Conditions: Genitourinary Cancer Kidney Cancer
Keywords: Genitourinary Cancer Kidney Cancer Metastatic Renal Cell Carcinoma mRCC Sunitinib Sunitinib malate SUO11248 Sutent Questionnaire Survey
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 60
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn more about the safety of giving sunitinib to patients with metastatic kidney cancer for 2 weeks followed by 1 week in which they receive no drug. Researchers want to learn more about the side effects of the drug and the effects of a different dosing schedule.

Detailed description:
Study Drug Administration:

If you are found to be eligible to take part in this study, you will take sunitinib capsules by mouth every day for 2 weeks, followed by 1 week in which you do not receive any study drug. This will then be repeated every 3 weeks.

Every 6 weeks will be 1 study cycle.

If you have any side effects tell the study doctor right away. The study doctor may change your dose of the study drug.

Study Visits:

Every day during the first week, and then at least 1 time each week during the study, your blood pressure will be checked (either at home, at the clinic, or by your local doctor). 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.

On Day 1 of Cycle 1:

* You will have a physical exam.
* Blood (about 3-4 tablespoons) will be drawn for routine and biomarker testing.
* You will fill out a questionnaire about the quality of your life and about how you are feeling. This should take about 5 minutes.

On Day 42 of every cycle:

* You will have a physical exam.
* Blood (about 3-4 tablespoons) will be drawn for routine tests.

On Day 42 of every even-numbered cycle (Cycles 2, 4, 6, and so on):

* You will have a CT scan of your chest, abdomen, and pelvis.
* Blood (about 1 tablespoon) will be drawn to check your thyroid function.
* Blood (about 2 tablespoons) will be drawn for biomarker testing. (Cycles 2 , 4, and 6 only)
* You will fill out the questionnaire about the quality of your life and about how you are feeling. (Cycles 2 , 4, and 6 only)

At any time that the doctor thinks it is needed, additional blood (about 1 tablespoon) may be drawn to check your thyroid function, and you may need to have a bone scan and CT scan or MRI of the brain to check the status of the disease.

Length of Study:

You may continue taking the study drug for as long as the study doctor thinks it is in your best interest. You will be taken off treatment if the disease gets worse, intolerable side effects occur, or if you are unable to follow study directions.

Your participation in this study will be over after the follow-up visit. However, the study team may perform a medical record review or follow-up call to check on how you are doing. If you are called, this should last about 5-10 minutes.

End-of-Treatment Visit:

After you are no longer receiving the study drug, you will have an end-of-treatment visit. You will have a physical exam and blood (about 3-4 tablespoons) will be drawn for routine and biomarker testing.

End-of- Treatment Follow-Up Visit:

About 30 days after your end-of-treatment visit you will have a follow-up visit and the following procedures will be performed:

* You will have a physical exam.
* Blood (about 3-4 tablespoons) will be drawn for routine tests.
* You will have CT scans of your chest, abdomen and pelvis to check the status of the disease.

This is an investigational study. Sunitinib is FDA approved and commercially available to treat advanced kidney cancer. The dosing schedule being used on this study is investigational.

Up to 60 participants will be enrolled in this study. Up to 60 may take part at MD Anderson.

Arms:
arm 1: Sunitinib starting dose 50 mg by mouth daily given for 2 weeks "on" followed by 1 week "off". 1 cycle is 6 weeks.

Interventions: intervention 1: Sunitinib intervention 2: Questionnaire
Intervention descriptions: intervention 1: Starting dose: 50 mg by mouth daily given for 2 weeks "on" followed by 1 week "off". 1 cycle is 6 weeks. intervention 2: Questionnaire completion on Day 1 of Cycle 1, and on Day 35 of Cycles 2, 4, and 6.

Protocol document:
Prot_SAP_000.pdf: 
STUDY NUMBER:
2013-0944 (version 3 January 6, 2015)
STUDY TITLE:
A Phase II Study of Alternative Sunitinib Scheduling in 
Patients with Metastatic Renal Cell Carcinoma (mRCC)
SUPPORTER:
Pfizer, Inc.
AGENT:
Sunitinib malate
PRINCIPAL 
Eric Jonasch, MD
INVESTIGATOR:
University of Texas MD Anderson Cancer Center
1155 Pressler Street Unit 1374
Houston, TX 77030
713-792-2830
ejonasch@mdanderson.org
CO-INVESTIGATORS:
Brian Rini, MD
Cleveland Clinic Taussig Cancer Institute
9500 Euclid Avenue
Cleveland, OH  44195
216-444-9567
rinib2@ccf.org
Kriti Mittal, MD, MS
Cleveland Clinic Taussig Cancer Institute
9500 Euclid Avenue
Cleveland, OH  44195
216-444-2200
mittalk@ccf.org
Kim Rathmell, MD, PhD
Lineberger Cancer Center
University of North Carolina
450 West Drive, CB 7295
Chapel Hill, NC  27599
919-966-8644
Rathmell@med.unc.edu
Sandy Srinivas, MD
Stanford University Medical Center
875 Blake Wilbur Drive
Stanford, CA 94305-5826
(650) 724-8372
sandysri@stanford.edu
Daniel M. Geynisman, MD
Fox Chase Cancer Center
333 Cottman Ave
Philadelphia, PA 19111
(215) 728-3614


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1.0
INTRODUCTION
1.1
Metastatic Renal Cell Carcinoma
The estimated incidence of cancers of the kidney and renal pelvis in the United States is
approximately 65,000 new cases in 2013, resulting in 13,680 deaths [1]. Renal cell 
carcinoma has historically presented physicians with many challenges. The often 
asymptomatic and clinically occult course of RCC has made it a difficult malignancy to 
diagnose resulting in a large proportion of patients being diagnosed with advanced or 
metastatic renal cell carcinoma (mRCC) [2]. In addition, prior studies have shown mRCC to 
be one of the most treatment-resistant solid tumors in oncology. Cytoreductive surgery and 
cytotoxic chemotherapy have shown limited effectiveness [3-5]. Immunotherapy has had 
better results, although response rates are still low and treatment is highly toxic [6-11]. The
VHL-HIF pathway is pivotal to the pathobiology of RCC, and has been crucial in the 
development of targeted agents that include VEGFR inhibitors as well as antibodies to 
circulating VEGF. Furthermore, mammalian target of rapamycin (mTOR) molecules that are 
downstream of phosphoinositide 3-kinase and protein kinase B pathways have also 
demonstrated an increased concentration of HIF-alpha; thus, playing a significant role in 
angiogenesis [12]. Thus, the therapeutic landscape of mRCC has changed dramatically since 
2005, with significant increases in overall survival [13]. This has subsequently resulted in the 
establishment of these agents as a first-line standard for patients with mRCC [14]. Despite 
their efficacy, these agents continue to be the focus of ongoing investigation, attempting to 
identify the best therapeutic regimen to maximize response and minimize toxicity.
1.2
Balancing toxicity with efficacy
Sunitinib, an oral inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, 3 
and platelet derived growth factor receptor (PDGFR), has demonstrated prolongation of 
median progression free survival (PFS) in a large phase III study of patients with mRCC [6]. 
This led to FDA approval in 2006 and sunitinib has become a standard of care in front line 
treatment of mRCC.
There is emerging evidence that supports the association of relative dose intensity (RDI) of 
antiangiogenic agents with improvement in response rates and treatment efficacy [15, 16]. 
Houk et al. conducted a retrospective pharmacologic analysis across six trials of sunitinib, 
and determined that patients with the highest drug exposure experience longer overall 
survival, longer time to progression, and greater tumor reduction [15]. As can be expected, 
tentative relationships were also identified between total drug exposure and the incidence of 
fatigue, reduction in neutrophil counts and diastolic hypertension.
While the therapeutic goal in the treatment of mRCC is prolongation of survival, it is 
important to keep treatment related toxicities to a minimum. In real-world practice,
maintenance of dose intensity of sunitinib can be challenging due to treatment-related 
adverse effects, including fatigue, hypertension, hand-foot syndrome (HFS) and diarrhea. In 
the original phase III trial, for instance, 38% and 32% of patients in the sunitinib arm 
underwent dose interruptions and reductions respectively, secondary to toxicities [6]. The 
impact of treatment related toxicities on patients can be significant, and for some patients, 
living longer may not always equate with living better. Wong et al. offered an interesting 


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insight into this, by quantifying preferences in patients with RCC who completed a survey 
with hypothetical treatment choice questions [17]. Their study revealed that fatigue and 
diarrhea were the most troublesome toxicities for patients, and that to reduce severe fatigue 
to mild-to-moderate fatigue, patients would be willing to forego 4.4 months of PFS. 
Interestingly, at the standard schedule of treatment for 4 weeks followed by a 2 week break 
(schedule 4/2), a cyclic scoring pattern is observed in patient reported quality of life 
indicators; with improvement in mean scores after the 2 week treatment break (i.e., between 
day 28 and day 42 scores) [18].
More recently, patient preferences for sunitinib versus active comparators were evaluated in 
randomized trials, results of which were presented at ESMO 2012. Data from the double 
blind cross-over PISCES trial comparing patient preferences between sunitinib and 
pazopanib, revealed that patient reported functional assessments of quality of life favored 
pazopanib over sunitinib with respect to fatigue, soreness of hands, feet and mouth [19]. 
Additionally, the phase III randomized COMPARZ study also highlighted differences in 
quality of life domains, which favored pazopanib over sunitinib [20]. Individual toxicities 
reported from this study are depicted in section 1.5. Thus, optimization of sunitinib 
administration is needed to maintain daily dose but to decrease the incidence of troublesome 
toxicity.
1.3
Sunitinib
1.3.1
Molecular formula and chemical name
Sunitinib is a small molecule with the molecular formula C22H27FN4O2. The free base has 
a molecular weight of 398.48 and the L-malate salt has a molecular weight of 532.57. The 
chemical name of the L-malate salt is 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-
2,4-dimethylpyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide
compound with (S)-2-hydroxy-succinic acid 1:1.
1.3.2
Preclinical Data 
Sunitinib is a potent inhibitor of the tyrosine kinase activity of the split-kinase domain 
receptor tyrosine kinases (RTKs) VEGFR2 and PDGFR, which are involved in angiogenesis, 
as well as for the RTKs, KIT, a receptor for stem cell factor (SCF), and FLT3 that are 
involved in certain solid tumors and hematological malignancies [21-24]. Sunitinib inhibits 
the ligand-dependent tyrosine phosphorylation of target RTKs and the in vitro mitogenic 
response of human umbilical vein endothelial cells (HUVECs) stimulated with VEGF or 
FGF, of PDGFR-expressing NIH-3T3 cells stimulated with PDGF, and of MO7E acute 
myeloid leukemia cells stimulated with SCF. In subcutaneous (SC) xenograft tumor models, 
oral administration of sunitinib results in potent inhibition of tumor growth, causing 
regression or stasis of large established tumors of multiple origins. The antitumor activity of 
sunitinib is associated with its ability to reduce tumor microvessel density in established 
tumors thereby acting as an inhibitor of tumor angiogenesis. Sunitinib also inhibits the 
growth of tumor metastases as indicated by its ability to inhibit lung colonization with B16-
F1 tumor cells injected into the tail vein of athymic mice.
1.3.3 Animal studies
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See the Investigator’s Brochure for full details. In summary, the toxicology and toxicokinetic 
data from studies in monkeys indicated that sunitinib treatment for up to 4 weeks with a 2-
week treatment rest period (repeated cycles) was well tolerated at the dose level of 6 
mg/kg/day without progression in lesion incidence and severity in the second cycle. 
Accumulation of sunitinib or its active metabolite was not observed in the cycling regimen 
indicating that plasma steady state was attained within 28 days of dosing. Similar plasma and 
tissue exposure is anticipated following repeated cycles of dosing. Through routine clinical 
monitoring, sunitinib-related adverse outcomes in animals were easily identifiable and 
reversible and were thus believed to be readily manageable in humans.
1.3.4 Clinical Data 
The clinical safety and efficacy of sunitinib has been studied in 15 phase 1 and 2 clinical 
trials. Dose escalation phase 1 studies were designed to determine the primary dose-limiting 
toxicity and maximum tolerated dose for sunitinib. Studies have also been designed to 
determine a safe and effective treatment schedule for repeated dosing. On all treatment 
schedules, patients without evidence of unacceptable toxicity or disease progression after the 
first cycle of treatment were permitted to receive continuing cycles of treatment until they 
experienced unacceptable toxicity or disease progression.
1.3.5  Pharmacokinetics
The results of both single-dose and multiple-dose studies have demonstrated the favorable 
pharmacokinetic properties of sunitinib [25]. The Cmax and AUC appear to have increased 
in a proportional manner with an increase in dose after single doses of 50 to 350 mg as well 
as after multiple doses of 25 to 100 mg. The elimination half-life of sunitinib and its active 
metabolite, SU012662, are approximately 40 hours and 80 hours, respectively. Consistent 
with the linear pharmacokinetics of sunitinib and its active metabolite SU012662, their 
steady state dose-corrected plasma exposures were similar between 4/2 schedule and 
continuous daily dosage (CDD) schedule. The time to achievement of steady state with daily
dosing of sunitinib has been assessed using trough concentrations of sunitinib, SU012662, 
and total drug measured during multiple dosing. These data indicate that steady-state 
conditions were achieved by approximately Day 10 to 14 for sunitinib. For SU012662 and 
total drug, steady-state conditions were achieved by Day 14 and Day 10, respectively. These 
findings are consistent with the half-life of sunitinib and SU012662.
Sunitinib and SU012662 concentrations measured through 3 cycles of therapy have shown 
that the Cmax, AUC 0-24 hr, and trough plasma drug concentrations (Cmin) during Cycle 2 
or Cycle 3 were not increased above those observed in Cycle 1. Therefore, increases in 
plasma drug concentration would not be expected during subsequent cycles of therapy. Food 
does not have a significant effect on the bioavailability of sunitinib, and thus sunitinib may 
be administered without regard to meals. Sunitinib is metabolized primarily by the 
cytochrome P450 enzyme, CYP3A4, producing the active metabolite, SU012662 which is 
also metabolized by CYP3A4. No other major metabolite has been identified. Accumulation 
with multiple doses of sunitinib has been noted but is consistent with the prolonged half-lives 
of sunitinib (~40 hours) and its active metabolite, SU012662 (~80 hours). Chronic 
accumulation has not been observed across dosing intervals.
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1.3.6 Clinical Safety
The primary DLT in the phase 1 studies appeared to be fatigue/asthenia, which generally 
occurred 10 to 15 days after start of therapy, and was readily reversible upon discontinuation 
of sunitinib malate treatment. Fatigue appeared to increase in frequency with an increase in 
drug exposure. The maximum tolerated dose has been defined as 50 mg in phase 1 clinical 
studies in subjects with advanced solid tumors, subjects with AML, and subjects with 
imatinib mesylate-resistant GIST.
The most serious treatment-related adverse events associated with sunitinib malate treatment 
of solid tumor subjects were pulmonary embolism (1.1%), thrombocytopenia (1.1%), tumor
hemorrhage (0.9%), febrile neutropenia (0.4%), and hypertension (0.4%). The most common 
treatment-related adverse events (experienced by at least 20% of the subjects) of any grade 
included fatigue (48.7%); gastrointestinal disorders, such as diarrhea (39.1%), nausea 
(35.6%), stomatitis (27.1%), dyspepsia (24.0%), and vomiting (22.2%); skin discoloration 
(29.3%); dysgeusia (27.8%); and anorexia (21.6%). The maximum severity of any of these 
adverse events was assessed as Grade 3. Fatigue (8.2%), hypertension (5.8%) and 
neutropenia (5.8%) were the most common treatment-related adverse events of Grade 3 
maximum severity and lipase increase (1.8%) was the most frequently occurring treatment-
related adverse event of Grade 4 maximum severity in subjects with solid tumors. The degree 
of adverse event severity appears to correlate with higher drug exposure and/or lower subject 
performance status. Most patients who experienced dose limiting toxicities (DLTs) in phase I 
studies were noted to have combined trough plasma concentrations of sunitinib and 
26].
Decreases in left ventricu
20% and to below the lower limit 
of normal occurred in subjects receiving both sunitinib malate and placebo. The LVEF 
declines do not appear to have a cumulative effect with repeated dosing or permanent effect 
since they often improved with temporary discontinuation of treatment and may not recur 
with reintroduction of sunitinib malate. At doses higher than the recommended human dose 
(RHD), sunitinib has the potential to inhibit the cardiac action potential repolarization 
process (e.g. prolongation of QT interval). The clinical relevance of these findings is 
unknown as no clinically significant QTc prolongation has been observed in completed 
clinical studies.
1.3.7 Efficacy Results
Two phase II trials of sunitinib in cytokine-refractory, metastatic RCC have been conducted 
[27, 28]. Both trials enrolled cytokine-refractory, metastatic RCC patients with measurable 
disease. Sunitinib was administered as 50 mg daily for the first 4 weeks of repeated 6-week 
cycles. The first trial included all histologic subtypes and demonstrated an objective partial 
response in 25 of 63 total patients (objective response rate 40%). The second trial restricted 
eligibility to clear cell RCC and required both prior nephrectomy and RECIST-defined 
progression after prior cytokine therapy. This trial of 106 patients reported 1 complete and 40 
partial responses (objective response rate 39%, much higher than previously reported for 
conventional cytokine based therapy for metastatic RCC).
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The success seen in the phase II trials led to a subsequent phase III trial comparing sunitinib 
(50 mg daily for four weeks, followed by two weeks off) to interferon-alpha (INFa) (9 
million units three times per week) in previously untreated patients with metastatic clear cell 
RCC [6]. Overall, a significantly better objective response rate (39% vs. 8%) and median 
progression-free survival (11 months vs. 5 months, hazard ratio 0.54) were determined. The 
final analysis of the trial showed that overall survival (OS) was prolonged with sunitinib 
(median 26.4 versus 21.8 months, hazard ratio 0.82, 95% CI 0.67-1.00, p=0.051) [29]
although the OS analysis was complicated as almost half the patients were given a VEGF 
inhibitor post progression (either as treatment after progressing on IFNa or as a second-line 
therapy after progression on sunitinib). Regardless, subsequent multivariate analysis of 
survival showed that initial treatment with sunitinib was a statistically significant predictor of 
prolonged survival, further demonstrating its efficacy in the first line setting.
1.4
Rationale
Alternate schedules: While early preclinical studies intended to administer a continuous 
dose of sunitinib, eventually, the current 4 weeks on followed by 2 weeks off (schedule 4/2) 
was chosen for clinical drug development to allow for recovery from bone marrow and 
adrenal toxicities that were observed in animal models [26]. Thus, the standard schedule (SS) 
of sunitinib (50 mg once a day for four weeks followed by a 2 week treatment break; 4/2) 
was tested in phase I studies and demonstrated clinical efficacy with acceptable toxicities.
In clinical practice, it is often noted that adverse effects increase throughout each cycle, and 
tend to be worst in the final two weeks of the treatment cycle. Alternative schedules of 
sunitinib have been explored in clinical studies with the goal of improving drug tolerance and 
delivered dose intensity. A recent phase II study comparing a 37.5 mg continuous daily dose 
(CDD) regimen to schedule 4/2 demonstrated no differences in drug tolerance or patient 
reported symptoms, but established superiority of schedule 4/2 over CDD in time to tumor 
progression [18]. These data support the notion that higher intermittent dosing is clinically 
superior to lower dose, continuous administration.
An alternative dosing schema that has been used is 2 weeks on / 1 week off (schedule 2/1), in 
an effort to decrease adverse effects while continuing treatment. The Cleveland Clinic 
experience of 30 patients on the 2/1 schedule has revealed a significant improvement in drug 
tolerance, with no grade 4 toxicities observed on the 2/1 schedule, with less than 30% of 
patients experiencing grade 3 toxicity [30]. In addition, 73% of patients’ worst toxicity on the 
2/1 schedule was less severe than on the 4/2 schedule, and no patient’s worst toxicity on the 
2/1 schedule was greater than that on the 4/2 schedule (p<.0001). Fatigue and hand-foot 
syndrome, two of the most common toxicities, were significantly less severe on the 2/1 
schedule than on the 4/2 schedule (p<.0003 in both cases). Median overall treatment duration 
of these patients initially on the 4/2 and, subsequently on the 2/1 schedule was 12.6 months 
and 11.9 months respectively. Median progression free survival (PFS) was approximately 
12.7 months. These data suggest that patients with dose limiting toxicities on the 4/2 
schedule are able to continue sunitinib treatment on a 2/1 schedule. 
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Neri et al. prospectively evaluated maintenance of dose intensity and drug tolerance in 31 
patients treated with schedule 2/1, 10 of whom had previously been on the standard schedule 
and 0% 
respectively [31]. Table 1 depicts a comparison of reported toxicities from schedule 4/2 
reported in clinical trials of sunitinib. 
MD Anderson Cancer Center evaluated one hundred eighty five patients treated with 
frontline sunitinib for clinical outcome and toxicity as a function of treatment schedule.  
Eighty- seven percent started out receiving sunitinib on a conventional 4/2 schedule. During 
treatment, 53% of patients continued on a conventional treatment schedule and 47% initiated 
or transitioned to an alternate schedule, which mainly consisted of treatment with sunitinib 
two weeks on and one week off. Baseline characteristics were similar. Adverse effects
prompting schedule modification included fatigue (64%), hand-foot syndrome (38%) and 
diarrhea (32%). Median time to schedule change was 5.6 months. Median overall survival 
(OS) was 17.7 months (95% CI = 10.8 to 22.2 months) on conventional schedule compared 
to 33.0 months (95% CI = 29.3 to not estimable) on an alternate schedule (P < 0.0001). By 
multivariable analysis; poor ECOG PS, increased LDH, decreased albumin, unfavorable 
Heng criteria, and conventional schedule were associated with decreased OS (P < 0.05). [32,
and unpublished data]. Comparison of toxicity prevalence before and after schedule 
adjustment demonstrated a clear reduction in toxicity rates Table 2.
Moreover, dynamic microbubble ultrasounds (DCE-US) in patients receiving sunitinib has 
demonstrated reduction of tumor blood volume at day 7 and day 14, compared to baseline, 
with no further reduction in blood flow from day 14-28 [33]. These findings suggest that the 
putative anti-tumor mechanism of sunitinib, i.e. reduction in tumor-associated blood flow, is 
optimized after 14 days, and dosing of sunitinib from day 15-28 may increase toxicity 
without meaningfully contributing to efficacy. Taken together, these data provide further 
impetus to explore modified schedules of sunitinib. We hypothesize that sunitinib 
-
foot syndrome and diarrhea when compared to historical data, while maintaining 
clinical efficacy.
Table 1:  Comparison of the incidence of selective toxicities of VEGFR inhibitors in metastatic renal 
cell carcinoma
Fatigue
HFS
Diarrhea
Low Platelets
No. of 
patient
s
All 
grade
Grade 
3+
All 
grade
Grade 
3+
All 
grade
Grade
3+
All 
grade
Grade
3+
Sunitinib
Phase III vs. 
IFN6
375
54%
11%
29%
9%
61%
9%
68%
9%
EFFECT18
146
65%
9%
32%
10%
59%
6%
75%
13%
COMPARZ20
548
63%
7%
50%
12%
57%
8%
34%
16%
CCF 2/130
30
54%
7%
17%
0%
36%
3%
7%
0%
MDACC* 
-
62%
-
32%
-
32%
-
3%
-
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before 
modification
MDACC* 
after 
modification
-
19%
-
2%
-
2%
-
0%
-
Pazopanib
Phase III35
290
19%
2%
<10%
<1%
52%
4%
32%
1%
COMPARZ20
554
55%
11%
29%
6%
63%
9%
10%
3%
Tivozanib
Phase III36
259
19%
3%
13%
2%
18%
2%
17%
1%
*unpublished data
Table 2: Prevalence of toxicity before and after schedule modification
(MD Anderson Cancer Center data)
Adverse Event
Before schedule 
modification
N = (%)
At first follow up after 
schedule modification
N = (%)
Fatigue
40 (64)
18 (29)
Hand foot syndrome
24 (38)
6 (10)
Diarrhea
20 (32)
4 (6)
Mucositis
14 (22)
3 (5)
Nausea/vomiting
9 (14)
7 (11)
Dysgeusia
6 (10)
0
Rash
6 (10)
0
Hypertension
6 (10)
3 (5)
Anorexia
5 (8)
1 (1.5)
Mouth sores
3 (5)
0
Laboratory Abnormalities
ANC < 1K/uL
3 (5)
1 (1.5)
Platelet count < 100 
K/uL
2 (3)
1 (1.5)
TSH level > 4.20 IU/mL
2 (3)
0
2.0
OBJECTIVES
2.1
Primary Objective 
treatment-related fatigue, hand-foot syndrome 
and/or diarrhea in metastatic renal cell carcinoma (mRCC) patients receiving 
sunitinib on a 2 weeks on / 1 week off schedule (schedule 2/1).
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2.2
Secondary Objective(s)
To assess the progression-free survival (PFS) of schedule 2/1 in patients with metastatic 
RCC.
grade 3 toxicities on schedule 2/1
To assess the incidence of dose reductions, dose interruptions, dose delays and rate of 
discontinuation for toxicity in patients with mRCC receiving sunitinib schedule 2/1.
To assess patient reported outcomes
To assess biologic correlatives by measuring circulating DNA levels
To assess correlation of tumor associated macrophages with response to therapy
3.0
STUDY DESIGN
3.1
Study schema
This is a single arm phase II study of sunitinib administered to treatment-naïve patients with 
clear cell mRCC. Patients will be treated with sunitinib at a starting dose of 50mg 2/1 with 
schedule/dose modifications for toxicity and treated until RECIST-defined progressive 
disease or unacceptable toxicity. Adverse events will be graded and categorized using 
CTCAE version 4.03 criteria. Staging studies will be assessed per RECIST v 1.
Sunitinib starting dose 50 mg by mouth daily given for 2 weeks “on” followed by 1 week “off”
1 cycle=6 weeks
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3.2
Study Calendar
Screeninga
C1D1 
(week 1)
Odd 
Cycles, 
D42
(up to Cycle 
11)
Even 
Cycles, 
D42
(up to Cycle 
12) 
Cycles 
Beyond 
C12h
End of 
Treatment
End of study
Informed consent
X
History, physical 
exam and weight
X
X
X
X
X
X
X
Vital signsb
X
X
X
X
X
X
X
Toxicity assessmentb
and concomitant 
medications
X
X
X
X
X
X
X
CBC differential,
plateletc
X
Xc
X
X
X
X
X
Serum chemistryc
X
Xc
X
X
X
X
X
TSHd
X
X
X
X
LDH
X
B-HCG for women of 
child-bearing age
X
CT or MRI braine
X
CT chest/
abdomen/pelvisf (with 
contrast)
X
X
X
Xi
Bone scane
X
FACT-G QOLg
X
X
Serum, plasma & 
buffy coat samples for 
biological correlatesj
X
X
X
X
aScreening studies must be completed within 28 days prior to administration of protocol therapy. Height to be collected at 
screening.
bVital signs to include temperature, blood pressure and pulse
Toxicity assessment using CTCAE v 4.03
C CBC, to be performed with differential and platelet count; Serum Chemistry to include albumin, alkaline phosphatase, 
total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose,  potassium, total protein, SGOT [AST], SGPT 
[ALT], sodium. CBC/chemistry does not need to be repeated at C1D1 if previous test was within last 14 days
dThyroid function studies (TSH) should be performed every other cycle or more frequently if clinically indicated
eBone scan and CT brain should be performed during screening. Subsequently, repeat scans to be performed 
only if clinically indicated. MRI brain in lieu of CT brain acceptable.
f CT chest/abdomen/pelvis to be repeated every 2 cycles
gFACT-G to be administered at visits during baseline, week 12, week 24 and week 36 assessments prior to MD 
encounter. Study team to check for completion of QOL data: more than 50% questions in each subscale, and at 
least 80% of questions overall in each questionnaire should be answered for the questionnaire to be considered 
complete.
One Cycle= 42 days (6 weeks).         
For each visit, the following variations in time are acceptable:
A window of ± 5 days is allowed for labs and follow-up visits (except C1D1); ±7 days is allowed for restaging scans.
Patients are to record blood pressure measurements in BP log daily for the first week and at least once per week thereafter. Daily 
intake of sunitinib should be recorded in the pill diary throughout treatment. Both will be collected during office visits by provider.
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h Labs and follow-up visits can be every 12 weeks after completion of 12 cycles, at the discretion of the treating 
physician
i EOS visit does not require CT scans if performed within the preceding 12 weeks. 
j Biological correlates to include characterization of circulating DNA and tumor associated macrophages. 
4.0 PATIENT SELECTION
4.1
Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment: 
1. Histologically or cytologically-confirmed metastatic renal cell carcinoma of clear cell 
histology. Prior nephrectomy is not a requirement for eligibility
2. Age 18 years
3. Measurable or evaluable metastatic disease per RECIST v 1
4. ECOG performance status 0-1
5. Normal organ and bone marrow function as defined by:
o
Serum aspartate transaminase (AST; serum glutamic oxaloacetic    
transaminase [SGOT]) and serum alanine transaminase (ALT; serum
normal (ULN)
o
o
o
o
o
o
6. Patients with a history of deep venous thromboembolism or pulmonary embolism on 
treatment with anticoagulation are eligible for the study.
7. Subjects must have the ability to understand and the willingness to sign a written 
informed consent document  
4.2
Exclusion Criteria
The presence of any of the following will exclude a patient from study enrollment.
1. Prior treatment with sunitinib or any other systemic therapy in the metastatic setting 
(prior neo/adjuvant therapy will be allowed if completed > 6 months prior to registration 
and therapy not discontinued for toxicity)
2. Uncontrolled hypertension (defined as blood pressure >140/90 mm Hg not controlled 
with anti-hypertensives)
3. Prior intraabdominal, intrathoracic, vascular, spinal or intracranial surgery or radiation 
therapy within 4 weeks of starting treatment
4. History of or known brain metastases, spinal cord compression, or carcinomatous 
meningitis
5. New York Heart Association (NYHA) grade II or greater congestive heart failure
6. Current treatment on another therapeutic clinical trial
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7. Any of the following within the preceding 6 months-
myocardial infarction, 
severe/unstable angina, severe peripheral vascular disease (claudication) or procedure on 
peripheral vasculature, coronary/peripheral artery bypass, graft, cerebrovascular accident 
or transient ischemic attack, clinically significant bleeding
8. Pregnant or breastfeeding women are excluded from this study because there is an 
unknown, but potential risk for adverse events in nursing infants secondary to treatment 
of the mother with sunitinib. Breastfeeding must be discontinued if the mother is treated 
with sunitinib
9.
Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-
related illness
10. HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with sunitinib.  In addition, these patients are at 
increased risk of lethal infections when treated with marrow suppressive therapy 
4.3
Inclusion of Women and Minorities
Both men and women and members of all races and ethnic groups are eligible for this trial.
5.0
REGISTRATION
All patients will be registered in the approved Office of Research Administration (ORA) 
database at MD Anderson.  For those subjects who are consented, but not enrolled, the reason 
for exclusion must be recorded. For registration procedures for this protocol, please refer to 
Section 15.2 of the protocol and the Multicenter Management Plan (Appendix D).
6.0
TREATMENT PLAN
6.1
Sunitinib Administration
Treatment will be administered on an outpatient basis. Sunitinib will be initially dosed at 50
mg by mouth daily (QD) for 2 weeks followed by a one week break. Cycles of treatment will 
be defined as 6 week intervals regardless of dosing interruptions. Thus patients will receive 
sunitinib during weeks 1, 2, 4 and 5 of each 6 week (42-day) cycle, with treatment breaks 
during weeks 3 and 6. Sunitinib will be given without regard to meals. Patients will record 
blood pressure measurements daily for the first week and at least once weekly 
thereafter throughout the course of treatment using blood pressure logs that will be 
provided to them [Appendix 2].
Patients who experience toxicity per Section 8 may undergo dose/schedule modification as 
indicated per section 7. Reported adverse events and potential risks of sunitinib are described 
in Section 8.0. Appropriate dose and schedule modifications for sunitinib are described in 
Section 7.0.
No investigational or commercial agents or therapies other than sunitinib may be 
administered with the intent to treat the patient's malignancy. The patient will be provided a 
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Patient Pill Diary [Appendix 1] and instructed regarding its use to record each dose of 
oral medication.
6.2
General Concomitant Medications and Supportive Care Guidelines
Patients may receive Epogen/Procrit/Aranesp for anemia and a bisphosphonate for 
hypercalcemia and/or bone metastases as required. Anti-emetic therapy of any kind is permitted. 
Full transfusional support is permitted. The prophylactic use of growth factors is not allowed. 
The use of pyridoxine (vitamin B6) for the treatment of hand-foot syndrome is permitted. 
Palliative radiotherapy is allowed as long as there is no progressive disease per RECIST criteria;
sunitinib may or may not be held during radiotherapy at the discretion of the treating physician. 
If held, dose changes must be recorded. No other approved or investigational anticancer 
treatment will be permitted during the study period, including chemotherapy, biological response 
modifiers, hormone therapy or immunotherapy. No other investigational drug may be used 
during treatment on this protocol, and concurrent participation in another clinical trial is not 
allowed.
Sunitinib is metabolized primarily by liver enzymes, in particular CYP3A4. Agents known to 
induce CYP3A4 including dexamethasone should be avoided. Agents known to inhibit this 
enzyme (e.g., grapefruit juice) should also be avoided. In particular, ketoconazole should be 
avoided if possible, since a clinical interaction study of sunitinib indicated that up to a 2-fold 
increase in plasma levels of sunitinib was induced by ketoconazole. In addition, concomitant 
treatment with the following drugs with dysrhythmic potential (ie, terfenadine, quinidine, 
procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, and 
indapamide) is not recommended.
6.3
Duration of Therapy
In the absence of treatment delays due to adverse events, treatment may continue indefinitely 
until one of the following criteria applies:
Disease progression per RECIST version 1.
The investigator considers it, for safety reasons, to be in the best interest of the patient. 
Unacceptable adverse event(s) related to treatment, defined as a grade 3 or 4 toxicity (per 
CTCAE v 4.03) that fails to recover to < Grade 2 in the absence of treatment within 4 
weeks
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator
Patient decision to withdraw from treatment (partial consent) or from the study (full 
consent)
Pregnancy during the course of the study for a child-bearing participant
The date and reason for discontinuation must be documented.  Every effort should be made 
to complete the appropriate assessments. 
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If in the opinion of the investigator, the patient demonstrates disease progression by RECIST, 
but the patient is demonstrating obvious clinical benefit to sunitinib therapy, the investigator 
may choose to continue patient on study. At the time that clinical benefit from study drug is 
no longer apparent, investigator will take patient off study and off study drug.  
6.4
Duration of Follow Up
Patients will be followed for toxicity for 30 days after treatment has been discontinued or 
until death, whichever occurs first. 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study 
participation will be recorded and reported immediately.
7.0
DOSING DELAYS / DOSE MODIFICATIONS
Table 3: Dose/Schedule Levels
Table 3a defines treatment levels of sunitinib with dose and schedule specifications. The starting 
dose for all patients will be 50 mg on a 2/1 schedule. Dosing schedule may be changed to 50 mg 
1 week on followed by 3 days off alternating with 1 week on and 4 days off and repeated for a 6-
week cycle at outlined in table 3a for toxicities described in table 3b. Patient requiring further 
reduction in treatment level will be dose reduced to 37.5 mg on a 2/1 schedule, and so on per 
table 3a. Intra-patient re-escalation back to the previous treatment level is permitted in the 
-hematologic treatment-related toxicity in the 
previous cycle. Table 3b outlines indications for withholding treatment and for reductions in 
treatment levels. 
Table 3a:  Treatment levels of sunitinib with dose and schedule specifications
Treatment Level
Sunitinib dose
Schedule
Level    0
(starting dose)
50 mg
2 weeks on/ 1 week off
Level   -1
50 mg
1 week on/ 3 days off
alternating with 1 week 
on/4 days off
Level   -2
37.5 mg
2 weeks on/ 1 week off
Level -3
37.5 mg
1 week on/ 3 days off 
alternating with 1 
week on/4 days off
Level -4
25 mg
2 weeks on/ 1 week off
Level -5
25 mg
1 week on/ 3 days off 
alternating with 1 
week on/4 days off
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Table 3b:  Indications for withholding treatment and reductions in treatment levels
Grade 
Type                     
Management/Next Dose for Sunitinib
Grade 1+
Any except vascular +
No change in treatment level
Grade 
2
Hematologic
Continue at same treatment level
Cardiac
Continue at same treatment level except in the event 
of:
-Decrease of LVEF by an absolute value of 20% and to 
below the lower limit of normal
-Non-urgent ventricular paroxysmal dysrhythmia 
requiring intervention.
In these cases: w
then reduce the treatment by 1 level and resume 
treatment. If the patient was on level 0, then need to 
resume at level -2
Non-cardiac and non-
hematologic
Continue at same dose level
Grade 
3
Hematologic***
Withhold dose until ANC>1,000 and Platelets > 50,000, 
then resume treatment at the same  level or reduce by 1 
level at the discretion of the investigator. 
Cardiac
to baseline, then resume treatment at the same level or 
reduce the dose by 1 level at the discretion of the 
investigator.**
Non-cardiac and non-
hematologic*
baseline, then resume treatment at the same  level or reduce 
by 1 level at the discretion of the investigator. 
Grade 
4
Hematologic***
Withhold dose until toxicity 
1 or has returned 
to baseline, then reduce by 1 level and resume 
treatment**.
Cardiac
Remove from protocol.
Non-cardiac and non-
hematologic
Withhold dose until toxi
1 or has returned 
to baseline, then reduce by 1 level and resume 
treatment, or discontinue at the discretion of the 
investigator.
+Except vascular- for all vascular toxicities, including grade 1, drug must be held and appropriate treatment 
initiated. Sunitinib may be restarted at the discretion of the treating MD.
* Patients with grade 3 asymptomatic biochemistry laboratory abnormalities may continue treatment at the same 
dose level without interruption at the discretion of the investigator. 
** Hypertension may be managed appropriately with anti-hypertensives, and the patient may continue sunitinib 
provided the blood pressure is controlled to < 160/90 mmHg within 4 weeks. Patients who are unable to have 
blood pressure controlled to < 160/90 mmHg within 4 weeks should be removed from the study. Patients with 
congestive heart failure must be removed from study. 
***Patients who develop grade 3 or 4 lymphopenia may continue study treatment without interruption. 
All intra-patient dose reductions are relative to the lowest dose level of the current cycle. If the current treatment
level is -5 and the toxicity guidelines above indicate a further treatment/dose reduction is necessary, treatment
should be discontinued. Patients are to be removed from study if toxicity does not resolve to grade 1 or less within 
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4 weeks off study drug. 
8.0
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
The following is a list of AEs (Section 8.1) and the reporting requirements associated with 
observed AEs (Sections 8.3 and 8.4). 
The clinical course of each event will be followed until resolution, stabilization, or until it has 
been determined that the study treatment or participation is not the cause. 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation will 
be recorded and reported immediately.
8.1
Adverse Events and Potential Risks
8.1.1
Adverse events and potential risks list
Adverse events will be assessed and will be graded according to the NCI CTCAE v4.03.
CTCAE v4.3 can be accessed on the internet at:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
dWatch 
form) to the Principal Investigator, the Data Safety and Toxicity Committee and the IRB.
To date, over 1500 subjects with advanced malignancies have been treated with sunitinib malate. 
Multiple phase 1, 2 and 3 studies have been conducted or are underway. Study subjects enrolled 
on the initial clinical studies received sunitinib malate in a free-base formulation, but study 
subjects enrolled on protocols activated after February 2002 were treated with the sunitinib 
malate salt formulation. A prior study demonstrated the bioequivalence of these 2 formulations. 
The primary DLT in the phase 1 studies appeared to be fatigue/asthenia, which generally 
occurred 10 to 15 days after start of therapy, and was readily reversible upon discontinuation of 
sunitinib malate treatment. Fatigue appeared to increase in frequency with an increase in drug 
exposure. DLT experienced during the first cycle of therapy was observed more frequently in 
subjects on Schedule 4/2 than in subjects on Schedule 2/2. Overall, the most frequent adverse 
events associated with sunitinib malate treatment of greatest severity have been constitutional 
(fatigue/asthenia), gastrointestinal (nausea, vomiting, diarrhea), and hematologic (neutropenia, 
thrombocytopenia). The degree of adverse event severity appears to correlate with higher drug 
exposure and/or lower subject performance status. A similar pattern was observed for subjects 
with previous chemotherapy in comparison to chemotherapy-naïve subjects. 
In studies evaluating starting doses that ranged from 75 to 100 mg daily, cardiac hypokinesis and 
clinical signs of congestive heart failure were reported in 4 of 62 advanced acute myeloid 
leukemia subjects; however, the causal relationship to sunitinib malate was confounded by 
disease morbidities and prior anthracycline exposure. At the 50-mg dose level, asymptomatic 
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decreases in cardiac ejection fraction were observed in <5% of solid tumor subjects, either with 
or without a prior history of cardiovascular disease or anthracycline exposure. Decrease in LVEF 
by MUGA is reversible and does not appear to have cumulative effect with repeat drug exposure. 
A review of cardiac and other safety data from clinical and preclinical studies is provided in the 
Investigator Brochure. 
The maximum tolerated dose has been defined as 50 mg in phase 1 clinical studies in subjects 
with advanced solid tumors, subjects with AML, and subjects with imatinib mesylate-resistant 
GIST. Subjects receiving this dose of sunitinib malate achieved target plasma concentrations of
sunitinib malate plus SU012662 in the range of 50 to 100 ng/mL. 
8.2
Definitions 
8.2.1
Adverse Events  
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to a research participant as a result 
of the participant’s involvement in a research study. The event can include abnormal laboratory 
findings, symptoms, or disease associated with the research study. The event does not necessarily 
have to have a causal relationship with the research, any risk associated with the research, the 
research intervention, or the research assessments. 
Adverse events may be the result of the interventions and interactions used in the research; the 
collection of identifiable private information in the research; an underlying disease, disorder, or 
condition of the subject; and/or other circumstances unrelated to the research or any underlying 
disease, disorder, or condition of the subject. In general, adverse events that are at least partially 
the result of (a) or (b) would be considered related to the research, whereas adverse events solely 
related to (c) or (d) would be considered unrelated to the research. 
External adverse events are adverse events experienced by subjects enrolled in multicenter 
clinical trials at sites other than the site(s) over which the Institutional Review Board has 
jurisdiction. 
Internal adverse events are adverse events experienced by subjects enrolled at the site(s) under 
the IRB’s jurisdiction for either multicenter or single-center research projects. 
The significance of an adverse event is used to describe the patient/event outcome or action 
criteria associated with events that pose a threat to a patient’s life or functioning (i.e., moderate, 
severe or life threatening).  Based on the National Cancer Institute Guidelines for the Cancer 
Therapy Evaluation Program, severity can be defined by the following grades of events:
Grades 1 are mild adverse events. (e.g., minor event requiring no specific medical intervention; 
asymptomatic laboratory findings only; marginal clinical relevance)
Grades 2 are moderate adverse events (e.g., minimal intervention; local intervention; non-
invasive intervention; transfusion; elective interventional radiological procedure; therapeutic 
endoscopy or operation).
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Grades 3 are severe and undesirable adverse events (e.g., significant symptoms requiring 
hospitalization or invasive intervention; transfusion; elective interventional radiological 
procedure; therapeutic endoscopy or operation).
Grades 4 are life threatening or disabling adverse events (e.g., complicated by acute, life-
threatening metabolic or cardiovascular complications such as circulatory failure, hemorrhage, 
sepsis; life–threatening physiologic consequences; need for intensive care or emergent invasive 
procedure; emergent interventional radiological procedure, therapeutic endoscopy or operation).
Grades 5 are fatal adverse event resulting in death.    
8.2.2
Serious Adverse Events 
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
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.
A congenital anomaly/birth defect.
8.2.3
Expectedness
Adverse Events can be Expected or Unexpected.
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol. 
An unexpected adverse event is an adverse event not previously known or anticipated to result 
from the research study or any underlying disease, disorder, or condition of the subject. 
8.2.4
Attribution
Attribution is the relationship between an adverse event or serious adverse event and the study 
drug.  Attribution will be assigned as follows:
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Definite – The AE is clearly related to the study drug.
Probable – The AE is likely related to the study drug.
Possible – The AE may be related to the study drug.
Unlikely – The AE is doubtfully related to the study drug.
Unrelated – The AE is clearly NOT related to the study drug.
8.3
Reporting Procedures for All Adverse Events
All participating investigators will assess the occurrence of AEs throughout the subject’s 
participation in the study, beginning at the time of initiation of treatment.  Subjects will be 
followed for toxicity for 30 days after treatment has been discontinued or until death, whichever 
occurs first.  The clinical course of each event will be followed until resolution, stabilization, or 
until it has been determined that the study treatment or participation is not the cause.  
The investigator is responsible for ensuring that all adverse events observed by the investigator 
or reported by the subject which occur after the subject has initiated treatment are fully recorded 
in the subject’s case report form, subject’s medical records, and/or any other institutional 
requirement. Source documentation must be available to support all adverse events.
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study), requiring treatment or causing apparent clinical manifestations, or 
judged relevant by the investigator, should be reported as an adverse event.  
The investigator will provide the following for all adverse events:
Description of the event
Date of onset and resolution
Grade of toxicity 
Attribution of relatedness to the investigational agent
Action taken as a result of the event
Outcome of event
In this study, descriptions and grading scales found in the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting, available at:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
Investigative sites will report adverse events to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events.
8.4
Serious Adverse Event Reporting Procedures
Serious adverse events that occur beginning with initiation of treatment, during treatment, or 
within 30 days of the last dose of treatment must be reported to the MD Anderson Cancer Center
Principal Investigator.
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Investigative sites will report serious adverse events to their respective IRB according to the 
local IRB’s policies and procedures in reporting serious adverse events.
8.4.1
Pfizer Reporting
The Investigator Initiated Research Serious Adverse Event Form provided by Pfizer will be 
utilized for reporting all SAEs to Pfizer. 
9.0
PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 8.0.   
Sunitinib
Chemical Name:     
5-(5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-
dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-
amide; compound with (S)-2-hydroxy-succinic acid.
Other Names:        
SUNITINIB L-Malate salt; SU010398; PHA-290940AD; Sutent; 
SUNITINIB, sunitinib malate
Classification:
Receptor tyrosine kinase inhibitor (RTK)
Molecular Formula:
C
22H
27FN
4O
2.C
4H
6O
5
Mode of Action:
Sunitinib malate is a receptor tyrosine kinase inhibitor involved 
in tumor proliferation and angiogenesis, specifically inhibiting 
platelet derived growth factor receptor, vascular endothelial 
growth factor receptor, stem cell factor receptor, Fms-like
tyrosine kinase-3 receptor, and ret proto-oncogene.
Metabolism:   
Cytochrome P450 (CYP) 3A-mediated N-deethylation to form 
SU012662 was the major pathway of the metabolism of sunitinib 
in liver microsomes from rats, monkeys, and humans. Sunitinib 
metabolism was predominately mediated by CYP3A4 and 
produced an active metabolite, SU012662. This metabolite and 
sunitinib were the only major drug-related compounds found in 
systemic circulation in mice, rats, monkeys, and humans. Minor
metabolites of sunitinib were mainly found in excreta and were 
either not found or found at very low levels in plasma. Sunitinib 
and SU012662 were not potent inducers or inhibitors of major 
CYP450 enzymes. The efflux transporters, P-gp and BCRP, did 
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not appear to play a significant role in the pharmacokinetics of 
sunitinib. Therefore, sunitinib and SU012662 are predicted to 
have a low potential to cause clinically relevant drug-drug 
interactions mediated by CYP450 enzymes and the efflux 
transporters. However, concomitantly administered CYP3A4 
inducers and inhibitors may affect the pharmacokinetics of 
sunitinib.
Product description:
Physical description: Yellow to orange powder
Molecular weight: 532.57 Daltons
Drug procurement: Sunitinib will be supplied by Pfizer will be used for this study. Sunitinib 
malate is distributed by Pfizer as 12.5 mg, 25 mg, and 50 mg capsules with mannitol, 
croscarmellose sodium, povidone, and magnesium stearate. Each opaque plastic bottle contains 
30 capsules
Storage requirements: Store at controlled room temperature (150 to 300 C), and protect from 
light.
Stability: The shelf life for the 12.5 mg capsule is 24 month. The shelf life for the 25 mg and 50 
mg capsules is 36 months.
Route of administration: Oral. Sunitinib malate may be administered without regard to meals.
Drug Accountability: The investigator or designated study personnel are responsible for 
maintaining accurate dispensing records of the study drug. All study drugs must be accounted 
for, including study drug accidentally or deliberately destroyed. Under no circumstances will the 
investigator allow the investigational drug to be used other than as directed by the protocol. If 
appropriate, drug storage, drug dispensing, and drug accountability may be delegated to the 
pharmacy section of the investigative site.
Drug Destruction: At the completion of the study, there will be a final reconciliation of drug 
shipped, drug consumed, and drug remaining. This reconciliation will be logged on a drug 
reconciliation form, signed and dated. Any discrepancies noted will be investigated, resolved, 
and documented prior to return or destruction of unused study drug. Drug destroyed on site will 
be documented in the study files.
Patient Care Implications: A yellow discoloration of the skin area may result following direct 
contact with the capsules. Wash the exposed area with soap and water immediately. 
Potential Drug Interaction: Sunitinib malate is metabolized primarily by liver enzymes, 
particularly CYP3A4. CYP3A4 inducers (e.g., rifampin, dexamethasone) and CYP3A4 inhibitors 
(e.g., grapefruit juice, ketoconazole) should be avoided, if possible. Rifampin lowers sunitinib 
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malate Cmax concentration by more than 2-fold. Ketoconazole increases sunitinib malate Cmax 
by 1.6 fold. Dose reduction with the CYP3A4 inhibitors is recommended, based on clinical 
symptoms. Concomitant treatment with dysrhythmic drugs, i.e., terfenadine, quinidine, 
procainamide, sotalol, probucol, bepridil, haloperidol, risperidone, and indapamide, is not 
recommended. 
10.0
PATIENT REPORTED OUTCOMES (PROs – See Appendix #3)
10.1
Quality of life (QOL) questionnaires 
QOL questionnaires will be utilized to evaluate patient reported outcomes. This would 
include the Functional Assessment of Cancer Therapy- General (FACT-G) scale.
The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System is a 
collection of health-related quality of life (HRQOL) questionnaires targeted to the 
management of chronic illness [34]. The validated FACT-G scale is a 27-item compilation of 
general questions divided into four primary QOL domains: Physical Well-Being, 
Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. It is 
appropriate for use with patients with any form of cancer is widely used for assessing health-
related QOL for different cancers. This questionnaire was designed for self-administration,
written at 4th grade reading levels, and can be completed in 5-10 minutes [34]. A higher total 
score suggests well-being, and a lower score is an indication of inferior QOL. 
10.2
Rationale 
With the availability of several new targeted agents that prolong survival in mRCC, there is 
increasing emphasis on patient preferences based on treatment related quality of life. Two 
recent randomized trials, COMPARZ and PISCES (pending publication), demonstrated 
differences in QOL amongst sunitinib and its active comparator, pazopanib [19, 20]. The 
impact of treatment related toxicities on patients’ QOL while receiving sunitinib on the 2/1 
schedule is thus an important end-point of interest.
10.3
Data collection
QOL questionnaires will be administered at the initiation of treatment (baseline), and then at 
week 12, week 24 and week 36. These will be administered by the study team prior to 
patient encounters with the physician. The study team will also check for completion of all
elements in each questionnaire, which will be collected from the patient at the end of that 
encounter. Only forms with more than 50% answers in each subscale will be considered 
acceptable. Moreover, at least 80% of questions overall in each questionnaire should be 
answered in order for it to be considered acceptable for analysis. 
Missing data: Prorating subscale scores is acceptable as long as more than 50% of the 
items have been answered (e.g., a minimum of 4 of 7 items, 4 of 6 items, etc). The total 
(FACT-G) score is considered appropriate to score as long as overall item response rate is 
greater than 80% (e.g., at least 22 of 27 FACT-G items complete) [34].
10.4
Data analyses
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The end-point for all three PROs would be the mean score at each time point- baseline, week 
12, week 24 and week 36. Descriptive summary statistics will be calculated for all 
continuous variables (means, standard deviations, medians, ranges, percentage of patients 
scoring in the highest category for each item) for the items in the subscales each time point. 
The mean trajectories of each group over time will be plotted for the total scores, along with 
scores for physical well-being, social well-being, emotional well-being and functional well-
being-specific scales for FACT-G.  
11.0
CORRELATIVE STUDIES
11.1
Circulating Tumor DNA
Cell-free circulating tumor DNA may provide prognostic and pharmacodynamic information 
in patients treated with anticancer therapy.  The advent of sensitive, high throughput 
sequencing has permitted the efficient investigation of tumor specific polymorphisms.   In 
collaboration with Dr. Raghu Kalluri, we will assess patient serum for presence of circulating 
tumor DNA and perform exome sequencing to determine whether tumor specific DNA 
polymorphisms can be detected.  Samples will be collected at baseline and defined restaging 
intervals to determine whether pretreatment levels correlate to outcome and whether 
treatment with and response to antiangiogenic therapy impacts levels of circulating tumor 
DNA. 
11.2
Tumor Associated Macrophages
Emerging data suggest that bone marrow derived cells residing in the tumor 
microenvironment may modulate response to antiangiogenic therapy.  Baseline infiltration of 
discrete populations of microenvironment modulating cells can be measured by co-staining
archival tumor tissue with appropriate antibodies.   These populations include tumor-
associated macrophages (TAM), myeloid derived suppressor cells (MDSC) and t-regulatory 
cells.  Quantitation of these cells and comparing them to clinical outcome will shed light on 
which of these cell populations is predictive for response to sunitinib therapy.
12.0
STUDY PARAMETERS
12.1
Screening Evaluation  
Screening studies and evaluations will be used to determine the eligibility of each subject for 
study inclusion. All evaluations must be completed < 28 days prior to administration of 
protocol therapy. 
Informed consent
Demographics 
Medical history 
Complete physical examination 
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Height
Weight
Vital signs including: Blood pressure, pulse and temperature
Concomitant medications assessment including prescription, over the counter and 
herbal medications
ECOG Performance Status  
Baseline symptoms assessment
Laboratory studies:
Complete Blood Count (CBC) with differential and platelets
Serum 
Chemistries: 
albumin, 
alkaline 
phosphatase, 
total 
bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium
LDH ,TSH
ß-HCG for women of childbearing potential 
CT scan of brain, chest, abdomen and pelvis (with contrast). An MRI brain 
performed with contrast in lieu of CT brain is acceptable, if within the study 
timeframe.
Bone scan at baseline 
12.2
Treatment Period
Treatment cycles are 6 weeks long. For each visit, the following variations in time are 
acceptable:
A visit window of ± 5 days is allowed for labs and follow-up visits.
A window of ±7 days is allowed for restaging scans.
Schedule changes due to Holidays or weather that result in study procedures outside these 
windows will not be considered a protocol deviation.
Cycle 1, Day 1
Cycle 1, Day 1 evaluations do not need to be repeated if conducted within 7 days prior to 
administration of protocol therapy.  
Physical Examination 
Weight
Vital signs including: blood pressure, pulse, and temperature
Concomitant medications assessment including all current medications
ECOG Performance Status  
Baseline symptoms assessment 
Laboratory Studies: (waive if performed within the last 14 days)
Complete Blood Count (CBC) with differential and platelets
Serum Chemistries: albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, 
calcium, chloride, creatinine, glucose,  potassium, total protein, SGOT [AST], SGPT 
[ALT], sodium.
Correlative Studies: QOL questionnaires: FACT-G
                              Biological correlates : Serum, plasma, buffy coat samples
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Cycle 1, Day 42
Physical Examination 
Weight
Vital signs including: blood pressure, pulse and temperature
Concomitant medications assessment including all current medications
ECOG Performance Status  
Toxicity Assessment 
Laboratory Studies: A window of ± 5 days is allowed for labs 
Complete Blood Count (CBC) with differential and platelets
Serum Chemistries: albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, 
calcium, chloride, creatinine, glucose,  potassium, total protein, SGOT [AST], SGPT 
[ALT], sodium.
Cycle 2, Day 42
Physical Examination 
Weight
Vital signs including: blood pressure, pulse and temperature
Concomitant medications assessment including all current medications
ECOG Performance Status  
Toxicity Assessment 
Laboratory Studies:
Complete Blood Count (CBC) with differential and platelets
Serum Chemistries: albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, 
calcium, chloride, creatinine, glucose,  potassium, total protein, SGOT [AST], SGPT 
[ALT], sodium.
Correlative Studies:
QOL questionnaires: FACT-G
Biological correlates : Serum, plasma, buffy coat samples
Restaging scans: CT scan of chest, abdomen and pelvis (with contrast)
Subsequent cycles – each visit at Day 42
The assessment and evaluation in subsequent visits will include all the items enlisted 
in cycle 2 day 42, except:
Restaging scans that will be performed every even numbered cycle (cycle 4, 6, etc.)
QOL questionnaires will be assessed at baseline, week 12, week 24 and week 36
only.
Biological correlate : Serum, plasma, buffy coat samples will be collected at at 
baseline, week 12, week 24, week 36, and at the time of disease progression. 
Bone scan will be repeated in patients with bone metastases at baseline or at the 
development of signs/symptoms consistent with bone metastases. 
CT/MRI brain will not need to be repeated unless a patient was to develop clinical 
symptoms that warrant brain imaging, in which case the decision to conduct CT 
versus MRI of the brain will be at the discretion of the treating physician.
TSH will be checked in every even numbered cycle and additionally if clinically 
indicated.
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After 12 cycles, labs and follow-up visits may be allowed every 12 weeks instead of 
every 6 weeks if clinically indicated at the discretion of the treating physician.
End of Treatment Visit
Physical Examination 
Weight
Vital signs including: blood pressure, pulse and temperature
Concomitant medications assessment including all current medications
ECOG Performance Status 
Toxicity Assessment 
Laboratory Studies:
Complete Blood Count (CBC) with differential and platelets
Serum Chemistries: albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, 
calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT 
[ALT], sodium.
End of Study - 30 Day Follow-Up
Physical Examination 
Weight
Vital signs including: blood pressure, pulse and temperature
Concomitant medications assessment including all current medications
ECOG Performance Status  
Toxicity Assessment 
CT scan of chest, abdomen and pelvis (with contrast) not required if performed within 
the preceding 12 weeks
Laboratory Studies:
Complete Blood Count (CBC) with differential and platelets
Serum Chemistries: albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, 
calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT 
[ALT], sodium.  
13.0
MEASUREMENT OF EFFECT
13.1
Antitumor Effect – Solid Tumors
For the purposes of this study, patients should be re-evaluated for response every 12 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 12 weeks following 
initial documentation of objective response.
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1) 
[Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
13.1.1 Definitions
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Evaluable for toxicity All patients will be evaluable for toxicity from the time of their first 
treatment with sunitinib.
Evaluable for objective response Only those patients who have measurable disease present at 
baseline, have received at least one cycle 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.)
Evaluable Non-Target Disease Response Patients who have lesions present at baseline that are 
evaluable, but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. 
13.1.2 Disease Parameters
Measurable Disease Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter for non-nodal lesions and short axis for nodal lesions to 
be recorded) as > 20 mm by chest x-ray, as > 10 mm with CT scan, or > 10 mm with calipers by 
clinical exam.  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 > 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable disease All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with > 10 to < 15 mm short axis) are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI) are considered as non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions.
Target lesions All measurable lesions up to a maximum of 2 lesions per organ and 5 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), be representative of all involved organs, but in addition should be 
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those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance, the next largest lesion which can be measured reproducible should be selected. 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 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 any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.
13.1.3 Methods 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.
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 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 
(e.g., skin nodules and palpable lymph nodes) and > 10 mm diameter as assessed using calipers 
(e.g., skin nodules). 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 This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If 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).
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
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image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-holding techniques, if possible. 
PET-CT should not be used as an imaging modality
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, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint.
Tumor markers not applicable
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.
13.1.4 Response Criteria
13.1.4.1
Evaluation of Target lesions
Response
Evaluation of Target Lesions
Complete Response 
(CR)
Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm.
Partial Response 
(PR)
At least a 30% decrease in the sum of diameters of 
target lesions, taking as reference the baseline sum of 
diameters.
Progressive Disease 
(PD)
At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  
Note: the appearance of one or more new lesions is 
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also considered progression.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study.
13.1.4.2
Evaluation of Non-Target lesions
Response
Evaluation of Non-Target Lesions
Complete Response 
(CR)
Disappearance 
of 
all 
non-target 
lesions 
and 
normalization of tumor marker level. All lymph nodes 
must be non-pathological in size (< 10 mm short axis).
Note: If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
Non-CR/ Non-PD
[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.  Unequivocal progression
should not 
normally trump target lesion status. It must be 
representative of overall disease status change, not a 
single lesion increase.
Although a clear progression of ‘non-target’ lesions 
only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and 
the progression status should be confirmed at a later 
time by the review panel (or Principal Investigator). 
13.1.4.3
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.
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For Patients with Measurable Disease (i.e., Target Disease)
Target 
lesions
Non-Target 
Lesions
New Lesions
Overall 
Response
Best 
Overall 
Response 
when 
Confirmation 
is
Required*
CR
CR
No
CR
> 4 wks. Confirmation **
CR
Non-CR/Non-PD
No
PR
> 4 wks. Confirmation **
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not evaluated
No
PR
SD
Non-CR/Non-
PD/not evaluated
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
*         See RECIST 1 manuscript for further details on what is evidence of a new lesion.
**       Only for non-randomized trials with response as primary endpoint.
***     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. 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesion
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD *
Not all evaluated
No
Not evaluated
Unequivocal PD
Yes or No
PD
Any 
Yes
PD
*        ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised.
13.1.5 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)
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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive 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, including the baseline measurements.
13.1.6 Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
14.0
MULTICENTER PROCEDURES
Participating multicenter institutions will follow the guidelines as addressed below, in the MD 
Anderson Multicenter Management Plan (Appendix D), and throughout this protocol.
14.1
Principal Investigators
The principal investigator(s) will be responsible for the conduct of the study and monitoring its 
progress.  The responsibility for all reports and data required by MD Anderson will be that of the 
principal investigator(s).
14.2
Centralized Patient Registration and Randomization
Patients who are candidates for the study will first be evaluated for eligibility by the local 
investigator. All patients will be registered by designated research staff in the GU department. 
All multicenter patients must be registered both locally and centrally with MD Anderson. 
At the time of registration, participating institutions will be required to submit a completed and 
signed eligibility checklist and informed consent document. No additional source documentation 
will be required for patient registration.
14.2.1 Eligibility Exceptions
All exceptions to eligibility must first be approved by the Protocol Chair with appropriate
rationale following MD Anderson guidelines. If eligibility clarifications are required from 
participating institutions, all eligibility questions should be routed to the MD Anderson GU
Department in order to document the question and Protocol Chair response.
14.3
Guidelines for Reporting Participating Site Serious Adverse Events to MD Anderson:
Any Serious Adverse Event (SAE) will be reported to the MD Anderson GU Department within 
24 hours of knowledge of the event.   MD Anderson GU Department will in turn notify Pfizer. 
The participating institution will submit the SAE to its own IRB according to institutional policy 
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and must forward a copy of the report to MD Anderson within 5 calendar days.  The MD 
Anderson GU department will submit participating site SAE reports to the MDACC IRB and 
Pfizer.
SAE notifications and reports will be submitted to:
Email a completed SAE Form to:
MD Anderson GU Department (notifications and reports)
Subject: 2013-0944 SAE Notification
Email: GU2013-0944@mdanderson.org
MD Anderson will maintain documentation of all Serious Adverse Events from each institution. 
MD Anderson will notify all investigators of any serious and unexpected adverse experiences 
that are possibly related to the study therapy.  The investigators are to file a copy in the protocol 
file and send a copy to their IRB according to their local IRB’s policies and procedures. 
14.4
Guidelines & Procedures for reporting Violations, Deviations and Unanticipated
Problems.
The Protocol Chair: is responsible for ensuring that clear documentation is available in the 
medical record to describe all protocol deviations, violations, and unanticipated problems. The 
Protocol Chair will also be responsible for ensuring that all protocol deviations, violations, and 
unanticipated problems are reported to the MD Anderson IRB per MD Anderson institutional 
guidelines.
Participating Institutions:
Protocol deviations, violations, and unanticipated problems 
occurring at a participating institution will be submitted to that institution’s own IRB. A copy of 
the participating institution’s IRB deviations, violations, and unanticipated problems report will 
be forwarded to MD Anderson by facsimile or via email within 7 calendar days after the original 
submission. 
14.4.1 Definitions 
The definitions for protocol violation and deviation as described by the MD Anderson IRB will 
be applied for reporting purposes for all institutions participating in the trial.
Protocol Deviation: Noncompliance with the protocol that does not have a significant effect on 
the subject’s rights, safety, welfare, and/or the integrity of the data. Deviations may be caused by 
the action of the subject, the investigator, the research staff, or natural events. 
Protocol Violation: Changes to protocol procedures without prior approval of the IRB/Sponsor. 
Violations may significantly alter the clinical effectiveness of the treatment or the evaluation of 
its toxicity and adversely affect patient's safety and rights.
Unanticipated Problems: An incident, experience or outcome, that is unexpected, related or 
possibly related to participation in the research and suggests that the research places subjects or 
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others at a greater risk of harm (including physical, psychological, economic, or social harm) that 
was previously known or recognized. These incidents do not meet the definition of an adverse 
event. Unanticipated problems are not limited to study participants, and may also include others 
such as family members and research staff. 
MD Anderson GU Department: Upon receipt of the violation/deviation/unanticipated problem 
report from the participating institution, the Protocol Chair will review and submit the report to 
the MD Anderson IRB for review.
14.5
Research Team Teleconferences
The MD Anderson and participating institution’s PIs and study teams will participate in 
teleconferences as needed to discuss the following information:
Status of patients enrolled at sites including
Eligibility for trial
Status of treatment
Adverse Events
Response evaluation
Any questions or concerns
15.0
DATA AND PROTOCOL MANAGEMENT
Protocol Compliance: All required interim and pretreatment data should be available, and the 
physician must assess tumor response and must provide a detailed description of toxicity, when 
appropriate.  If dose modifications or treatment interruptions are necessary, the details must be 
carefully documented.  Performance status must be documented at each toxicity assessment. 
Data Capture: Data will be entered in the MD Anderson GU departmental oracle system.  
Registration data entry and randomization will occur prior to initiation of therapy.  All eligibility 
criteria must be satisfied.  
Accuracy of Data Collection: The MD Anderson Principal Investigator will be the final arbiter of 
response and toxicity, should a difference of opinion exist. 
15.1
Schedule of Data Submission 
MD Anderson protocol specific Case Report Forms and/or electronic Case Report Forms will be 
used for collection of all study data. The schedule for submission of case report forms is as 
follows: 
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Case Report Forms/Source 
Documents
Schedule for Submission
Informed Consent/Patient 
Authorization for the Release of 
Personal Health Information
Prior to study registration 
Eligibility Checklist 
Prior to study registration
On-Study Form
Supporting Source Documents (e.g. 
Pathology reports, Medical 
Administration Records, 
Radiology/Laboratory Reports, History 
and Physical, Progress Notes)
14 days after treatment initiation
Chemotherapy/Treatment 
by 
Cycle 
Form 
(Chemotherapy, 
Laboratory 
Results, Concomitant Medications)
Supporting Source Documents
14 days after cycle completion
Adverse Event Form
Supporting Source Documents
14 days after cycle completion
Response Assessment Forms (Disease 
Measurements)
Supporting Source Documents
14 
days 
after 
protocol 
defined 
imaging assessment
Off Treatment
Supporting Source Documents
14 days after last treatment date
Survival Update Form
Supporting Source Documents
14 
days 
after 
protocol 
defined 
survival review
Off Study Form
Supporting Source Documents
14 days after patient removed from 
study
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16.0
STATISTICAL CONSIDERATIONS
16.1
Definition of primary outcome/endpoint: 
Composite rate of toxicity defined as the percentage of patients who experience one or more 
that are possibly, 
probably, or definitely related to study therapy: fatigue, HFS or diarrhea.
16.2
Definition of secondary outcomes/endpoints:
Progression-free survival (PFS) defined as the time from treatment initiation to disease 
progression using RECIST v 1 or death.
percentage of patients who experience any grade 3 or greater toxicity that is possibly, 
probably, or definitely related to study therapy.
Dose reductions, dose interruptions, dose delays will be recorded using pill diaries 
maintained by patients that will be reviewed and recorded at each visit. This outcome will be 
reported as the percentage of patients who underwent one or more dose reductions, dose 
interruptions and/or treatment delays. The number of patients who discontinue treatment due 
to unacceptable toxicities will be recorded, and reported as a percentage of the total number 
of enrolled patients. 
Changes in the patient reported outcomes in FACT-G (general) scale during treatment on 
schedule 2/1
Changes in circulating DNA levels with antiangiogenic treatment
Correlation of tumor associated macrophages (TAM) with response to therapy
16.3
Sample size justification:
The primary goal of the trial is to estimate the likelihood that with a 2 weeks on/1 week off 
schedule a patient will experience at least one of the most commonly reported and troublesome 
grade 3 or worse sunitinib-related toxicities – fatigue, hand-foot syndrome, and diarrhea. The 
primary endpoint is the percentage of patients who experience one or more of these adverse 
events. A total of 60 patients will be accrued in order to estimate the likelihood of toxicity using 
a 95% confidence interval that has a half-width of  <10% (assuming the observed composite 
toxicity rate is approximately 10-15%). If the upper bound of the confidence interval is  less than 
25% this will be taken as an indication that the 2/1 schedule has a better toxicity profile than the 
standard 4/2 schedule since from earlier randomized studies approximately 25-30% of patients 
on the 4/2 schedule can be expected to have these toxicities
16.4
Analytic plan for primary objective:
Toxicities will be tabulated by type and grade. A point estimate and its 95% confidence interval 
of the primary endpoint will be calculated and presented based on a Bernoulli distribution. 
16.5
Analytic plan for secondary objectives:
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PFS will be measured from the date of initiation of treatment to the first of documented 
progression or death; and will be estimated using the Kaplan-Meier method. PFS is expected 
to be comparable to that seen with 4/2 (11 month median); however if the upper bound of the 
interval is less than 8 months this will be taken as an indication that the efficacy of 2/1 is 
inferior to that of 4/2.
will be calculated by CTCAE v 4.03 along with a 95% confidence interval
The percentage of patients who underwent one or more dose reductions, dose interruptions 
and/or treatment delays will be estimated along with a 95% confidence interval. The number 
of patients who discontinue treatment due to unacceptable toxicities will be recorded, and 
reported as a percentage of the total number of enrolled patients along with 95% confidence 
interval. 
Health-related quality of life (HRQOL) will be assessed by FACT-G questionnaires as a 
secondary endpoint.  Questionnaires will be administered at baseline, week 12, week 24 and 
week 36. Descriptive summary statistics will be calculated for all continuous variables 
(means, standard deviations, medians, ranges, percentage of patients scoring in the highest 
category for each item) for the items in the subscales each time point. The mean trajectories 
of each group over time will be plotted for the total scores, along with scores for physical 
well-being, emotional well-being, functional well-being, and renal-specific scales for FACT-
G.  
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17.0 REFERENCES
1. SEER Stat Fact Sheets: Kidney and Renal Pelvis. Accessed July 2013
http://seer.cancer.gov/statfacts/html/kidrp.html
2. Murai M, Oya M. Renal cell carcinoma: etiology, incidence and epidemiology. Curr Opin 
Urol 2004;14:229–33.
3. Mickisch GH. Multimodality treatment of metastatic renal cell carcinoma. Expert Rev 
Anticancer Ther 2002;2:681–5
4. Childs R, Chernoff A, Contentin N, et al. Regression of metastatic renal-cell carcinoma after 
nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 
2000;343:750–8.
5. Motzer RJ, Russo P. Systemic therapy for renal cell carcinoma. J Urol 2000;163:408–17.
6. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-
cell carcinoma. N Engl J Med 2007;356:115–24.
7. Eton DT, Cella D, Bacik J, Motzer RJ. A brief symptom index for advanced renal cell 
carcinoma. Health Qual Life Outcomes 2006;4:68. 
8. Bukowski RM. Natural history and therapy of metastatic renal cell carcinoma: the role of 
interleukin-2. Cancer 1997;80: 1198–220.
9. Ramsey S, Aitchison M. Treatment for renal cancer: are we beyond the cytokine era? Nat 
Clin Pract Urol 2006;3: 478–84.
10. Yang JC, Topalian SL, Parkinson D, et al. Randomized comparison of high-dose and low-
dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim 
report. J Clin Oncol 1994;12:1572–6.
11. Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and low-dose 
interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003;21:3127–32.
12. Mittal K, Wood L, Rini BI: Axitinib in metastatic renal cell carcinoma. Biol Ther 2012; 2(5)
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Chen I, Motzer RJ: Overall survival with sunitinib versus interferon (IFN)-alfa as first-line 
treatment of metastatic renal cell carcinoma (mRCC). J Clin Oncol 2008;26(Suppl):5024. 
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survival in second-line treatment of advanced renal cell carcinoma. J Med Econ 2012;
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19. Cella D, Kaiser K, Beaumont J, et al: Quality of life (QOL) among renal cell carcinoma 
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33. Khalil B, Hudson JM, Williams R, et al: An individualized dose/schedule strategy for
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APPENDIX 1: PILL DIARY
APPENDIX 2: BLOOD PRESSURE LOG
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Patient Signature and Date: 
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APPENDIX 3: FACT-G questionnaire
Below is a list of statements that other people with your illness have said are important.
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days.
PHYSICAL WELL-BEING
Not 
at all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GP1
I have a lack of energy........................................................
0
1
2
3
4
GP2
I have nausea ......................................................................
0
1
2
3
4
GP3
Because of my physical condition, I have trouble 
meeting the needs of my family .........................................
0
1
2
3
4
GP4
I have pain ..........................................................................
0
1
2
3
4
GP5
I am bothered by side effects of treatment .........................
0
1
2
3
4
GP6
I feel ill ...............................................................................
0
1
2
3
4
GP7
I am forced to spend time in bed ........................................
0
1
2
3
4
SOCIAL/FAMILY WELL-BEING
Not 
at all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GS1
I feel close to my friends ....................................................
0
1
2
3
4
GS2
I get emotional support from my family ............................
0
1
2
3
4
GS3
I get support from my friends.............................................
0
1
2
3
4
GS4
My family has accepted my illness ....................................
0
1
2
3
4
GS5
I am satisfied with family communication about my 
illness..................................................................................
0
1
2
3
4
GS6
I feel close to my partner (or the person who is my main 
support)...............................................................................
0
1
2
3
4
Q1
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section.
GS7
I am satisfied with my sex life.............................................
0
1
2
3
4
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Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days.
EMOTIONAL WELL-BEING
Not 
at all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GE1
I feel sad ..............................................................................
0
1
2
3
4
GE2
I am satisfied with how I am coping with my illness..........
0
1
2
3
4
GE3
I am losing hope in the fight against my illness ..................
0
1
2
3
4
GE4
I feel nervous .......................................................................
0
1
2
3
4
GE5
I worry about dying .............................................................
0
1
2
3
4
GE6
I worry that my condition will get worse ............................
0
1
2
3
4
FUNCTIONAL WELL-BEING
Not 
at all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GF1
I am able to work (include work at home) ..........................
0
1
2
3
4
GF2
My work (include work at home) is fulfilling.....................
0
1
2
3
4
GF3
I am able to enjoy life..........................................................
0
1
2
3
4
GF4
I have accepted my illness...................................................
0
1
2
3
4
GF5
I am sleeping well................................................................
0
1
2
3
4
GF6
I am enjoying the things I usually do for fun ......................
0
1
2
3
4
GF7
I am content with the quality of my life right now..............
0
1
2
3
4
43