever occurs first. Patients removed from treatment for unacceptable adverse events 
will be followed until resolution or stabilization of the adverse event (Grade 1 or lower).  
5.7 
Off Study Criteria 
Patients can be taken off study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or administrative 
reasons. The reason(s) for discontinuation from study will be documented and may 
include: 
5.7.1 
Patient withdraws consent (termination of treatment and follow-up); 
5.7.2 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment; 
5.7.3 
Patient is unable to comply with protocol requirements; 
5.7.4 
Treating physician judges continuation on the study would not be in the patients 
best interest; 
5.7.5 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.7.6 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment or which would 
interfere with this study (per PI); 
5.7.7 
Termination of the study by The University of Michigan; 
5.7.8 
Patient completes protocol treatment and follow-up criteria. 
5.8 
Patient Replacement 
 
Subjects who are removed or withdraw consent from the study will not be replaced.  
6.0 
STUDY PROCEDURES 


Protocol UMCC 2016.013 
 
Page 14 of 34 
 
6.1 
Pharmacokinetic Assessment 
Analysis of the samples for plasma concentration of pazopanib by the Pharmacokinetics 
Core at the College of Pharmacy of the University of Michigan at various time points 
(please refer to Section 10.0 for details) will be per previously established assays6.  
6.2 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 28 days prior to registration unless 
otherwise stated. The screening procedures include: 
6.2.1 Informed Consent 
6.2.2 Medical history 
 
Complete medical and surgical history, history of infections 
6.2.3 Demographics 
 
Age, gender, race, ethnicity 
6.2.4 Review subject eligibility criteria 
6.2.5 Review previous and concomitant medications 
6.2.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
6.2.7 Performance status 
Performance status evaluated prior to study entry according to Appendix 4. 
6.2.8 Adverse event assessment 
Baseline adverse events will be assessed. See Section 8.0 for Adverse Event 
monitoring and reporting. 
6.2.9 Hematology 
 
Complete blood count with differential, platelet count.  
6.2.10 Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, 
ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, 
calcium, chloride, bicarbonate, magnesium), glucose, and total bilirubin. 
6.2.11 Pregnancy test (for all females) 
 
Urine or serum.  
6.2.12 Tumor assessment 
To be performed with computed tomography or MRI of chest, abdomen and 
pelvis; CT or MRI of the brain.  
 


Protocol UMCC 2016.013 
 
Page 15 of 34 
 
For all axial imaging studies, intravenous contrast administration is preferred if 
judged safe by treating investigator. 
6.2.13 Other  
• 
A baseline transthoracic echocardiogram will be obtained to assess baseline 
LVEF 
• 
12-lead ECG will be obtained in triplicate at least 5 minutes apart from each 
other to determine QTc interval at baseline.  
• 
A Urine Protein Creatinine ratio and TSH will also be obtained to evaluate for 
baseline proteinuria and hypothyroidism, respectively, as part of screening for 
the study.  
• 
Whole blood sample (10 mL) into EDTA-containing blood collection tube 
to be stored at the “Sample Preservation Freezer Facility" 
6.3 
Procedures During Treatment 
6.3.1 
Day 1 of each cycle (e.g. C1 D1, C2 D1…etc. until C6 D1) 
• Physical exam, vital signs 
• Hematology: Complete blood count with differential, platelet count. 
• Serum chemistries: Comprehensive metabolic panel (CMP) to include: 
albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, 
electrolytes (sodium, potassium, calcium, chloride, and bicarbonate, 
magnesium), glucose, and total bilirubin. 
• Review of toxicities (refer to section 5.2). 
• Review of concomitant medications. 
• 12-lead ECG will be obtained in triplicate at least 5 minutes apart from each 
other to determine QTc interval.  
6.3.2 
Procedures for Cycle 1 Day 1, Cycle 2 Day 1 and Cycle 3 Day 1 ONLY 
• Patient will be given pazopanib to take by mouth with low fat meal by 
research/MCRU staff who will record time. 
• Whole blood samples (5mL each) will be collected from patient into EDTA-
containing blood collection tubes at specified times per section 10.0.  
6.3.3 
EOT visit (end of cycle 6 ± 7 days)  
• End of Treatment (EOT) visit will be post 12 weeks of protocol therapy  
• CT chest, abdomen, pelvis with or without intravenous contrast (with 
intravenous contrast preferred if clinically felt safe to do so by treating 
investigator). MRI abdomen pelvis can be substituted for CT abdomen pelvis. 
• A repeat transthoracic echocardiogram will be obtained once to re-assess 
LVEF after 12 weeks of therapy. 
• A Urine Protein Creatinine ratio and TSH will also be obtained to evaluate for 
baseline proteinuria and hypothyroidism, respectively, as part of screening for 
the study. If TSH is abnormal, add-on labs of free T3 and free T4 may be 
added to blood sample per treating investigator discretion. 
• 12-lead ECG will be obtained in triplicate at least 5 minutes apart from each 
other to determine QTc interval. 
•  Whole blood sample (10 mL) into EDTA-containing blood collection tube to 
be stored at the “Sample Preservation Freezer Facility" 
6.3.4 
28 days after EOT visit (± 7 days) 
• Physical exam, vital signs 


Protocol UMCC 2016.013 
 
Page 16 of 34 
 
• Hematology: Complete blood count with differential, platelet count. 
• Serum chemistries: Comprehensive metabolic panel (CMP) to include: 
albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, 
electrolytes (sodium, potassium, calcium, chloride, bicarbonate, magnesium), 
glucose, and total bilirubin 
• Toxicity check  
6.4 
Time and Events Table/Study Calendar 
Study  
Calendar  
 
Screen
ing 
(within 
28 d) 
C1 D1 
± 3d 
C2 D1 
± 3d 
C3 D1 
± 3d… 
C4/5/6
D1 
± 3d 
 EOT 
±7d 
28 
days 
after 
EOT 
± 7d 
Informed 
Consent 
X 
 
 
 
 
 
 
History and PE 
Weight 
X 
X 
X 
X 
X 
X 
X 
ECOG 
Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
Toxicity 
Assessment 
X 
X 
X 
X 
X 
X 
X 
Patient Diaries 
(blood pressure 
logs and pill 
diary) 
X 
X 
X 
X 
X 
X 
 
Dietician visit 
 
X 
 
 
 
 
 
CBC with 
differential, 
platelet count 
X 
X 
X 
X 
X 
X 
X 
COMP   
X 
X 
X 
X 
X 
X 
X 
TSH  
X 
 
 
 
 
X 
 
Concomitant 
Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG in 
triplicate 
X 
X 
X 
X 
X 
X 
 
Transthoracic 
Echocardiogram 
with LVEF 
estimation 
X 
 
 
 
 
X 
 
PK samples*  
 
X 
X 
X 
 
 
 
Blood sample for 
storage at SPFF 
X 
 
 
 
 
X 
 
Urine Protein 
Creatinine ratio 
X 
 
 
 
 
X 
 
CT chest, 
abdomen, pelvis  
X 
 
 
 
 
X 
 
CT or MR head 
X 
 
 
 
 
X (if 
clinicall
y 
 


Protocol UMCC 2016.013 
 
Page 17 of 34 
 
indicat
ed 
Pregnancy 
Test** 
X 
 
 
 
 
 
 
Pazopanib with 
low fat meal 
 
X 
 
 
 
*Please refer to section 10.0 
**Serum or urine pregnancy test for all females 
*** Sample Preservation Facility (U of M- MSRB3) .  
 
 
7.0 
MEASUREMENT OF EFFECT 
7.1 
Antitumor Effect- Solid Tumors 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
Committee]. The largest diameter (unidimensional measurement) of the tumor lesions are 
used in the RECIST v1.1 criteria. 
7.1.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first dose of study drug. 
 
Evaluable for objective response. Only those patients who have measurable 
disease present at baseline, have received at least 4 cycles of therapy, and have 
had their disease re-evaluated will be considered evaluable for response. These 
patients will have their response classified according to the definitions stated 
below. (Note: Patients who exhibit objective disease progression prior to the end 
of cycle 1 will also be considered evaluable.) 
 
7.1.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
 
• 
10mm by CT scan (irrespective of scanner type) for studies with a slice 
thickness of <5mm or twice the slice thickness or MRI 
• 
10mm caliper measurement by clinical exam (lesions which cannot be 
             accurately measured with calipers should be recorded as  
             non-measurable)          
• 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
                           
                         All tumor measurements must be recorded in millimeters (or decimal fractions of     
                         centimeters). 
 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baselineand28 days post therapy, only the short axis will be measured and 
followed. 


Protocol UMCC 2016.013 
 
Page 18 of 34 
 
 
Note: Tumor lesions that are situated in a previously irradiated area might or 
might not be considered measurable, and the conditions under which such 
lesions should be considered may be defined in the protocol when appropriate. 
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm using 
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. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total 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), be representative of all involved organ, 
but in addition should be those that lend themselves to reproducible repeated 
measurements. 
 
Lymph nodes merit special mention since they are normal anatomical structures 
which may be visible by imaging even if not involved by tumor. Pathological 
nodes which are defined as measurable and may be identified as target lesions 
must meet the criterion of a short axis of ≥15mm by CT scan. Only the short axis 
of these nodes will contribute to the baseline sum. The short axis of the node is 
the diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI 
the plane of acquisition may be axial, sagittal or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as 
being 20mm x 30mm has a short axis of 20mm and qualifies as a malignant, 
measurable node. In this example, 20mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10mm but <15 
mm) should be considered non-target lesions. Nodes that have a short axis 
<10mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters. If lymph nodes are to be included in the sum, then as noted above, 
only the short axis is added into the sum. The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including pathological 
lymph nodes should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required and these lesions should 
be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. 
‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
7.1.3 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start and never more than 4 weeks before the 
beginning of the treatment. 
 


Protocol UMCC 2016.013 
 
Page 19 of 34 
 
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 should always be done rather than clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they 
are superficial and >10mm diameter as assessed using calipers (e.g. skin 
nodules). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is suggested. As noted above, 
when lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than X-ray, 
particularly in identifying new lesions. However, lesions on chest X-ray may be 
considered measurable if they are clearly defined and surrounded by aerated 
lung. 
 
CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined 
measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5mm or less. When CT scans have slice thickness greater than 5 
mm, the minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique 
and measurements will be taken from one assessment to the next. If new lesions 
are identified by ultrasound in the course of the study, confirmation by CT or MRI 
is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in 
trials where recurrence following complete response or surgical resection is an 
endpoint. 
 
Cytology, Histology: These techniques can be used to differentiate between PR 
and CR in rare cases if required by protocol (for example, residual lesions in 
tumor types such as germ cell tumors, where known residual benign tumors can 
remain). When effusions are known to be a potential adverse effect of treatment 
(e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable 
disease) and progressive disease. 


Protocol UMCC 2016.013 
 
Page 20 of 34 
 
7.1.4 
Response Criteria 
7.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new 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. There can be no appearance of new lesions. 
 
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. 
7.1.4.2 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. 
7.1.4.3 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 
Best 
Response for 
this Category 
Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non-
CR/SD 
No 
PR 
 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at 
least once >4 
wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, 
PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


Protocol UMCC 2016.013 
 
Page 21 of 34 
 
* 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of 
treatment. 
 
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 
7.1.5 
Duration of Response 
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. 
 
 
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.  
7.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from 
registration to time of progression. 
7.2 
Safety/Tolerability 
 
 Analyses will be performed for all patients having received at least one dose of study 
drug (pazopanib). The study will use the CTCAE version 4.0 for reporting of non-
hematologic adverse events (http://ctep.cancer.gov/reporting/ctc.html) and modified 
criteria for hematologic adverse events. 
8.0 
ADVERSE EVENTS 
8.1 
Experimental Therapy 
For the most recent safety update, please refer to the current Investigator’s Brochure or 
Study Agent Prescribing Information for pazopanib. 
(https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_In
formation/Votrient/pdf/VOTRIENT-PI-MG.PDF). 
 
8.2 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is 
done to ensure the safety of subjects enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Data on adverse events will be collected from 
the time of the initial study treatment through 30 days after the last dose of study 
treatment or study intervention. Any serious adverse event that occurs more than 30 days 


Protocol UMCC 2016.013 
 
Page 22 of 34 
 
after the last study treatment and is considered related to the study treatment must also 
be reported. Serious Adverse Events (SAEs) will continue to be followed until: 
• 
Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
• 
There is satisfactory explanation other than the study treatment for the changes 
observed; or  
• 
Death. 
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The definitions 
of AEs and SAEs are given below. It is the responsibility of the principal investigator to 
ensure that all staff involved in the trial is familiar with the content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration is considered to be pre-existing in nature. Any known pre-
existing conditions that are ongoing at time of study entry should be considered medical 
history. 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.3, 
occurring from the initial study treatment through 30 days following the last dose of the 
study treatment must be recorded as an adverse event in the patient’s source documents 
and on the CRF regardless of frequency, severity (grade) or assessed relationship to the 
study treatment.  
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of 
a pre-existing condition that occurs after the patient begins study treatment is also 
considered an adverse event. 
8.3 
Definitions 
8.3.1 Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an experimental intervention, whether or not related to the intervention.  
8.3.2 Serious Adverse Event 
An adverse event is considered “serious” if, in the view of the investigator, it 
results in any of the following outcomes: 
  
o 
Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
 
o 
A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of either the 
investigator, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event that, had it occurred in a more 
severe form, might have caused death.  
 
o 
Inpatient hospitalization or prolongation of existing hospitalization for > 24 
hours. 


Protocol UMCC 2016.013 
 
Page 23 of 34 
 
 
o 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
o 
A congenital anomaly/birth defect 
 
o 
Important medical event 
Any event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition 
of “Serious Adverse Event”. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; convulsions that do not result in inpatient hospitalization or the 
development of drug dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries should 
not be reported as SAEs unless the underlying medical condition has worsened 
during the course of the study. Preplanned hospitalizations or procedures for 
preexisting conditions that are already recorded in the patient’s medical history at 
the time of study enrollment should not be considered SAEs. Hospitalization or 
prolongation of hospitalization without a precipitating clinical AE (for example, for 
the administration of study therapy or other protocol-required procedure) should 
not be considered SAEs. However, if the preexisting condition worsened during 
the course of the study, it should be reported as an SAE. 
 
8.3.3 Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
• 
For approved and marketed drug, such as pazopanib, those adverse 
events are described in the approved Package Insert (Label).  
• 
In clinical research studies, information on expected adverse events is 
also summarized in the protocol and in the consent document.  See 
section 9.1 for the list of expected adverse events related to the drug 
under study. 
8.3.4 Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the 
Package Insert, Investigator’s Brochure, in published medical literature, in the 
protocol, or in the informed consent document.  
8.4 
Adverse Event Characteristics 
8.4.1 CTCAE Term 
(AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be down 
loaded from the CTEP web site. (http://ctep.cancer.gov) 
8.4.2 Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 


Protocol UMCC 2016.013 
 
Page 24 of 34 
 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
8.5 
Serious Adverse Event Reporting Guidelines 
8.5.1 
The Principal Investigator must be notified within 1 business day of study team’s 
knowledge of any event meeting the criteria and definition of a serious adverse 
event, regardless of attribution, occurring during the study or within 30 days of 
the last administration of the study drug. 
8.5.2 
The investigator must report all events meeting the criteria and definition of a 
serious adverse event(s) that are unexpected and possibly related (definite, 
probable or possible) to study treatment administration to the local IRB within 7 
calendar days if death or life threatening, and within 14 calendar days for all 
others.   
8.5.3 
All Serious Adverse Events that are unexpected and possibly related (definite, 
probable or possible) to study treatment administration will be reported to the IRB 
using the CTO Serious Adverse Event form. 
• 
PI needs to be notified of all SAEs within 1 business day- contact information is 
below:   
 
 
Ajjai Alva, MD  
 
 
 
 
University of Michigan  
 
 
 
 
1500 E. Medical Center Drive 
 
 
 
 
Ann Arbor, MI 48109 
 
 
 
 
Phone: (734) 936-0091 
 
 
 
 
Fax: (734) 615-2719 
 
 
 
 
Email: ajjai@med.umich.edu 
• 
The study will comply with the regulations found in 21 CFR 312.32 regarding IND 
safety reports.   
8.6 
Routine Reporting 
All other adverse events- such as those that are expected, or are unlikely or definitely not 
related to the study participation- are to be reported annually as part of regular data 
submission. 
8.7 
Reporting of Unanticipated Problems 
There are types of incidents, experiences and outcomes that occur during the conduct of 
human subjects research that represent unanticipated problems but are not considered 
adverse events. For example, some unanticipated problems involve social or economic 
harm instead of the physical or psychological harm associated with adverse events. In 
other cases, unanticipated problems place subjects or others at increased risk of harm, 
but no harm occurs. 
 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse 
event) that may represent an unanticipated problem, the investigator should assess 
whether the incident, experience, or outcome represents an unanticipated problem. The 
incident, experience or outcomes is considered unanticipated if it meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 


Protocol UMCC 2016.013 
 
Page 25 of 34 
 
3. Suggests that the research places subjects or others at a greater risk of harm 
than was previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the IRB within 14 calendar days 
of the study team becoming aware of the problem. 
8.8 
Stopping Rules for the Study at Interim Analysis 
• 
Please refer to section 11 
9.0 
DRUG INFORMATION 
9.1 
Pazopanib 
• 
Brand name: Votrient  
 
• 
Description: 200 mg capsule-shaped, gray tablets dispensed in bottles with 120 
tablets.  
 
• 
Classification: Inhibitor of multiple tyrosine kinases  
 
• 
Mode of action: Inhibition of VEGFR (vascular endothelial growth factor receptor), 
PDGFR (platelet derived growth factor) and c-kit,  
 
• 
Pharmacokinetics: Pazopanib is routinely administered without food i.e. at least 1 
hour before or 2 hours after a meal 
(https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribin
g_Information/Votrient/pdf/VOTRIENT-PI-MG.PDF). When thus administered 
WITHOUT food, pazopanib has a median absolute bioavailability of 21% and mean 
half-life of 30.9 hours. The median time to peak concentration is 2-4 hours after dose, 
and repeated daily dosing results in 1-4 fold increase in AUC and Cmax with a daily 
dose up to 800mg daily. Doses above 800mg daily did not show a consistent 
increase in AUC and Cmax. Administration with food results in about 2 fold increase 
in AUC and Cmax. Crushing the tablet also resulted in increased AUC, increased 
Cmax and decreased Tmax when compared to administration of the tablet as a 
whole. Based on these observations, it was recommended that pazopanib be 
administered as a whole tablet 1 hour before or 2 hours after a meal. Additionally, the 
bioavailability of pazopanib is affected by drugs that increase gastric pH, such as 
esomeprazole, resulting in reduce plasma concentration of pazopanib. 
 
Once absorbed, pazopanib is highly bound to albumin (~99%) with no concentration 
dependence in the 10-100 microgram/milliliter range, and a subsequent small volume 
of distribution (<40% total body water). It is a substrate for human P-gp and human 
BCRP transporters, which mediate the efflux of substrates from cells in tissues such 
as small intestine, blood-brain barrier, testes and liver. Therefore, any factors that 
influence these transporters will also influence the tissue distribution of pazopanib. 
Furthermore, pazopanib is not a highly metabolized drug, as evidenced by low 
concentration of metabolites in vivo (<10% of parent drug concentration), and 
therefore pazopanib is the active drug and the major circulating species. Pazopanib 
does have 4 metabolites, GSK1268997, GSK1268992, GSK1071306 and 
GW700201, of which only GSK1268997 was active with similar inhibition of VEGF-
induced endothelial receptors as pazopanib. Primary route of pazopanib metabolism 
is hepatic, and it is thereby excreted through the feces. Less than 4% of administered 
dose is excreted renally. CYP3A4 is the major metabolizing enzyme, with minor 
contributions from CYP1A2 and CYP2C8. Routes of metabolism are mono-


Protocol UMCC 2016.013 
 
Page 26 of 34 
 
oxygenation, dioxygenation and potential oxygenation of a methyl group to a 
carboxylic acid. Glucuronidation was also detected in human hepatocytes. Steady-
state plasma concentrations were reached by 10 days of repeated dose 
administration. Pharmacokinetics of pazopanib was otherwise not affected by age, 
race, gender, body weight and creatinine clearance.  
 
• 
Side effects: Please refer to pazopanib’s package insert 
((https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribin
g_Information/Votrient/pdf/VOTRIENT-PI-MG.PDF) for a comprehensive list of 
adverse events.  
• 
Drug Interactions: Strong inhibitors of CYP3A4, P-glycoprotein (P-gp) and Breast 
Cancer Resistance Protein (BCRP), all three of which include pazopanib as a 
substrate, should be avoided due to risk of increased toxicity associated elevated 
levels of pazopanib. Ketoconazole is an inhibitor of both CYYP3A4 and P-gp. 
Lapatinib is a weak inhibitor of CYP3A4, Pgp and BCRP, and has been shown to 
increase pazopanib concentrations. Examples of strong CYP3A4 inhibitors are 
itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, 
saquinavir, telithromycin, voriconazole. Grapefruit juice may also increase plasma 
levels of pazopanib through the same mechanism. Strong CYP3A4 inhibitors should 
be avoided.   
 
On the other hand, CYP3A4 inducers, such as rifampin, may decrease pazopanib 
plasma levels, and therefore an alternative medication to rifampin is also 
recommended. In vitro studies showed pazopanib inhibited CYP enzymes 1A2, 3A4, 
2B6, 2C8, 2C9, 2C19, 2E1 and potentially induced CYP3A4. Pazopanib 800mg daily 
has no clinically relevant effect on pharmacokinetics of caffeine (CYP1A2), warfarin 
(CYP2C9 substrate) or omeprazole (CYP2C19 substrate) in clinical pharmacology 
studies. Concomitant administration of pazopanib with midazolam (CYP3A4 
substrate) and dextromethorphan (CYP2D6 substrate) resulted in an increase in the 
AUC and Cmax, and increase in urine dextromethorphan to dextrorphan 
concentrations, respectively. Pazopanib also increased the AUC and Cmax of 
paclitaxel when administered concurrently.  
 
 
Pazopanib is also a potent inhibitor of UGT1A1 and OATP1B1, and therefore may 
increase the concentrations of drugs primarily metabolized by these enzymes. One 
such drug is irinotecan, which also has an active metabolite, SN-38, that is 
metabolized by OATP1B1 and several UGT enzymes. Co-administration of irinotecan 
and pazopanib resulted in increased concentrations of irinotecan and its active 
metabolite SN-38. 
 
• 
Storage and stability: Pazopanib should be stored at room temperature between 20 
and 25 degrees Celsius, with excursions permitted to 15 to 30 degrees Celsius.  
 
• 
Preparation and Dispensing: Pazopanib is dispensed in a bottle and may be 
repackaged to a pill dispenser bottle.  
 
• 
Administration:  
• 
Pazopanib will be administered with a low-fat meal, defined as a meal 
containing less than 400 calories and less than 20% fat or 10 grams per 
meal, once daily orally.  
• 
All pazopanib pills for the day must be taken together.  
• 
Patient compliance with drug administration will be assessed at each visit 
through a pill diary that will record rate, time of pazopanib intake, number of pills, 
and if low fat meal was eaten.  


Protocol UMCC 2016.013 
 
Page 27 of 34 
 
 
• 
Availability: commercially available 
• 
Return and Retention of Study Drug: Patients may keep their supply of pazopanib as 
it will not be supplied by the study. They should dispose of any unused pazopanib 
after their therapy course is complete or if their supply has expired by returning it to 
their local pharmacy. It should not be thrown in household garbage or disposed of in 
wastewater  
 
• 
Drug Accountability: None, pazopanib is a current standard of care for metastatic 
renal cell carcinoma and therefore will be billed and provided as such.  
10.0 
Correlatives: 
Pharmacokinetics: 
A published, validated assay has been established at the Pharmacokinetics Core, College of 
Pharmacy at the University of Michigan to determine plasma pazopanib concentrations from 
these samples6. 
 
• 
Patient to take the whole dose of pazopanib by mouth with low fat meal and record time of 
intake. 
• 
Blood samples (6 mL drawn in EDTA tube) will be placed on ice and centrifuged within 10 
minutes of collection, for 10 minutes at 2,000 x g for fractionation followed by transfer of the 
top (plasma) layer to a secondary non-breakable cryovials for storage at -80*C until shipment 
to the PK Core lab.  
• 
Samples will be shipped with dry ice.   
• 
Sample should be shipped (with email notification to wenb@med.umich.edu) to 
Pharmacokinetics Core for analysis:       
 
     
 
 
 
Bo Wen 
 
    
University of Michigan 
 
     
 
    
Room 3400 of Building 520  
 
     
North Campus Research Complex 
 
     
1600 Huron Parkway 
 
     
Ann Arbor, MI 48109. 
  
    
 
    
Phone: (734) 615-3470 
 
     
Email: wenb@med.umich.edu 
 
• 
The time points for the PK samples are as follows ((± 15 minutes): 
 
Day 
Timing of PK blood draw 
C1D1 post-dose 
+2 hrs 
C2D1 pre-dose 
Once anytime between 0 to -4 hrs 
C2D1 post-dose 
+0.5 hrs, +1 hr, +2 hrs, +3 hrs, +4 hrs 
C3D1 pre-dose 
Once anytime between 0 to -4 hrs 
C3D1 post-dose 
+2 hrs 
 
 
11.0 
STATISTICAL CONSIDERATIONS 


Protocol UMCC 2016.013 
 
Page 28 of 34 
 
11.1 
Study Design/Study Endpoints and Data Assessment Plan  
Pazopanib with a low fat diet is a pilot study with a primary endpoint of feasibility and 
safety.   
 
The primary outcome will be a description of toxicity and feasibility with the following 
endpoints: any hematologic toxicity of grade 4 or non-hematologic toxicities of grades 3 
and 4 (excluding alopecia, and also excluding nausea and vomiting if the 
symptoms were manageable with standard care or antiemetic therapy); frequency and 
proportion of toxicities of all grades according to the CTCAE version 4.0 criteria; the 
frequency of dose reductions; the duration of treatment and the mean (or median) total 
dose taken. Each endpoint will include a 95% confidence around the reported statistic.  
Examples of exact confidence interval ranges with a sample size of 16 are presented in 
table 3. 
  
 
 
Table 5:  
 
 
 
 
 
 
 
 
 
The secondary objectives include overall response proportion by RECIST 1.1 including 
complete response and partial response at 12 weeks after start of pazopanib therapy 
start (CT chest, abdomen and pelvis). Each response proportion will be expressed with 
95% exact binomial confidence intervals.  
 
The pharmacokinetic data (Cmax in units of ng/mL and the trough concentration in units 
of micro g/mL) will be reported in context of known PK data of pazopanib administered in 
the fasting state7 and described in the context of the toxicity data. 
 
An interim safety analysis will be conducted after 8 patients have been treated for 2 
cycles on pazopanib with a low fat meal. If greater than 5 patients of the 8 experience 
hematologic toxicity of grade 4 or non-hematologic toxicities of grades 3 or 4 (excluding 
alopecia, and also excluding nausea and vomiting if the symptoms were manageable 
with standard care or antiemetic therapy), the study will be pause. Further study may be 
continued with an amendment to decrease the starting dose to 200 mg PO daily with low 
fat meal subject to PRC review/approval and IRB review/approval. 
11.2 
Sample Size and Accrual 
A sample size of 16 patients with metastatic renal cell carcinoma will be enrolled over a 
12 month period with an interim analysis for safety after 8 patients have completed 2 
cycles. As a pilot study, this sample size is a convenience sample and sufficient to 
determine the feasibility of administering pazopanib with a low-fat meal in advanced renal 
cell carcinoma, the associated toxicity profile and preliminary efficacy measures such as 
ORR, PFS or overall survival.  
Frequency 
Proportion 
95% Confidence Interval 
1 
6.25% 
0.2%, 30.2% 
2 
12.5% 
1.6%, 38.4% 
3 
18.75% 
4.1%, 45.7% 
6 
37.5% 
15.2%, 64.5% 
8 
50% 
24.7%, 75.4% 


Protocol UMCC 2016.013 
 
Page 29 of 34 
 
Based on data form this pilot study, a larger follow-up study may be warranted to 
definitively address the cost savings of administering pazopanib with low fat meal and the 
efficacy of the drug when given with low fat meal. 
12.0 
DATA AND SAFETY MONITORING 
This trial will be monitored in accordance with the NCI approved University of Michigan 
Comprehensive Cancer Center Data and Safety Monitoring Plan. The study specific Data and 
Safety Monitoring Committee (DSMC), consisting of the protocol investigators, data manager or 
designee, and other members of the study team involved with the conduct of the trial, will meet 
quarterly or more frequently depending on the activity of the protocol to provide continuous review 
of the data and patient safety. The discussion will include matters related to the safety of study 
participants (SAE/UaP reporting), validity and integrity of the data, enrollment rate relative to 
expectations, characteristics of participants, retention of participants, adherence to the protocol 
(potential or real protocol deviations) and data completeness. At the regular DSMC meetings, the 
protocol specific Data and Safety Monitoring Report form will be completed. The report will be 
signed by the Principal Investigator or by one of the co-investigators. Data and Safety Monitoring 
Reports will be submitted to the University of Michigan Comprehensive Cancer Center Data and 
Safety Monitoring Board (DSMB) on a quarterly basis for independent review. 
13.0 
REFERENCES 
 
 
1. 
Sternberg CN, Davis ID, Mardiak J, et al: Pazopanib in locally advanced or 
metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28:1061-8, 
2010 
 
2. 
Motzer RJ, Hutson TE, Cella D, et al: Pazopanib versus sunitinib in metastatic 
renal-cell carcinoma. N Engl J Med 369:722-31, 2013 
 
3. 
Motzer RJ, Agarwal N, Beard C, et al: NCCN clinical practice guidelines in 
oncology: kidney cancer. J Natl Compr Canc Netw 7:618-30, 2009 
 
4. 
Heath EI, Chiorean EG, Sweeney CJ, et al: A phase I study of the 
pharmacokinetic and safety profiles of oral pazopanib with a high-fat or low-fat meal in patients 
with advanced solid tumors. Clin Pharmacol Ther 88:818-23, 2010 
 
5. 
Stover JT, Moore RA, Davis K, et al: Reversal of PSA progression on abiraterone 
acetate through the administration with food in men with metastatic castration-resistant prostate 
cancer. Prostate Cancer Prostatic Dis 18:161-6, 2015 
 
6. 
Sparidans RW, Ahmed TT, Muilwijk EW, et al: Liquid chromatography-tandem 
mass spectrometric assay for therapeutic drug monitoring of the tyrosine kinase inhibitor 
pazopanib in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 905:137-40, 2012 
 
7. 
Hurwitz HI, Dowlati A, Saini S, et al: Phase I trial of pazopanib in patients with 
advanced cancer. Clin Cancer Res 15:4220-7, 2009 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol UMCC 2016.013 
 
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Appendix 1. Low Fat Meal (LFM) requirements and examples: 
 
 
DEFINITION: A low-fat meal contains less than ~400 calories and less than 20% fat or 10 
grams per meal. 
High fat containing food like bacon, sausage, etc. is not permitted with pazopanib in this study. 
 
Examples of a low-fat breakfast include (if coffee/tea is added please use only fat free additives 
such as sugar or non-fat creamer or fat-free milk): 
 
• 
2 slices of  wheat toast with 1 tablespoon of light margarine and 1 tablespoon of jelly, and 
8 ounces of low-fat (1%) milk, 1 small apple (415 calories and 9.4 grams fat) 
 
• 
½ cup apple juice, 1/2 cup uncooked oatmeal, 1 cup low-fat (1%) milk, 1 tbsp. light 
margarine, 1 tbsp. raisins, 2 tsp brown sugar (420 calories and 10 grams fat). 
 
 
• 
2 - 4” corn tortillas, 2 tbsp. salsa, ½ ounce (1/2 slice) cheddar cheese, 2 large egg whites, 
1 large egg,1 cup fat-free (skim) milk, 1 nectarine (410 calories and 11 grams fat). 
 
• 
1 cup low-fat cottage cheese with cinnamon and topped with ½ cup diced peaches, 1 
slice whole wheat toast with 1 tbsp. light margarine and 1 tbsp. jam (398 calories and 8.3 
grams fat). 
 
 
• 
1 whole wheat bagel with 1 Tbsp. creamy peanut butter, 1 cup of fat-free milk (425 
calories and 10 grams fat).  
Note: can substitute 2 Tbsp. light cream cheese for the peanut butter  
 
• 
Fruit Smoothie - 1 cup low-fat (1%) milk, 6 ounces of plain traditional Greek yogurt (~6 
gm fat/serving), ½ cup blueberries 2 tsp. honey, 1 small banana (423 calories and 9.5 
grams fat).  
 
 
• 
3 cups air popped popcorn with 1 tbsp. light margarine, ½ cup cinnamon applesauce, 6 
ounces traditional Greek fruit-flavored yogurt (403 calories and 10.7 grams fat). 
 
• 
1 cup of cereal (such as honey nut cheerios), 8 ounces of 1% milk, 1 slice of toast with 1 
tbsp. light margarine, 1 small orange (435 calories and 10.4 grams fat). 
 
• 
1 flour tortilla (2.2 oz.), 1 ounce reduced fat (2%) cheddar, ¼ cup black beans (drained), 
2 tbsp. salsa, 1 pear (414 calories, 10.8 gm fat) 
 
You can learn more or schedule a cancer nutrition services appointment by calling Cancer 
Nutrition Services at 877-907-0859. 
 
 
 
 
 
 


Protocol UMCC 2016.013 
 
Page 31 of 34 
 
 
 
 
 
Appendix 2: Common Pazopanib Toxicities and Guidance: 
 
Adverse event 
Supportive measure (s) 
Fatigue 
• Check for other possible contributing 
etiologies such as anemia 
• Take at night before bed with evening 
meal 
Hand foot skin reaction 
• Preventive measures: regular use of 
alcohol-free emollients, use of mild 
soaps, avoiding extreme temperatures 
and direct sun exposure 
• 
Avoid friction or pressure on the hands 
and feet, including avoiding tight-fitting 
footwear 
• Clobetasol 0.05% cream 
• Urea 20% cream 
HTN 
• Add anti-hypertensives (ACEI/ARB/CCB) 
• Maintain and review BP log 
Echo heart (Transthoracic) 
• At baseline and after 12 weeks of 
therapy. If LV dysfunction (<50% or 
<10% decline from baseline) is noted, 
refer to cardiology/institute CHF 
measures including beta blocker, 
ACEI/ARB etc. 
AST/ALT elevations 
• Please refer to table 3 of protocol 
Diarrhea 
• Imodium and/or lomotil as in their 
respective package inserts 
• Creon 24,0000 U of lipase, 2-3/meal and 
1-2/snack for a subject of 70 kg (500-
2500 u/kg/meal) 
• Consultation with Registered Dietitian for 
dietary adjustments to alleviate diarrhea 
Nausea and vomiting/ 
GERD/Dyspepsia/bloating/gas 
• Anti-emetics e.g. ondansetron 
• Antacids (avoid proton pump inhibitors) 
• Simethicone and other symptomatic 
measures 
• Consultation with Registered Dietitian for 
dietary adjustments to alleviate diarrhea 
Stomatitis 
• Use of a soft toothbrush or swab 
• Regular rinsing with an alcohol-free 
mouthwash, saline solution or 
bicarbonate 
• Eating soft, room-temperature foods and 
avoiding hot, spicy or acidic food and 
drinks 
• Good oral hygiene 
 
 


Protocol UMCC 2016.013 
 
Page 32 of 34 
 
 
 
 
 
Appendix 3:  
Toxicity data Treatment-Emergent Adverse Events with frequencies observed in the 
pazopanib phase 3 trial2 
 
Adverse event 
All Grades 
%  
Grade 3 
% 
Grade 4 
% 
    Diarrhea 
52 
3 
< 1 
    Hypertension 
40 
4 
    Hair color changes 
38 
< 1 
    Nausea 
26 
< 1 
    Anorexia 
22 
2 
    Vomiting 
21 
2 
< 1 
    Fatigue 
19 
2 
    Asthenia 
14 
3 
    Abdominal pain 
11 
2 
    Headache 
10 
0 
 
Clinical chemistry 
    ALT increase 
53 
10 
2 
    AST increase 
53 
7 
< 1 
    Hyperglycemia 
41 
< 1 
    Total bilirubin increase 
36 
3 
< 1 
    Hypophosphatemia 
34 
4 
    Hypocalcemia 
33 
1 
1 
    Hyponatremia 
31 
4 
1 
    Hypomagnesemia 
11 
3 
    Hypoglycemia 
17 
< 1 
Hematologic 
    Leukopenia 
37 
 
 
    Neutropenia 
34 
1 
< 1 
    Thrombocytopenia 
32 
< 1 
< 1 
    Lymphocytopenia 
31 
4 
<1 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol UMCC 2016.013 
 
Page 33 of 34 
 
 
 
 
 
Appendix 4: ECOG Performance Status 
 
 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair 
5 
Dead 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol UMCC 2016.013 
 
Page 34 of 34 
 
 
 
Appendix 5: BP log, diet compliance and study pill diary 
 
Initials: 
Subject ID: 
 
 
Date 
Number of Pills and Time of 
Day taken 
Compliant 
With  
Low Fat 
Meal* 
 
BP 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
 
 
Yes   No 
 
  
 
*DEFINITION: A low-fat meal contains less than ~400 calories and less than 20% fat or 10 
grams per meal.