A Randomized Phase II Trial of Sunitinib/Gemcitabine or Sunitinib in Advanced Renal Cell Carcinoma With Sarcomatoid Features
Phase: PHASE2
Conditions: Kidney Cancer
Sponsor: ECOG-ACRIN Cancer Research Group

E1808 
 
1 
A Randomized Phase II Trial of Sunitinib/Gemcitabine or 
Sunitinib in Advanced Renal Cell Carcinoma with 
Sarcomatoid Features 
 
STUDY CHAIR: 
Naomi B. Haas, M.D. 
 
STUDY CO-CHAIR: 
David McDermott, M.D. 
 
STUDY STATISTICIAN: 
Judith Manola, M.S. 
 
PATHOLOGY CO-CHAIR: 
Michael Pins, M.D. 
 
GU COMMITTEE CHAIR: 
Michael Carducci, M.D. 
 
RENAL SUBCOMMITTEE CHAIR: 
Naomi B. Haas, M.D. 
 
[DELETED IN UPDATE #2] 
 
 
Version Date: February 22, 2016 
NCI Update Date: March 14, 2013 
STUDY PARTICIPANTS 
ACTIVATION DATE 
US Sites Only 
June 17, 2010 
ALLIANCE / Alliance for Clinical Trials in Oncology 
Update #1 – 7/10 
NRG / NRG Oncology Foundation, Inc 
Addendum #1 – 10/10 
SWOG / SWOG 
Addendum #2 – 12/10 
 
Addendum #3 – 3/12 
 
Update # 2 – 3/13 
 
Update # 3 – 3/13 
 
Addendum # 4 – 7/13 
 
Addendum #5 – 4/14 
 
Addendum #6 – 5/14 
 
Addendum #7 - 8/14 
 
Addendum #8 – 1/15 
 
Addendum #9 – 11/15 
 
Addendum #10 – 3/16 
 
 
 
Rev. 3/12 
Rev. 3/12 
Rev. 3/13 
Rev. 4/14, 
8/14 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
2 
Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 RCC Subtypes and sarcomatoid features: ................................................. 7 
1.2 Treatment of RCC with Sarcomatoid features .......................................... 7 
1.3 Known Molecular Characteristics of RCC with Sarcomatoid Features ..... 7 
1.4 Rationale for a randomized phase II trial of sunitinib/gemcitabine versus 
sunitinib ..................................................................................................... 8 
1.5 Hypothesis ................................................................................................. 9 
2. Objectives ......................................................................................................... 10 
2.1 Primary Objective .................................................................................... 10 
2.2 Secondary Objectives .............................................................................. 10 
3. Selection of Patients ......................................................................................... 11 
3.1 Randomization ........................................................................................ 11 
4. Registration Procedures.................................................................................... 14 
4.1 Protocol Number ..................................................................................... 16 
4.2 Investigator Identification ....................................................................... 16 
4.3 Patient Identification .............................................................................. 17 
4.4 Eligibility Verification .............................................................................. 17 
4.5 Additional Requirements ........................................................................ 17 
4.6 Instructions for Patients who Do Not Start Assigned Protocol Treatment17 
5. Treatment Plan ................................................................................................. 18 
5.1 Administration Schedule ......................................................................... 18 
5.2 Adverse Event Reporting Requirements ................................................. 18 
5.3 Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Sunitinib Malate (NSC 736511) ............................................................... 23 
5.4 Dose Modifications ................................................................................. 28 
5.5 Supportive Care ....................................................................................... 35 
5.6 Duration of Therapy ................................................................................ 36 
5.7 Duration of Follow-up ............................................................................. 36 
6. Measurement of Effect ..................................................................................... 37 
6.1 Antitumor Effect – Solid Tumors ............................................................. 37 
7. Study Parameters .............................................................................................. 44 
8. Drug Formulation and Procurement ................................................................. 46 
8.1 Sunitinib (NSC 736511) ........................................................................... 46 
8.2 Gemcitabine ............................................................................................ 48 
9. Statistical Considerations .................................................................................. 51 
9.1 Sample Size and Revised Design for the Sunitinib/Gemcitabine Arm .... 51 
9.2 Sample Size and Design for the Sunitinib Alone Arm ............................. 51 
9.3 Progression Free Survival ........................................................................ 52 
9.4 Toxicity .................................................................................................... 52 

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NCI Update Date: March 14, 2013 
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9.5 Gender and Ethnicity .............................................................................. 53 
10. Pathology Review .............................................................................................. 54 
10.1 The pathology materials required for this protocol are: ........................ 54 
10.2 Shipping Procedures ............................................................................... 55 
10.3 Central Biorepository and Pathology Facility: Sample processing and 
Routing .................................................................................................... 55 
10.4 Histologic Confirmation .......................................................................... 55 
10.5 ECOG-ACRIN Sample Tracking System .................................................... 57 
10.6 Banking .................................................................................................... 57 
10.7 Sample Inventory Submission ................................................................. 57 
10.8 Lab Data Transfer Guidelines .................................................................. 58 
11. Records to Be Kept ............................................................................................ 59 
12. Patient Consent and Peer Judgment ................................................................ 59 
13. References ........................................................................................................ 60 
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) [Deleted in Update #2] .................................................................... 62 
Appendix II  Pathology Submission Guidelines ....................................................... 63 
Appendix III  Patient Thank You Letter .................................................................... 68 
Appendix IV  Patient Medication Calendar (Pill Diary) ............................................ 69 
Appendix V  Oral Antihypertensive Medications .................................................... 73 
 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
4 
 
 
STUDY CHAIR 
 
STUDY CO-CHAIR 
 
 
 
 
 
 
 
Naomi B. Haas, M.D. 
University of Pennsylvania 
3400 Spruce St., 16 Penn Tower 
Philadelphia, PA 19104 
Phone: 215-662-7402 
Fax: 215-349-8550 
Email: naomi.haas@uphs.upenn.edu 
 
David McDermott, M.D. 
Beth Israel Deaconess Medical Center 
Hematology/Oncology 
375 Longwood Ave. 
MASCO 428 
Boston, MA 02215 
Phone: (617)632-9270 
Email: dmcdermo@bidmc.harvard.edu 
 
 
STUDY CHAIR LIAISON (SCL) 
 
 
 
 
 
 
 
Mary Walicki, RN 
University of Pennsylvania 
3400 Spruce Street, 16 Penn Tower 
Philadelphia, PA 19104 
Phone: 215-662-6388 
Fax: 215-614-0811 
Email: mary.walicki@uphs.upenn.edu   
 
 
 
[Deleted in Update #2] 
 
 
 
Rev. 3/13 
Rev. 7/10, 
3/13, 4/14 
Rev. 3/12 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
5 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email: 
CTSURegulatory@ctsu.coccg.org 
(for submitting regulatory 
documents only) 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com. 
ECOG-ACRIN Operations Office 
- Boston, FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
(ATTN: DATA). 
Phone # 617-632-3610 
Fax # 617-632-2990 
Data should be sent via postal 
mail (preferred), however fax is 
accepted. 
 
Do not submit study data or 
forms to CTSU Data Operations. 
Do not copy the CTSU on data 
submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS.  
For clinical questions (i.e. patient eligibility or treatment-related) Contact the Study PI of the lead 
protocol organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website 
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU Regulatory 
and Monitoring Policy 
The CTSU Website is located at https://www.ctsu.org. 
 
Rev. 8/14 

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Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
6 
Schema 
Gemcitabine 1,000 mg/m2 IV over 30 minutes 
(days 1, 8, 22 and 29 of each cycle)
and 
Sunitinib 37.5 mg once daily (days 1-14 and 
days 22-35 of each cycle)1
Followed until progression
1   There will be a one week (7 day) break taking place on days 15-21 and an additional one week break on days 36-42 of each cycle.
NOTE: Gemcitabine dosing is based on body surface area calculated using actual (not ideal) body weight.
NOTE: Treatment will be repeated for a total of one year (per Section 5.1)
Accrual Goal = 85 patients
Cycle = 6 weeks = 42 days 
R
A
N
D
O
M
I
Z
E
Arm A
Sunitinib 50 mg once daily (days 1-14 and 
days 22-35 of each cycle)1 
Arm B
Stratify
•
Good risk (clear cell and < 
20% sarcomatoid and PS 0)
•
Intermediate risk (20-50% 
sarcomatoid and PS 0)
•
Poor risk (non-clear cell or > 
50% sarcomatoid or PS 1 or 
non-clear cell)
 
 
Rev. 11/15 

ECOG-ACRIN 
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Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
7 
1. 
Introduction 
1.1 
RCC Subtypes and sarcomatoid features: 
The clinical behavior of the 37,000 cases of renal cell carcinoma (RCC) 
diagnosed annually can vary dramatically (1) and parameters besides subtype 
are increasingly important (2). The pathologic stage, tumor size, Fuhrman 
nuclear grade, and the presence of tumor necrosis and sarcomatoid features are 
powerful prognostic indicators (3,4,5,6,7,). Sarcomatoid features, defined by 
spindle cell morphology, can arise in RCC of any type.(8,9) and are present in 
10% of all renal cell carcinomas (8). Patients with RCC containing sarcomatoid 
features, have a poorer prognosis than patients with non-sarcomatoid-containing 
tumors (median survival of 3-10 months) and usually do not respond to cytokine 
therapy (8,11,12). Furthermore, the extent of sarcomatoid morphology may be 
related to survival, with tumors exhibiting at least 50% sarcomatoid component 
having an especially poor outcome (8). 
1.2 
Treatment of RCC with Sarcomatoid features 
There are few published trials focused on RCC with sarcomatoid features. The 
overall benefit of specific therapies in these patients is limited and based 
primarily on case reports, retrospective reviews and small prospective trials. 
Golshayan A, et al. retrospectively reviewed the Cleveland Clinics’ experience 
with VEGF-targeted therapy in RCC with sarcomatoid features (13). A partial 
response rate of 19% and stable disease rate of 49% was observed in 43 
patients, all with prior nephrectomy, and good performance status. The median 
progression-free survival (PFS) was 5.3 months and the median overall survival 
(OS) was 11.8 months. The authors concluded that patients who had less than 
20% sarcomatoid features were more likely to respond to VEGF-targeted therapy 
than patients with a higher percentage of these features.   
In fact, RCC with sarcomatoid change appears to be more sensitive than 
conventional RCC to cytotoxic therapy: Building on the work of Nanus (14), we 
conducted a phase II trial (E8802) of doxorubicin 50mg/m2 IV push and 
gemcitabine 1500mg/m2 IV over 30 minutes every 2 weeks in 39 patients with 
locally advanced or metastatic renal cell carcinoma with sarcomatoid features in 
the cooperative group setting (15).There were 6 responses (5 partial response 
[PR] and 1 complete response [CR]), and 9 patients had stable disease (15). In 
addition, a seventh patient had an unconfirmed PR and an eighth patient 
experienced over 50 percent decrease in her tumor burden after an initial 
progression. The median overall survival was 8.8 months (95% CI, 6.1 – 11.1 
months), which exceeded historical survival data for this population.  
We hope to analyze whether tumors with a higher percentage of sarcomatoid 
features respond better to cytotoxic therapy than those with a lower percentage 
of sarcomatoid features in this recently completed trial. 
1.3 
Known Molecular Characteristics of RCC with Sarcomatoid Features 
The evidence cited above supports that these patients have a poorer outcome 
and warrants focused study of this patient group and their tumor characteristics. 
Molecular features of the cells which comprise sarcomatoid differentiation have 
not been extensively characterized. Increased expression of skp2 was reported 

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in some tumors with sarcomatoid morphology (16). Skp2 association with p27 
promotes ubiquitin mediated degradation, and may plausibly confer a poorer 
prognosis through this pathway (16).The myc target genes Mina 53 and Ki67, are 
also overexpressed in some RCC with sarcomatoid morphology (17,18). 
Increased expression of VEGF, kit, S6 kinase, hypoxia inducible factor 1 alpha, 
carbonic anhydrase IX, glucose transport protein, and P53 mutations  suggest 
the importance of angiogenesis;(19,20). However, others report lower 
microvessel density in renal cell carcinoma with sarcomatoid features, as 
compared with RCC lacking these features, which suggests that standard anti-
angiogenic therapy alone may be less effective;(21) The relationship of these 
molecular phenotypes to morphology and to response are areas of active 
investigation further confounded by the fact that sarcomatoid change is present 
in a variety of RCC subtypes. 
Collectively, these findings suggest several lines of therapeutic investigation for 
renal cell cancers with sarcomatoid features. The relationship of these molecular 
phenotypes to morphology and to response will be a focus of this work.  
1.4 
Rationale for a randomized phase II trial of sunitinib/gemcitabine versus sunitinib 
Some argue that as sarcomatoid change in renal cancer can be present in all 
subtypes of RCC this confounds standard definition. However, this should not 
preclude investigations to better classify and treat this group of patients that 
clearly have a poorer prognosis. No large studies have incorporated newer 
targeted therapies alone or in combination with cytotoxic therapy against tumors 
expressing this histology. The fact that there was any activity in the E8802 trial of 
doxorubicin/ gemcitabine regimen indicates two things: First, RCC dominated by 
sarcomatoid change are fundamentally different from non-sarcomatoid RCC that 
is traditionally chemo-resistant. Second, the exploration of chemotherapy in 
combination with targeted therapy may expand alternatives for these patients. 
Additionally, we will be gathering useful information about these to potentially 
improve classification and to predict response. 
The combination of doxorubicin and gemcitabine showed encouraging activity 
but was also moderately toxic. Furthermore, a non gemcitabine but doxorubicin 
based trial was inactive (22), and gemcitabine is the cytotoxic agent of greatest 
interest in this disease. Combinations of gemcitabine with sorafenib (23) and 
sunitinib (24) (FDA approved and active in RCC) are feasible without much 
additive toxicity; thus, we have a unique opportunity to characterize these 
combinations in renal cell carcinoma with sarcomatoid features. A Phase I trial of 
sunitinib /gemcitabine in solid tumors demonstrated tolerability at several doses 
of gemcitabine and sunitinib as well as 5 partial responses in 9 patients with 
aggressive RCC (24). A continuation of this trial using a 3 week cycle (2 weeks 
on, 1 week off) of gemcitabine 1000 mg/m2 IV (days 1 and 8) in combination with 
sunitinib 37.5 mg (days 1-14) in RCC with poor risk features (including 
sarcomatoid features) is ongoing. Another abstract reported 4 disease 
stabilizations and 1 PR in poor risk patients with disease progression on sunitinib 
who had gemcitabine added to their regimens (25). 
These provide a strong argument for testing the combination of a tyrosine kinase 
inhibitor with gemcitabine in this group of tumors. We propose to evaluate the 
schedule of sunitinib /gemcitabine versus sunitinib in a randomized phase II 
design specific to RCC with sarcomatoid features. The schedule of the sunitinib 

ECOG-ACRIN 
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Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
9 
Arm B alone will be 2 weeks on/1 week off repeated for a cycle duration of 6 
weeks, as this schedule is often used for renal cell carcinoma with rapid growth 
and this agent schedule is similar to that of Arm A. In addition to comparing 
activity to the previous doxorubicin/gemcitabine trial, this design will assess if the 
addition of gemcitabine to a VEGF targeted therapy contributes to its activity and 
advances the treatment of this aggressive histology, as well as lend confidence 
to a decision for a future Phase III study. Furthermore this design permits 
consideration of predictive (refinement of the characteristics of this poor 
prognosis renal cell patient population) and biologic (association of molecular 
features that predict therapeutic effect) questions. 
1.5 
Hypothesis  
Advancing the treatment of aggressive renal cell carcinomas containing 
sarcomatoid histology depends on two factors: the refinement of the pathologic 
definition of these diseases through molecular analysis and 
immunohistochemical studies and the exploration of new therapeutic strategies 
that may or may not be predicted by results in clear cell carcinoma. Given the 
limited reserves of cooperative groups to perform phase II studies in the less 
common diseases, we propose a strategy to juxtapose the biologic and 
therapeutic studies in this trial. The primary endpoint of this trial is to determine 
the response rates to sunitinib/gemcitabine and sunitinib alone. Secondary 
endpoints are as follows: 1. To determine the progression free survival of 
sunitinib/gemcitabine and sunitinib alone. 2. Sample acquisition with central 
pathology review at the ECOG-ACRIN Central Biorepository and Pathology 
Facility (CBPF) and characterization and quantification of the sarcomatoid and 
non-sarcomatoid components of each tumor specimen. Sarcomatoid features are 
hypothesized to be a final aggressive histologic change derived from the original 
tumor and thus a poor prognostic indicator. 3. To bank paraffin blocks from each 
tumor specimen for future correlative studies. Ultimately these samples will be 
used to assess the relationship of correlates to response rate. An application for 
funding is being submitted for such work to be conducted at the ECOG-ACRIN 
CBPF and the University of Pennsylvania. 
 
Rev. 1/15 

ECOG-ACRIN 
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Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
10 
2. 
Objectives 
2.1 
Primary Objective 
2.1.1 
To evaluate response rate of both the combination of sunitinib and 
gemcitabine and sunitinib alone in patients with advanced renal cell 
carcinoma with sarcomatoid features.  
2.2 
Secondary Objectives 
2.2.1 
To evaluate progression-free survival following treatment with both the 
combination of sunitinib and gemcitabine and sunitinib alone in this 
patient population. 
2.2.2 
To evaluate overall survival following treatment with both the 
combination of sunitinib and gemcitabine and sunitinib alone in this 
patient population. 
2.2.3 
To describe the toxic effects of both the combination of sunitinib and 
gemcitabine and sunitinib alone in this patient population. 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
11 
3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. 
 
 
Patient’s Initials (L, F) 
 
 
Physician Signature and 
Date 
 
NOTE: All questions regarding eligibility should be directed to the Study Chair or Study 
Chair Liaison. 
NOTE: Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to randomization by the treating 
physician. 
3.1 
Randomization 
3.1.1 
Patients must have histologically confirmed renal cell carcinoma (of 
any subtype) containing any sarcomatoid features. There must be 
histologic confirmation by the treating center of either the primary or 
metastatic lesion. 
3.1.2 
Patients must not have collecting duct or medullary carcinoma. 
3.1.3 
Patients must have measurable advanced disease (as defined in 
Section 6.1.1), that is not resectable by surgery. All sites must be 
assessed within 4 weeks prior to randomization. 
3.1.4 
Prior radiation therapy must have been completed > 2 weeks prior to 
randomization and the patient must be recovered from any acute 
toxicities associated with radiation therapy. Previously irradiated 
lesions must not be the sole site of disease. 
Prior radiation therapy?_______Date______ 
3.1.5 
 No prior systemic chemotherapy for metastatic disease. One prior 
therapeutic regimen with a non-tyrosine kinase inhibitor, such as an 
mtor inhibitor is allowed. Patients who were randomized to placebo on 
an adjuvant study are eligible. 
3.1.6 
Patients with resected or radiated brain metastases or those treated 
with stereotactic radiation therapy are eligible, provided they have 
been off steroids for at least 2 weeks. No history of stroke within the 
past 6 months.  
_____
_____ 
_____ 
_____
_____
_____
Rev. 3/12 
Rev. 4/14 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
12 
3.1.7 
Patients must have ECOG-ACRIN performance status of 0-2. 
3.1.8 
[Removed in Addendum #3] 
3.1.9 
Patients must have a paraffin embedded tumor specimen from the 
kidney or metastatic site available for central review of tumor 
histology. Tumor samples will be shipped as specified in Section 10.  
3.1.10 
Patients must have the following baseline laboratory values obtained 
within 4 weeks prior to randomization:  
3.1.10.1 
ANC ≥ 1500 cells/mm3 
 
ANC:______  Date of test: _____ 
3.1.10.2 
Platelets ≥ 100,000 cells/mm3 
   
Platelet Count:_______  Date of test:________ 
3.1.10.3 
Hgb  9.0 g/dL (transfusions allowed) 
   
Hgb: ________  Date of test:________ 
3.1.10.4 
Serum creatinine clearance (CrCl)  30ml/min. 
Serum creatinine clearance: ____________ Date of test: 
___________ 
3.1.10.5 
SGOT, SGPT ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases 
is present. 
Liver metastases present? Yes ____ No ____ 
SGOT: ____________ Date of test: ____________  
ULN: ____________ 
SGPT: ____________ Date of test: ____________  
ULN: ____________ 
3.1.10.6 
Total Bilirubin 1.5 X ULN 
Total Bilirubin:______  Date of test:______  
ULN:________ 
3.1.11 
Patient must be at least 18 years of age.   
3.1.12 
No clinically significant cardiovascular disease, defined as one of the 
following: 
• 
Uncontrolled hypertension (Blood Pressure > 150/100 mm/Hg at 
the time of enrollment) Patients with hypertension and blood 
pressure  150/100 mm Hg on stable antihypertensive regimen 
are eligible.  
• 
History of myocardial infarction or unstable angina < 24 weeks 
prior to randomization. 
• 
New York heart association grade II or greater congestive heart 
failure, serious cardiac arrhythmia requiring medication, unstable 
angina pectoris 
• 
Grade II or greater peripheral vascular disease 
_____ 
_____ 
_____
_____
_____
_____
Rev. 10/10 
Rev. 3/12 
Rev. 3/12 
Rev. 3/12 
Rev. 4/14 

ECOG-ACRIN 
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Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
13 
3.1.13 
Patient must not have ongoing ventricular cardiac dysrhythmias of 
NCI CTCAE Version 4 grade > 2. Patients with a history of serious 
ventricular arrhythmia (VT or VF > 3 beats in a row) are also 
excluded. Additionally, patients with ongoing atrial fibrillation are not 
eligible. 
3.1.14 
Patients must have QTc interval < 500 msec on baseline EKG.  
3.1.15 
Patient must be able to swallow pills. 
3.1.16 
Patient must not have pre-existing thyroid abnormality with thyroid 
stimulating hormone that cannot be maintained at less than or within 
the normal range with medication.  
3.1.17 
Patients must not be taking ketoconazole, dexamethasone, the 
dysrhythmic drugs (terfenadine, quinidine, procainamide, sotalol, 
probucol, bepridil, indapamide or flecainide), haloperidol, risperidone, 
rifampin, grapefruit, or grapefruit juice within two weeks of 
randomization and during the course of therapy. Topical and inhaled 
steroids are permitted.  (Please see Appendix V.) 
3.1.18 
Patients with a history of prior malignancy are eligible provided they 
were treated with curative intent and have been disease free for the 
time period considered appropriate to not interfere with the outcome 
of this study. 
3.1.19 
No serious concurrent medical illness or active infection which would 
jeopardize the ability of the patient to receive the treatment outlined in 
this protocol. 
3.1.20 
If female, patient must not be pregnant or breastfeeding. All females 
of childbearing potential must have a blood test or urine study within 2 
weeks prior to randomization to rule out pregnancy. 
Woman of childbearing potential? Yes_____ No______ 
If YES, date of blood or urine test: _______________ 
3.1.21 
The effects of sunitinib on the developing human fetus are unknown. 
For this reason, women of childbearing potential and men must agree 
to use an accepted and effective method of contraception prior to 
study entry and for the duration of study participation. Should a 
woman become pregnant while participating in this study, she should 
inform her treating physician immediately. If a man impregnates a 
woman while participating in this study, he should inform his treating 
physician immediately as well. 
3.1.22 
Patients with known HIV are excluded due to possibility of unknown 
side effects on the immune system by sunitinib. The potential impact 
of pharmacokinetic interactions of retroviral therapy with sunitinib is 
unknown. Appropriate studies may be undertaken in patients with HIV 
and those receiving combination anti-retroviral therapy in the future. 
 
_____
_____
_____ 
_____
_____
_____
_____
_____
_____
_____
Rev. 3/12 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
14 
4. 
Registration Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
Registration requires the submission of: 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
Fillable PDF forms and additional information can be found on the CTEP website at 
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
pmbregpend@ctep.nci.nih.gov. 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm.  For questions, please 
contact the CTEP Associate Registration Help Desk by email at 
ctepreghelp@ctep.nci.nih.gov. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Study centers can 
check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU members’ website by entering 
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credentials at https://www.ctsu.org.  For sites under the CIRB initiative, IRB data will 
automatically load to RSS. 
Downloading Site Registration Documents: 
Site registration forms may be downloaded from the E1808 protocol page located on the 
CTSU members’ website. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol E1808 
• 
Click on the Site Registration Documents link 
Requirements For E1808 Site Registration: 
• 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the 
NCI CIRB)  
Submitting Regulatory Documents:  
Submit completed forms along with a copy of your IRB Approval and Model Informed 
Consent to the CTSU Regulatory Office, where they will be entered and tracked in the 
CTSU RSS.  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 215-569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
Required Protocol Specific Regulatory Documents 
1.  CTSU Regulatory Transmittal Form. 
2.  Copy of IRB Informed Consent Document. 
NOTE: Any deletion or substantive modification of information concerning 
risks or alternative procedures contained in the sample informed 
consent document must be justified in writing by the investigator and 
approved by the IRB. 
3.  A. CTSU IRB Certification Form. 
 
Or 
B.  HMS OMB No. 0990-0263. 
 
Or 
C.  IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 

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• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
Checking Your Site’s Registration Status: 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Patient Enrollment 
Patients must not start protocol treatment prior to randomization. 
Treatment must start within ten working days after randomization. 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at https://eapps-
ctep.nci.nih.gov/iam/index.jsp) and a ‘Registrar’ role on either the LPO or participating 
organization roster. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following: 
• 
All eligibility criteria has been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. The following information will be requested: 
4.1 
Protocol Number  
4.2 
Investigator Identification  
4.2.1 
Institution and affiliate name 
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4.2.2 
Investigator’s name 
4.3 
Patient Identification  
4.3.1 
Patient’s initials and chart number 
4.3.2 
Patient’s Social Security number 
4.3.3 
Patient demographics 
4.3.3.1 
Sex 
4.3.3.2 
Birth date (mm/yyyy) 
4.3.3.3 
Race 
4.3.3.4 
Ethnicity 
4.3.3.5 
Nine-digit ZIP code 
4.3.3.6 
Method of payment 
4.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3.0. An 
eligibility checklist has been appended to the protocol.  A confirmation of 
registration will be forwarded by the ECOG-ACRIN Operations Office – Boston. 
4.4.1 
Stratification Factors 
• 
Good risk (clear cell and < 20% sarcomatoid and PS 0) 
• 
Intermediate risk (20-50% sarcomatoid and PS 0) 
• 
Poor risk (non-clear cell or > 50% sarcomatoid or PS 1 or non-
clear cell) 
4.5 
Additional Requirements  
4.5.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
4.5.2 
Pathological materials must be submitted as indicated in Section 10. 
4.6 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted according to the 
instructions in the E1808 Forms Packet. Document the reason for not starting 
protocol treatment on the E1808 Off-Treatment form. Also report the date and 
type of the first non-protocol treatment that the patient receives. 
 

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5. 
Treatment Plan 
Patients will receive sunitinib/gemcitabine (Arm A) or sunitinib alone (Arm B) at the 
schedule outlined below.  Patients will be stratified by clear or nonclear histologic 
subtype and by < or  50% sarcomatoid features in the registered pathology. Following 
randomization, central pathology review will be performed to confirm histology and 
percentage sarcomatoid features.  
5.1 
Administration Schedule 
Doses of gemcitabine are based on actual (not ideal) body weight. If there is a 
weight change of 10% from baseline, the dose should be recalculated on day 1 
of subsequent cycles using the new weight.  
Treatment 
Arm A Chemotherapy with gemcitabine and sunitinib malate  
Gemcitabine 1,000 mg/m 2 IV over 30 minutes (days 1, 8, 22 and 29 of cycle) in 
combination with  
Sunitinib 37.5 mg once daily (days 1-14 and days 22-35 of each cycle)  
There will be a one week (7 day) break from sunitinib taking place on days 15-21 
and an additional one week break on days 36-42 of each cycle. Each cycle is 42 
days (6 weeks) and should be repeated for a total of one year. 
NOTE: 
Sunitinib should be taken at the same time each day and is best 
tolerated in the evening. Do not make up skipped, missed or vomited 
doses. 
Arm B Sunitinib malate monotherapy 
Sunitinib 50 mg once daily (days 1-14 and days 22-35 of each cycle). 
There will be a one week (7 day) break from sunitinib taking place on days 15-21 
and an additional one week break on days 36-42 of each cycle. Each cycle is 42 
days (6 weeks) and should be repeated for a total of one year. 
NOTE: 
Sunitinib should be taken at the same time each day and is best 
tolerated in the evening. Do not make up skipped, missed or vomited 
doses. 
5.2 
Adverse Event Reporting Requirements  
5.2.1 
Purpose 
Adverse event data collection and reporting, which are required as 
part of every clinical trial, are done to ensure the safety of patients 
enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial (please refer to the E1808 Forms 
Packet for the list of forms with directions for routine adverse event 
reporting).  Additionally, certain adverse events must be reported in 
an expedited manner for more timely monitoring of patient safety and 
care. The following sections provide information about expedited 
reporting. 
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5.2.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) 
whether the patient has received an investigational or commercial 
agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the 
prior experience (expectedness) of the adverse event; 3) the phase 
(1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event. 
Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source. The NCI, rather than a 
commercial distributor, may on some occasions distribute commercial 
agents for a trial. 
Steps to determine if an adverse event is to be reported in an 
expedited manner: 
Step 1: Identify the type of event:. The descriptions and grading 
scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A 
copy of the CTCAE version 4.0 can be downloaded from the 
CTEP web site (http://ctep.cancer.gov). 
Step 2: Grade the event using Version 4.0 of the NCI CTCAE. 
Step 3: Determine whether the adverse event is related to the 
protocol therapy (investigational or commercial). Attribution 
categories are as follows: Unrelated, Unlikely, Possible, 
Probable, and Definite. 
Step 4: Determine the prior experience of the adverse event. 
Expected events are those that have been previously 
identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the 
severity of the event is NOT listed in:  
• 
Arm A and B– the drug package insert or protocol  
Step 5: Review Section 5.2.6 for E1808 and/or ECOG-ACRIN 
specific requirements for expedited reporting of specific 
adverse events that require special monitoring.   
NOTE:  For general questions regarding expedited reporting 
requirements, please contact AEMD Help Desk at 
aemd@tech-res.com or 301-897-7497. 
5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
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and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (617-632-3610) and  
• 
the FDA (800-332-0178)  
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be faxed to ECOG-ACRIN (617-632-2990), 
Attention: AE within 48-72 hours.  In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) in the same 
timeframe.  
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.4 
When to Report an Event in an Expedited Manner 
When an adverse event requires expedited reporting, submit a full 
CTEP-AERS report within the timeframes outlined in Section 5.2.6. 
NOTE: 
Adverse events that meet the reporting requirements in 
Section 5.2.6 and occur within 30 days of the last dose of 
protocol treatment must be reported on an expedited 
adverse event report form (using CTEP-AERS). For any 
adverse events that occur more than 30 days after the last 
dose of treatment, only those that have an attribution of 
possibly, probably, or definitely AND meet the reporting 
requirements in Section 5.2.6 must be reported on an 
expedited adverse event report form (using CTEP-AERS). 
5.2.5 
Other Recipients of Adverse Event Reports 
Adverse events determined to be reportable must also be reported by 
the institution, according to the local policy and procedures, to the 
Institutional Review Board responsible for oversight of the patient. 
5.2.6 
Expedited reporting for commercial agents 
Commercial reporting requirements are provided below. The 
commercial agents used in arm A and B of this study are Sunitinib 
and Gemcitabine.  

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Expedited reporting requirements for adverse events experienced by patients on arm(s) with commercial agents 
only – Arm A and B 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
 
Unrelated or 
Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning of the 
event. 
a 
This includes all deaths within 30 days of the last dose of treatment regardless of attribution. NOTE:  Any death 
that occurs > 30 days after the last dose of treatment and is attributed possibly, probably, or definitely 
to the treatment must be reported within 7 calendar days of learning of the event.   
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited 
reporting for this trial: 
Serious Events: Any event following treatment that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS within 7 calendar 
days of learning of the event.  For instructions on how to specifically report these events via 
CTEP-AERS, please contact the AEMD Help Desk at aemd@tech-res.com  or 301-897-7497. 
5.2.7 
Reporting Second Primary Cancers 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN: 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine 
reporting as follows: 
1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office – Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Submit a copy of the pathology report to ECOG-ACRIN 
confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
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1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office – Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
3.  Submit a copy of the pathology report to ECOG-ACRIN and 
NCI/CTEP confirming the diagnosis. 
4. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
and NCI/CTEP. 
NOTE: The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even if 
ECOG-ACRIN was not the patient's most recent trial. 
NOTE: Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should be 
submitted via CTEP-AERS or by the Second Primary Form. 

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5.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Sunitinib 
Malate (NSC 736511) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. They are 
developed and continuously monitored by the CTEP Investigational Drug Branch 
(IDB). The information listed in the CAEPR(s) below, as well as the other 
resources described in the 'Determination of reporting requirements' part of the 
Adverse Event Reporting section in this protocol, can be used to determine 
expectedness of an event when evaluating if the event is reportable via CTEP-
AERS. Frequency is provided based on 7115 patients. Below is the CAEPR for 
sunitinib malate. 
Version 2.12, January 14, 20161 
 
 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 4.0 Term) 
[n= 7115] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
 
Hemolytic uremic syndrome 
 
 
Thrombotic thrombocytopenic purpura 
CARDIAC DISORDERS 
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
 
 
Heart failure 
 
 
Left ventricular systolic dysfunction 
 
 
Myocardial infarction 
ENDOCRINE DISORDERS 
 
 
Endocrine disorders - Other 
(thyroiditis) 
 
 
 Hyperthyroidism 
 
Hypothyroidism 
 
EYE DISORDERS 
 
 
Eye disorders - Other (macular 
edema) 
 
 
Eye disorders - Other (vision 
deterioration) 
 
Papilledema 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal distension 
 
Abdominal pain 
 
 
Anal mucositis 
 
 
Constipation 
 
 
Diarrhea 
 
 
 
Dry mouth 
 
Dyspepsia 
 
 
 
 
 Esophagitis 
 
Flatulence 
 
 
Gastritis 
 
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 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 4.0 Term) 
[n= 7115] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Gastroesophageal reflux disease 
 
 
 
Gastrointestinal perforation2 
Mucositis oral 
 
 
Nausea 
 
 
 
Oral pain 
 
 
 
 Pancreatitis 
Rectal mucositis 
 
 
Small intestinal mucositis 
 
 
Vomiting 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
 
 
Edema limbs 
 
Fatigue 
 
 
 
Fever 
 
 
Non-cardiac chest pain 
 
HEPATOBILIARY DISORDERS 
 
 
Cholecystitis 
 
 
Hepatic failure 
IMMUNE SYSTEM DISORDERS 
 
 
Allergic reaction3 
INFECTIONS AND INFESTATIONS 
 
 
Infection and infestations - Other 
(necrotizing fasciitis) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
Wound complication 
INVESTIGATIONS 
 
Alanine aminotransferase increased  
 
Alkaline phosphatase increased 
 
 
Aspartate aminotransferase 
increased 
 
 
Blood bilirubin increased 
 
 
CPK increased 
 
 
Creatinine increased 
 
 
 
Electrocardiogram QT corrected 
interval prolonged 
 
Lipase increased 
 
 
Lymphocyte count decreased 
 
 
Neutrophil count decreased 
 
 
Platelet count decreased 
 
 
Serum amylase increased 
 
 
Weight loss 
 
 
White blood cell decreased 
 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
 
 
 
Dehydration 
 
 
Hyperuricemia 
 
 
Hypoalbuminemia 
 

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 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 4.0 Term) 
[n= 7115] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Hypoglycemia 
 
Hypophosphatemia 
 
 
 
Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Back pain 
 
 
 
Musculoskeletal and connective 
tissue disorder - Other 
(rhabdomyolysis) 
 
Myalgia 
 
 
 
Osteonecrosis of jaw 
 
Pain in extremity 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
Dysgeusia 
 
 
 
Headache 
 
 
 
Leukoencephalopathy 
 
 
Nervous system disorders - Other 
(cerebral infarction) 
 
 Paresthesia 
 
 
 
Reversible posterior 
leukoencephalopathy syndrome 
 
 
Transient ischemic attacks 
PSYCHIATRIC DISORDERS 
 
Depression 
 
 
Insomnia 
 
RENAL AND URINARY DISORDERS 
 
 
 Acute kidney injury 
 
 
 Proteinuria 
 
 
 Renal and urinary disorders - Other 
(nephrotic syndrome) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
 
Dyspnea 
 
 
Epistaxis 
 
Laryngeal mucositis 
 
 
Pharyngeal mucositis 
 
 
Tracheal mucositis 
 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 
 
Dry skin 
 
 
 
Erythema multiforme 
Palmar-plantar erythrodysesthesia 
syndrome 
 
 
 
Pruritus 
 
 
Rash maculo-papular 
 
 
Skin and subcutaneous tissue 
disorders - Other (hair color change) 
 

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NCI Update Date: March 14, 2013 
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 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 4.0 Term) 
[n= 7115] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 Skin and subcutaneous tissue 
disorders - Other (pyoderma 
gangrenosum) 
 
Skin hypopigmentation 
 
 
 
Stevens-Johnson syndrome 
 
 
Toxic epidermal necrolysis 
VASCULAR DISORDERS 
 
Hypertension 
 
 
Vascular disorders - Other 
(hemorrhage)4 
 
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
3 Allergic reactions observed include anaphylaxis and angioedema. 
4 The majority of hemorrhage events were mild.  Major events, defined as symptomatic bleeding in a 
critical area or organ (e.g., eye, GI tract, GU system, respiratory tract, nervous system [including fatal 
intracranial hemorrhage, and cerebrovascular accident], and tumor site) have been reported. 
Adverse events reported on Sunitinib malate (SU011248 L-malate) trials, but for which 
there is insufficient evidence to suggest that there was a reasonable possibility that 
Sunitinib malate (SU011248 L-malate) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Pericardial effusion 
GASTROINTESTINAL DISORDERS - Ascites; Dysphagia; Gastrointestinal disorders - Other 
(enteritis); Hemorrhoids; Ileus; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Pain 
INVESTIGATIONS - GGT increased; INR increased 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypocalcemia; Hypokalemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain 
NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Nervous system disorders - Other 
(spinal cord compression); Peripheral sensory neuropathy; Seizure; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion 
RENAL AND URINARY DISORDERS - Hematuria; Urinary retention 
REPRODUCTIVE SYSTEMS AND BREAST DISORDERS - Hematosalpinx 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Pharyngolaryngeal pain; 
Pleural effusion; Pneumothorax 
VASCULAR DISORDERS - Flushing; Hypotension; Thromboembolic event 

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NOTE: 
Sunitinib malate (SU011248 L-malate) in combination with other agents could cause 
an exacerbation of any adverse event currently known to be caused by the other 
agent, or the combination may result in events never previously associated with 
either agent. 

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5.4 
Dose Modifications  
There will be no dose escalation above the original starting dose. 
All toxicities should be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.  
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP web site (http://ctep.cancer.gov). 
In cases where the dose modifications trigger a toxicity that is known to be 
related to sunitinib, it is not required to modify the dose of gemcitabine. 
Likewise, for toxicities that are known to be related to gemcitabine, but not 
sunitinib, it is not required to modify the dose of sunitinib. 
5.4.1 
Dose Modifications for Arm A Sunitinib and Gemcitabine 
NOTE: Sunitinib 12.5 mg will be the only strength used. 
Dose Level 
Sunitinib 
Dose Adjustment sunitinib 
Dose Adjustment Gemcitabine 
0 
37.5 mg days 1-
14, 22-35 
▪ 3 sunitinib capsules q day 
▪ 1000 mg/m2 IV days 1, 8, 22 and 29 
-1 
25 mg days 1-14, 
22-35 
▪ 2 sunitinib capsules q day 
▪ 750 mg/m2 IV days 1, 8, 22 and 29 
-2 
12.5 mg days 1-
14, 22-35 
▪ 1 sunitinib capsule q day 
▪ 600 mg/m2 IV days 1, 8, 22 and 29 
5.4.2 
Management of Treatment-emergent Hypertension (Arm A) 
 
Grade of 
Event 
(Version 4) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Sunitinib 
Modification 
Gemcitabine 
 
grade 1 
None 
Routine 
No change 
No Change 
 
grade 2 
asymptomatic 
Initiate monotherapy 
[suggest ACE-inhibitors 
or angiotensin receptor 
blockers (preferred for 
renal insufficiency)] 
Restart of weekly home 
blood pressure 
determinations; verify 
elevated BPs by health care 
provider. 
No change 
No Change 
 
grade 2 
(symptomatic/ 
persistent) 
OR 
diastolic BP  
≥ 110 mm Hg 
OR 
grade 3 
Add agents: (suggest) 
Ca++ blocker (if not 
already used), K+ 
channel opener, beta-
blocker, thiazide 
diuretic) 
Increase frequency and 
monitoring (by health care 
professional) every 2 days 
until stabilized; continued 
q2d monitoring to 
stabilization after dosing 
restarted. 
Continue or Hold * 
Sunitinib until 
symptoms resolved 
and diastolic BP  
≤ 100 mmHg. 
Resume treatment at 
same or Next lower 
dose level.** 
No Change 
 
grade 4 
 
 
Discontinue protocol 
therapy 
No Change 
 
* May be able to resume full dose later. 
** Patients requiring > 2 dose reductions should go off protocol therapy. 

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Current CTCAE definitions used by CTEP: 
Grade 1: Prehypertension (systolic BP) 120-139mm Hg or diastolic 
BP 80-89mm Hg). 
Grade 2: Stage 1 hypertension (systolic BP 140-159mm Hg or 
diastolic BP 90-99mm Hg); medical intervention indicated; 
recurrent or persistent (> = 24 hrs); symptomatic increase 
by 20mm Hg (diastolic) or to > 140/90mm Hg if previously 
WNL; monotherapy indicated. Pediatric: recurrent or 
persistent (> = 24hrs) BP > ULN; monotherapy indicated. 
Grade 3: Stage 2 hypertension (systolic BP > = 160mm HG or 
diastolic BP > = 100mm Hg); medical intervention 
indicated; more than one drug or more intensive therapy 
than previously used indicated. Pediatric: same as adult. 
Grade 4: Life-threatening consequence (e.g. malignant 
hypertension, transient or permanent neurologic deficit, 
hypertensive crisis); urgent intervention indicated. 
Pediatric: Same as adult. 
5.4.3 
Dose Modifications for Hematologic Toxicity Arm A* 
On Day 1 of each cycle, prior to receiving the Day 1 and Day 22 dose 
of gemcitabine and sunitinib, patients must have an absolute 
neutrophil count of  1200 cells/mm3 and a platelet count of  
100,000 cells/mm3. For day 1 or day 22, if the neutrophil count or 
platelet count is below the cutoff, treatment should be held until the 
counts have recovered to the required levels. For day 8 and 29 dosing 
of gemcitabine and sunitinib please see Table below. 
 
Category 
Grade 
Sunitinib Dose 
Gemcitabine dose 
 
Neutropenia 
Grades 1-2 
Continue at same dose 
Continue at same dose 
 
 
Grade 3 
Continue at same dose or 
reduce 1 dose level if nadir is 
thought not to be attributable 
to gemcitabine. 
Treat with 1 dose level reduction 
and add growth factor support for 
this and all subsequent cycles on 
day 9 and 30. 
 
• 
Grade 4 
Withhold until < grade 2, then 
resume at same dose or 
reduce 1 dose level if nadir is 
thought not to be attributable 
to gemcitabine. 
  
Hold dose and add growth factor 
support at visit and all subsequent 
cycles on day 9 and 30. When  
< grade 2, then resume at 1 dose 
level reduction or withdraw 
treatment at doctor discretion. 
 
Thrombocytopenia 
• 
Grades 1 
and 2 
Continue at same dose. 
Same dose or 1 dose level dose 
reduction. 
 
 
• 
Grade 3 
Withhold until < grade 2, then 
resume at same dose. 
Withhold until < grade 2, then 
reduce by 1 dose level. 
 
• 
Grade 4 
Withhold until < grade 2, then 
reduce 1 dose level if nadir is 
thought not to be attributable 
to gemcitabine. 
Withhold until < grade 2, then 
reduce by 1 dose level 
or withdraw treatment at doctor 
discretion. 
 
* Dose modifications in addition to those listed above are permitted at the discretion of the investigator. 
 Recurring grade 3 toxicity requires dose reduction for sunitinib 
Rev. 12/10 
Rev. 12/10 
Rev. 3/12 

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5.4.4 
Dose Modifications for non-hematologic Toxicity (Arm A)* 
NOTE: The occurrence of gastrointestinal perforation (of any grade) 
will require that the patient’s protocol treatment be 
discontinued. 
 
Category 
Grade 
Sunitinib  
Gemcitabine 
 
Fever, chills, flu-like 
Grades 1 and 2 
Continue at same dose 
Continue at same 
dose 
 
 
Grade 3  
Continue at same dose 
Continue at same 
dose 
 
Grade 4  
Withhold until < grade 2, then 
reduce 1 dose level 
Withhold until < grade 
2, then reduce 1 dose 
level 
 
Fatigue (lethargy, 
malaise, asthenia) 
Grades 1 and 2 
Continue as same dose 
Continue as same 
dose 
 
 
Grade 3  
Continue as same dose  
Continue as same 
dose 
 
Grade 4  
 
Withhold until < grade 2, then 
reduce 1 dose level 
Withhold until < grade 
2, then reduce 1 dose 
level 
 
Hand-foot 
Syndrome 
Grade 1 
Continue at same dose 
Continue as same 
dose 
 
 
Grade 2 
Continue at same dose or dose 
reduce by -1 if intolerable 
Continue as same 
dose 
 
Grade 3 
Withhold until < grade 1, then 
resume at same dose or reduce 1 
dose level 
Continue as same 
dose 
  Rev. 
  10/10 
AST and/or ALT 
(SGOT, SGPT)*** 
Grades 1 and 2  
Continue as same dose 
Continue as same 
dose 
 
 
Grade 3  
(AST and ALT are  
> 5- 20 XULN; 
Bilirubin > 3-10 X 
ULN) 
Sunitinib should be dose delayed 
if elevation of ALT is > 5 × ULN, 
AST is > 5 × ULN, and/or bilirubin 
is > 3 × ULN. Sunitinib may be re-
administered at same dose level 
or reduce 1 dose level when 
levels of ALT and AST are ≤ 5 × 
ULN and bilirubin is ≤ 3 × ULN.  
Withhold until < grade 
1, then reduce by 
25% 
 
Grade 4  
(AST and ALT are  
> 20 X ULN; 
Bilirubin > 10.0 X 
ULN) 
Withhold sunitinib until levels of 
ALT and AST are ≤ 5 × ULN and 
bilirubin is ≤ 3 × ULN.  
then reduce 1 dose level 
Withhold until < grade 
1, then reduce by 
25% 
  Rev. 
  10/10 
Hepatic Failure*** 
Grade 1 and 2 
 
 
 
 
Grade 3 
(asterixis;mild 
encephalopathy; 
limited self care 
ADL) 
Discontinue sunitinib 
Hold gemcitabine 
until resolution to 
grade 2 or less 

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Grade 4 (moderate 
to severe 
encephalopathy, 
coma, life-
threatening 
consequences) 
Discontinue sunitinib 
Hold gemcitabine 
until resolution to 
grade 2 or less 
 
All Other Non-
Hematologic 
(including 
symptomatic 
cardiac events) 
Grade 1 
Continue at same dose 
Continue as same 
dose 
 
 
Grade 2  
Continue at same dose 
Continue as same 
dose 
 
Grade 3 + 
Withhold until < grade 1 then 
resume at same dose level or 
reduce 1 dose level at discretion 
of investigator 
Withhold until < grade 
1, then resume at 
same dose level or 
reduce by 25% 
 
Grade 4 + 
Withhold until < grade 1 then 
resume at same dose level or 
reduce 1 dose level at discretion 
of investigator 
Withhold until < grade 
1, then resume at 
same dose level or 
reduce by 25% 
All sunitinib modifications are within days 1-14. Do not shift sunitinib administration into the designated 
break period (days 15-22). 
* 
Dose modifications in addition to those listed above are permitted at the discretion of the investigator. 
 Recurring grade 3 toxicity requires dose reduction 
*** CTCAE v4.0 
+ 
For grade 3 or 4 symptomatic cardiac events, you must contact the study chair for further treatment 
instructions. 
For grade  2 CNS or pulmonary hemorrhage, off study  
For Grade 3 and asymptomatic grade 4 thrombosis, hold sunitinib until stable anticoagulation on warfarin 
and then resume; continue gemcitabine 
5.4.5 
Dose Modifications for Arm B Sunitinib Monotherapy 
Dose Level 
Sunitinib 
Dose Adjustment sunitinib 
0 
50 mg days 1-14, 22-35 
4 sunitinib capsules q day 
-1 
37.5 mg days 1-14, 22-35 
3 sunitinib capsules q day 
-2 
25 mg days 1-14, 22-35 
2 sunitinib capsules q day 
 
Rev. 
10/10 
Rev. 
12/10 

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5.4.6 
Management of Treatment-emergent Hypertension (Arm B) 
 
 
 
Grade of Event 
(Version 4) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Sunitinib 
Modification 
 
grade 1 
None 
Routine 
No change 
 
grade 2 
asymptomatic 
Initiate monotherapy 
[suggest ACE-inhibitors 
or angiotensin receptor 
blockers (preferred for 
renal insufficiency)] 
Restart of weekly 
home blood pressure 
determinations; verify 
elevated BPs by health 
care provider. 
No change 
 
grade 2 
(symptomatic/ 
persistent) 
OR 
diastolic BP ≥ 110 
mm Hg 
OR 
grade 3 
Add agents: (suggest) 
Ca++ blocker (if not 
already used), K+ 
channel opener, beta-
blocker, thiazide diuretic) 
Increase frequency 
and monitoring (by 
health care 
professional) every 2 
days until stabilized; 
continued q2d 
monitoring to 
stabilization after 
dosing restarted. 
Continue or Hold * 
Sunitinib until 
symptoms resolved 
and diastolic BP ≤ 
100 mmHg. Resume 
treatment at same or 
next lower dose 
level.** 
 
grade 4 
 
 
Discontinue protocol 
therapy 
 
* May be able to resume full dose later. 
** Patients requiring > 2 dose reductions should go off protocol therapy. 
Current CTCAE definitions used by CTEP: 
Grade 1: Prehypertension (systolic BP) 120-139mm Hg or diastolic 
BP 80-89mm Hg). 
Grade 2: Stage 1 hypertension (systolic BP 140-159mm Hg or 
diastolic BP 90-99mm Hg); medical intervention indicated; 
recurrent or persistent (> = 24 hrs); symptomatic increase 
by 20mm Hg (diastolic) or to > 140/90mm Hg if previously 
WNL; monotherapy indicated. Pediatric: recurrent or 
persistent (> = 24hrs) BP > ULN; monotherapy indicated. 
Grade 3: Stage 2 hypertension (systolic BP > = 160mm HG or 
diastolic BP > = 100mm Hg); medical intervention 
indicated; more than one drug or more intensive therapy 
than previously used indicated. Pediatric: same as adult. 
Grade 4: Life-threatening consequence (e.g. malignant 
hypertension, transient or permanent neurologic deficit, 
hypertensive crisis); urgent intervention indicated. 
Pediatric: Same as adult. 
 
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5.4.7 
Dose Modifications for Hematologic Toxicity Arm B* 
Category 
Grade 
Sunitinib Dose  
Neutropenia 
Grades 1-2 
Continue at same dose 
 
Grade 3 
Continue at same dose or 
reduce 1 dose level. 
Grade 4 
Withhold until < grade 2, then 
resume at same dose or 
reduce 1 dose level. 
Thrombocytopenia 
Grades 1 and 2 
Continue at same dose 
 
Grade 3 
Withhold until < grade 2, then 
resume at same dose 
Grade 4 
Withhold until < grade 2, then 
reduce 1 dose level. 
* Dose modifications in addition to those listed above are permitted at 
the discretion of the investigator. 
 Recurring grade 3 toxicity requires dose reduction for sunitinib 
 

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5.4.8 
Dose Modifications for non-hematologic Toxicity (Arm B)* 
NOTE: 
The occurrence of gastrointestinal perforation (of any 
grade) will require that the patient’s protocol treatment be 
discontinued. 
 
Category 
Grade 
Sunitinib 
 
Fever, chills, flu-like 
Grades 1 and 2 
Continue at same dose 
 
 
Grade 3  
Continue at same dose 
 
Grade 4  
Withhold until < grade 2, then reduce 1 dose 
level 
 
Fatigue lethargy, malaise, asthenia) 
Grades 1 and 2 
Continue as same dose 
 
 
Grade 3  
Continue as same dose  
 
Grade 4  
Withhold until < grade 2, then reduce 1 dose 
level 
 
Palmar-plantar erythrodysesthesia 
Syndrome 
Grade 1 
Continue at same dose 
 
 
Grade 2 
Continue at same dose or dose reduce by -1 if 
intolerable 
 
Grade 3 
Withhold until < grade 1, then resume at same 
dose or reduce 1 dose level 
Rev. 10/10 
AST and/or ALT (SGOT, SGPT)*** 
Grades 1 and 2  
Continue as same dose 
 
 
Grade 3 (AST and 
ALT are > 5-20 XULN; 
Bilirubin > 3-10 X ULN 
Sunitinib should be dose delayed if elevation of 
ALT is > 5 × ULN, AST is > 5 × ULN, and/or 
bilirubin is> 3 × ULN. Sunitinib may be re-
administered at same dose level or reduce 1 
dose level when levels of ALT and AST are ≤ 5 
× ULN and bilirubin is ≤ 3 × ULN.  
 
 
 
Rev. 3/13 
Grade 4 (AST and ALT 
are > 20 X ULN; 
Bilirubin > 10.0 X ULN) 
Withhold sunitinib until levels of ALT and AST 
are ≤ 5 × ULN and bilirubin is ≤ 3 × ULN, then 
reduce 1 dose level. 
Rev. 10/10 
Hepatic Failure*** 
Grade 1 and 2 
 
 
 
Grade 3 (asterixis; mild 
encephalopathy; limited 
self care ADL) 
Discontinue sunitinib 
 
 
Grade 4 (moderate to 
severe encephalopathy, 
coma, life-threatening 
consequences) 
Discontinue sunitinib 
All Other Non-Hematologic (including 
symptomatic cardiac events) 
Grade 1 
Continue at same dose 
 
Grade 2  
Continue at same dose 
Grade 3 + 
Withhold until < grade 1 then resume at same 
dose level or reduce 1 dose level at discretion 
of investigator 
Grade 4 + 
Withhold until < grade 1 then resume at same 
dose level or reduce 1 dose level at discretion 
of investigator 
* Dose modifications in addition to those listed above are permitted at the discretion of the investigator. 
 Recurring grade 3 toxicity requires dose reduction 
*** CTCAE v4.0 
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+ For grade 3 or 4 symptomatic cardiac events, you must contact the study chair for further treatment 
instructions. 
For grade  2 CNS or pulmonary hemorrhage, off study 
5.5 
Supportive Care  
5.5.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.5.2 
Erythropoietin or blood transfusion may be administered for 
anemia/fatigue at the investigators’ discretion.  
5.5.3 
For ARM A ONLY: GCSF (neupogen) or neulasta is allowed as 
specified in the dose modification for hematologic toxicity (for Arm A 
only). Neulasta must be limited to administration on days 9 or 10 and 
days 30 or 31 of each cycle. GCSF can be administered days 9 up 
thru 20 and days 30 up thru 41 of subsequent cycles. GCSF should 
not be administered on days that gemcitabine is administered or in the 
days between days 1 and 8 and days 22 and 29. 
5.5.4 
Frequent blood pressure monitoring is important for patients receiving 
sunitinib. Experience to date suggests that increases in blood 
pressure may occur following dosing with sunitinib for a number of 
weeks and that these increases may occur relatively quickly. Blood 
pressure must be monitored weekly during the first cycle. This may be 
performed at a doctor’s office or using any calibrated electronic 
device, such as may be found in market or shopping mall. Weekly 
blood pressures performed outside of the office of the treating 
physician will be documented on the patient’s pill diary. Section 5.4.2 
includes specific guidelines on the management and, if appropriate, 
dose modifications for treatment-emergent hypertension. 
5.5.5 
An increase in blood pressure above baseline of more than 20 mmHg 
for systolic and 10 mmHg diastolic should be reported to the treating 
physician immediately.  
5.5.6 
Patients with discomfort due to hand-foot syndrome may be treated 
with topical emollients, low potency topical corticosteroids or urea-
containing creams. 
5.5.7 
Patients taking warfarin for therapeutic anticoagulation must have 
their INR measured weekly for the first cycle, then once per cycle 
thereafter. Follow-up labs can be obtained +/- 5 days. 
5.5.8 
Sunitinib is primarily metabolized via the liver enzymes, especially 
CYP3A4, e.g., 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 SU11248 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. See Appendix V. 
Rev. 12/10, 3/12 
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5.6 
Duration of Therapy 
Patients will receive protocol therapy unless: 
5.6.1 
Extraordinary Medical Circumstances: If at any time the constraints of 
this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued. In this event submit forms according to the 
instructions in the E1808 Forms Packet. 
5.6.2 
Patient withdraws consent. 
5.6.3 
Patient develops disease progression as defined by Section 6. 
5.6.4 
Patient develops grade 3 or 4 toxicity exceeding 6 weeks. 
5.6.5 
Patient develops any of the following conditions: 
1.  GI perforation 
2.  Arterial thrombotic event 
3.  Wound dehiscence requiring medical or surgical therapy 
4. 
Grade 4 hypertension or reversible posterior 
leukoencephalopathy 
5.  Nephrotic syndrome 
6.  Grade 4 congestive heart failure 
7.  Symptomatic grade 4 venous thromboembolic event 
5.7 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression, even if non-protocol therapy 
is initiated, and for survival for 3 years from the date of randomization. All 
patients must also be followed through completion of all protocol therapy. 

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6. 
Measurement of Effect 
6.1 
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 not less than 4 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 1.1) [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 RECIST. 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor 
burden at baseline to which subsequent measurements will be compared. All 
baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than four weeks before registration. 
2. Measurable disease is defined by the presence of at least one measurable 
lesion. 
3. All measurements should be recorded in metric notation by use of a ruler or 
calipers.  
4. The same method of assessment and the same technique must be used to 
characterize each identified lesion at baseline and during follow-up.  
6.1.1 
Definitions 
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 lesion assessment. The 
response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  

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6.1.2 
Disease Parameters 
Measurable Disease 
Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) 
as ≥ 20 mm 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. 
NOTE: Tumor lesions that are situated in a previously irradiated 
area are not considered measurable.  
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. Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
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 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 
reproducibly should be selected.   

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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 of the 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 or absence of 
unequivocal progression of each should be noted throughout follow-
up. 
6.1.3 
Methods for Evaluation of 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 registration. 
The same method of assessment and the same technique must 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 
in 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 
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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 must 
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 image 
acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
PET-CT 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements. However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET 
portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed. 
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. 
6.1.4 
Response Criteria 
6.1.4.1 
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. 

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Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the 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 also considered progression, See Section 
6.1.4.3). 
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. (Note: a change of 20% or 
less that does not increase the sum of the diameters by 5 
mm or more is coded as stable disease) 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval (not less than six 
weeks for both arms).  
6.1.4.2 
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 
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 (see 
Section 6.1.4.3). Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, not a 
single lesion increase. 

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When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of one or more on-target lesions is 
usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on 
the basis of change in non-target disease in the face of SD 
or PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease:  i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy.  
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). 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). A growing lymph node that did not meet the 
criteria for reporting as a measurable or non-measurable 
lymph node at baseline should only be reported as a new 
lesion (and therefore progressive disease) if it a) increases 
in size to ≥ 15 mm the short axis, or b) there is new 
pathological confirmation that it is disease (regardless of 
size). 
6.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence or non-protocol therapy (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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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-PD/not 
evaluated 
No 
PR 
Rev. 4/14 
SD 
Non-PD/not 
evaluated 
No 
SD 
Documented at least 
once ≥ 6 weeks from 
study entry. 
 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
 
Any 
PD*** 
Yes or No 
PD 
 
Any 
Any 
Yes 
PD 
 
*  
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
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. 
Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria 
are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment 
started). 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that 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.  
To be assigned a status of stable disease, measurements must have met the 
stable disease criteria at least once after study entry at a minimum interval (in 
general, not less than six to eight weeks).  

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7. 
Study Parameters 
1. 
Prestudy scans and X-Rays used to assess all measurable or non-measurable sites of disease must be done ≤ 4 weeks 
prior to randomization and should be performed as closely as possible to the beginning of randomization. 
2. 
Prestudy CBC (with differential and platelet count) should be done ≤ 4 weeks before randomization.  
3. 
All required prestudy chemistries, as outlined in Section 3, should be done ≤ 4 weeks before randomization – unless 
specifically required on Day 1 as per protocol.  
4. 
Each cycle is 42 days (6 weeks). 
Table (Both Arms) 
 
 
Within 4 weeks 
prior to 
randomization 
Every cycle 
Every 2 
cycles 
Post Treatment to 
3 years from study 
entry7 
 
History and height 
X 
 
 
 
 
Physical exam, weight 
X 
X 
 
X 
 
Performance status 
X 
X 
 
 
 
Vital signs, including temperature1 
X 
X9 
 
 
 
Laboratory parameters2,3 
X 
X9 
 
X 
 
CT scan of chest, abdomen and pelvis 
with IV and oral contrast4 or chest CT 
and MRI of the abdomen and pelvis. 
X 
 
X 
X 
 
ECHO or MUGA10 
 
PRN 
 
 
 
Bone scan5 
X 
 
X 
 
 
Beta HCG6 
X 
 
 
 
 
EKG 
X 
 
 
 
 
Pill count/diary 
 
X 
 
 
 
Tumor tissue submission8 
X 
 
 
 
1. 
Blood pressure must be evaluated weekly during the first cycle. Measurements may be obtained outside of the 
treating physicians office, however, the patient must contact the treating physician within 24 hours of obtaining 
the measurement and the measurement must be recorded on the patient’s CRF.  Measurements should be 
made using a calibrated electronic device, unless performed in a doctor’s office where a manual blood 
pressure measurement is acceptable. 
Rev. 3/12 
Rev. 3/12 

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2. 
CBC (with differential and platelet count), Chemistries (Na, K, Cl, CO2, BUN, creatinine), LDH, hemoglobin, 
Liver function tests (SGOT, SGPT, total bilirubin), serum calcium, albumin, total protein, and alkaline 
phosphatase. Institutional thyroid function tests (cycle 1, 2 and then as indicated). Patients taking warfarin for 
therapeutic anticoagulation must have their INR measured weekly for the first cycle, then once per cycle 
thereafter. Follow-up labs can be obtained +/- 5 days 
3. 
CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb, and Hct required for 
protocol therapy must be done < 24 hours prior to the treatment cycle. 
4. 
MRI scan of the abdomen and pelvis with gadolinium and a non-contrast CT of the chest can be substituted if 
patient is not able to have CT scans with intravenous contrast. Follow-up scans can be obtained +/- 5 days. 
5. 
Recommended if patient has rising alkaline phosphatase and/or bone pain. 
6. 
For women of childbearing potential to rule out pregnancy within 2 weeks prior to randomization. 
7. 
Every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-3 years from study entry 
8. 
Original diagnostic tumor tissue specimens including immunological study slides and pathology reports MUST 
be submitted for central pathology review. Refer to Section 10 and Appendix II for submission guidelines.  
9. 
For Both Arms: Must be done on Day 1 of each cycle. Arm A Only: Must also be done on Days 8, 22 and 29 
of each cycle. 
10. PRN - ECHO or MUGA may be performed if the patient has symptoms of fatigue or shortness of breath. The 
sunitinib label reports low incidence of decline in LVEF in patients treated with sunitinib. Therefore a baseline 
MUGA or ECHO is recommended but not required for E1808. A follow-up evaluation should be considered in 
patients who develop clinical signs or symptoms of heart failure. 
 
Rev. 12/10 
Rev. 3/12 

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8. 
Drug Formulation and Procurement 
8.1 
Sunitinib (NSC 736511) 
8.1.1 
Other Names  
SU011248 L-Malate salt; SU010398; PHA-290940AD; Sutent; 
SU011248  
8.1.2 
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 
8.1.3 
Molecular Formula 
C22H27FN4O2.C4H6O5 
8.1.4 
Molecular Weight  
Sunitinib L-Malate Salt:  532.57 Daltons 
Sunitinib (free base):  398.48 Daltons 
8.1.5 
Classification 
Receptor tyrosine kinase inhibitor (RTK) 
8.1.6 
Physical Description 
Yellow to orange powder 
8.1.7 
Cas Registry Number 
341031-54-7 
8.1.8 
Aqueous Solubility 
Solvent 
Solubility (mg/mL) 
0.1 M HCl 
63.1 
Simulated intestinal fluid 
25.3 
Simulated gastric fluid 
54.1 
0.1 M NaOH 
Not detected 
In water 
4.9 
8.1.9 
Solubility in Various Solvents 
Solvent 
Solubility (mg/mL) 
Acetonitrile 
0.4 
Dimethyl sulfoxide 
68.4 
Isopropyl Alcohol 
0.2 
Methanol 
2.2 
Ethanol 
0.5 
Acetone 
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N, N-Dimethylacetamide 
39.9 
Dimethyl sulfoxide / Water 50:50 v/v 
5.3 
Methanol/Water 50:50 v/v 
8.4 
8.1.10 
Mechanism of Action 
Sunitinib 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. 
8.1.11 
How Supplied 
“Sunitinib malate” will be supplied as a size 4 Swedish Orange hard 
gelatin capsule for oral administration. For “Sunitinib”, each capsule 
contains 12.5mg of the free base (sunitinib) with mannitol, 
croscarmellose sodium, povidone, and magnesium stearate (non-
bovine). The hard gelatin capsule contains black iron oxide, red iron 
oxide, yellow iron oxide, titanium dioxide, and gelatin. 
For this study, each 60ml, tamper-evident, child-resistant, white, 
opaque, high-density polyethylene (HDPE) bottle will contain 120 
capsules of Sunitinib 12.5mg. 
NOTE: Sunitinib 12.5 mg will be the only strength used. Please 
prescribe 12.5 mg capsules ONLY (84 capsules for Arm A per 
cycle and 112 capsules for Arm B per cycle). 
8.1.12 
Storage and Stability 
Sunitinib must be stored at controlled room temperature (15ºC to 
30ºC, 59ºF to 86ºF) and protected from light.  Shelf-life studies with 
sunitinib are continuing and investigators will be notified when lots 
have expired. 
8.1.13 
Dose Specifics 
For Arm A of this study, sunitinib will be administered at a dose of 
37.5mg (3 X 12.5 mg capsules) orally once daily for 14 days (2 
weeks) followed by rest for 7 days (1 week), then sunitinib will be 
repeated for another 14 days (2 weeks) followed by an additional rest 
period of 7 days (1 week) each cycle to be repeated for 1 year (One 
cycle = 42 days = 6 weeks).. 
For Arm B of this study, sunitinib will be administered at a dose of 50 
mg (4 x 12.5 mg capsules) orally once daily for 14 days (2 weeks) 
followed by rest for 7 days (1 week), then sunitinib will be repeated for 
another 14 days (2 weeks) followed by an additional rest period of 7 
days (1 week) of each cycle to be repeated for 1 year (one cycle = 42 
days = 6 weeks). 
8.1.14 
Route of Administration 
Oral. Sunitinib may be administered without regard to meals. 

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8.1.15 
Potential Drug Interactions 
Sunitinib is metabolized primarily by liver enzymes, particularly 
CYP3A4. Rifampin lowers sunitinib Cmax concentration by more than 
2-fold.   
Concomitant treatment with P450 enzyme-inducing antiepileptic drugs 
(phenytoin, carbamazepine or phenobarbital), St John's Wort, 
ketoconazole, dexamethasone, the dysrhythmic drugs (terfenadine, 
quinidine, procainamide, sotalol, probucol, bepridil, indapamide or 
flecainide), haloperidol, risperidone, rifampin, grapefruit, or grapefruit 
juice is prohibited during the course of therapy. 
8.1.16 
Patients 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. 
8.1.17 
Compliance 
Patients will be required to record dose of pills in diary and return pill 
bottles and diary with each cycle. 
8.1.18 
Availability  
Commercial 
8.1.19 
Side Effects  
Refer to Section 5.3 of the protocol. Please visit www.sutent.com for 
more information regarding hepatotoxicty. 
8.2 
Gemcitabine 
8.2.1 
Other Names 
2'-Deoxy-2',2'-difluorocytidine monohydrochloride, Gemzar 
8.2.2 
Classification 
Antimetabolite (nucleoside pyrimidine analogue) 
8.2.3 
Mode of Action 
Gemcitabine exhibits cell phase specificity, primarily killing cells 
undergoing DNA synthesis (S phase) and also blocking the 
progression of cells through the G1/S phase boundary. Gemcitabine 
is metabolized intracellularly by nucleoside kinases to the active 
diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The 
cytotoxic effect of gemcitabine is attributed to a combination of two 
actions of the diphosphate and the triphosphate nucleosides, which 
leads to inhibition of DNA synthesis. First, gemcitabine diphosphate 
inhibits ribonucleotide reductase, which is responsible for catalyzing 
the reactions that generate the deoxynucleoside triphosphates for 
DNA synthesis. Inhibition of this enzyme by the diphosphate 
nucleoside causes a reduction in the concentrations of 
deoxynucleotides, including dCTP. Second, gemcitabine triphosphate 
competes with dCTP for incorporation into DNA. The reduction in the 
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intracellular concentration of dCTP (by the action of the diphosphate) 
enhances the incorporation of gemcitabine triphosphate into DNA 
(self-potentiation). After the gemcitabine nucleotide is incorporated 
into DNA, only one additional nucleotide is added to the growing DNA 
strands. After this addition, there is inhibition of further DNA synthesis. 
DNA polymerase epsilon is unable to remove the gemcitabine 
nucleotide and repair the growing DNA strands (masked chain 
termination). In CEM T lymphoblastoid cells, gemcitabine induces 
internucleosomal DNA fragmentation, one of the characteristics of 
programmed cell death. 
8.2.4 
Storage and Stability 
Unreconstituted drug vials are stored at controlled room temperature 
(15ºC to 30ºC, 59ºF to 86ºF). Reconstituted solution should be stored 
at controlled room temperature and used within 24 hours. Solutions of 
gemcitabine should not be refrigerated; as crystallization may occur. 
The unused portion should be discarded. 
8.2.5 
Dose Specifics 
1000 mg/m2 IV over 30 minutes on days 1, 8, 22 and 29 of each 
cycle. 
8.2.6 
Preparation 
Reconstitute the 200 mg vial with 5ml and the 1 gm vial with 25 ml 
preservative free normal saline to make a solution containing 38 
mg/ml. Shake to dissolve. Gemcitabine may be further diluted with NS 
as per institutional standards. 
8.2.7 
Route of Administration 
IV infusion. 
8.2.8 
Incompatibilities 
No information available. 
8.2.9 
Availability 
Gemcitabine is commercially available in 200 mg and 1 gm vials. 
8.2.10 
Side Effects 
1. Hematologic: Neutropenia, anemia, thrombocytopenia, and 
leukopenia are reported. 
2. Dermatologic: A rash is seen in about 25% of patients and is 
associated with pruritus in about 10% of patients. The rash is 
usually mild, not dose-limiting, and responds to local therapy. 
Desquamation, vesiculation, and ulceration have been reported 
rarely. Alopecia is usually minimal. Injection-site reactions. 
3. Gastrointestinal: Nausea and vomiting are reported in about two-
thirds of patients and requires therapy in about 20% of patients. It 
is rarely dose limiting, and is easily manageable with standard 
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4. Hepatic: Abnormalities of hepatic transaminase enzymes occur in 
two-thirds of patients, but they are usually mild, nonprogressive, 
and rarely necessitate stopping treatment. However, gemcitabine 
should be used with caution in patients with impaired hepatic 
function. 
5. Pulmonary: Bronchospasm and/or dyspnea within a few hours of 
infusion of the drug, cough, rhinitis, pneumonitis.  
6. Neurologic: Somnolence, insomnia, paresthesia, pain. 
7. Cardiovascular: A few cases of hypotension were reported. Some 
cases of myocardial infarction, congestive heart failure, and 
arrhythmias have been reported. Peripheral edema is reported in 
about 30% of patients. Some cases of facial edema have also 
been reported. Edema is usually mild to moderate, rarely dose-
limiting, sometimes painful, and reversible after stopping 
gemcitabine treatment. 
8. Other: Flu-like symptoms are reported for about 20% of patients. 
This includes fever, headache, back pain, chills, myalgia, 
asthenia, and anorexia. Malaise and sweating are reported. 
8.2.11 
Nursing/Patient Implications 
1. If the patient reports burning at the injection site, slow down rate to 
allow the dose to run in over 1 hour. 
2. Rash can be treated with topical therapy or the administration of 
diphenhydramine prior to administration. 
3. Flu-like symptoms can be treated with acetaminophen. 
 

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9. 
Statistical Considerations 
The primary endpoint is response rate. Progression-free survival, overall survival and 
safety are secondary endpoints. 
As of September, 2015, the accrual rate has been slower than anticipated. The single 
agent sunitinib arm reached its accrual target and was closed on August 26, 2015. To 
expedite completion of the Sunitinib/Gemcitabine arm, the study was amended to cap 
accrual on that arm at 45 total patients.  Among 33 patients on that arm assessed for 
response at the time of the amendment, the response rate was 21% (90% exact 
binomial confidence interval, 9.0 to 38.9%). 
Patients will be allocated to treatment with either sunitinib/gemcitabine or sunitinib alone. 
A two-stage design will be used in each arm. During periods when both arms are open, 
the allocation will be by 1:1 randomization, stratified on risk level as described in Section 
2. If one arm is suspended or closed, allocation will be by direct assignment. Total 
accrual of 85 patients is planned, based on expected participation from SWOG and 
CALGB and posting of the study on the CTSU menu.   
9.1 
Sample Size and Revised Design for the Sunitinib/Gemcitabine Arm 
While the combination of doxorubicin and gemcitabine showed encouraging 
activity in E8802 (15.4%), a single-agent doxorubicin-based trial was inactive. 
Therefore, it seems likely that gemcitabine is the active agent. We will consider 
sunitinib to have additive benefit if the true response rate is 30%, while a rate of 
15% will not be of interest. 
First, 23 patients will be enrolled. If 3 or fewer responses are observed, the arm 
will be closed to further accrual. If 4 or more responses are observed, the arm 
will reopen for accrual of 20 additional eligible, treated patients. The regimen will 
be declared worthy of further study if 10 or more responses are observed. These 
decision rules result in 54% probability of stopping early if the regimen is inactive, 
85% probability of declaring the regimen active given a true response rate of 
30% and 9% probability of declaring the regimen active given a true response 
rate of 15%. 
To assure that 43 eligible patients are assigned to this arm, total accrual of 45 
patients is projected, 25 in stage 1 and 20 in stage 2. 
9.2 
Sample Size and Design for the Sunitinib Alone Arm 
A response rate of 20% to sunitinib alone will be of interest, while further testing 
would not be pursued if the response rate is 5% or lower. Initially, 12 eligible 
patients will be accrued. If 1 or more responses are observed, then an additional 
25 eligible patients will be accrued. Four or more responses out of 37 eligible 
patients will be considered evidence warranting further study of the regimen.  
This design provides 90% probability of declaring the regimen effective if the true 
response rate is 20% and 9% probability of declaring the regimen effective if the 
true response rate is 5%. The probability of stopping early if the regimen is 
ineffective is 54%. 
To assure that 37 eligible patients are assigned to this arm, total accrual of 40 
patients (13 in stage 1 and 27 in stage 2) is projected.   
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Since patients with a high proportion of sarcomatoid features have previously 
been found to have lower response rates to angiogenic inhibitors than patients 
with lower proportions, response rates within subsets of patients with high and 
low levels of sarcomatoid features will be examined. These analyses will be 
descriptive in nature. 
If the necessary number of responses is observed on each arm to consider the 
regimen worthy of further study, then a comparison of the response rate between 
the two arms will be conducted. There will be 81% power to detect a 22% 
difference in response rates (20% vs 42%) using a one-sided Fisher’s exact test 
with Type I error of 15%. 
9.3 
Progression Free Survival 
Another important secondary endpoint of the study is progression-free survival, 
defined as time from randomization to documented progression of disease per 
RECIST criteria or death from any cause. The previous ECOG-ACRIN study in 
patients with renal cell carcinoma with sarcomatoid features demonstrated 
median progression-free survival of 3.4 months. This study will compare PFS on 
each arm to this historical control rate. An improvement of 50%, to median PFS 
of 5.1 months, will be considered worthy of further study. We assume accrual to 
each arm of 3.5 eligible patients per month. With target accrual on the 
combination arm of 42 eligible patients, accrual is expected to take 66 months 
and no additional follow-up is required.  Among these patients and using an 
exponential test, there will be 88% power to demonstrate 50% improvement, with 
one-sided Type I error of 10%.  Full information will exist when 37 patients have 
progressed or died. 
With target accrual on the single agent arm of 37 eligible patients, accrual is 
expected to take 10.6 months and 5.5 months of follow-up are required.  Among 
these patients and using an exponential test, there will be 80% power to 
demonstrate 50% improvement, with one-sided Type I error of 10%.  Full 
information will exist when 28 patients have progressed or died. 
As both arms are experimental, a statistical comparison of PFS on the two arms 
of this study is not planned.  In the absence of a statistically significant 
improvement in response rates of the sunitinib/gemcitabine combination or 
sunitinib alone over the null rates, decisions about whether to carry forward one 
of these regimens or the prior ECOG 8802 (doxorubicin/gemcitabine) regimen 
into Phase III testing (or, if Phase III testing is deemed infeasible in this limited 
subset, recommendations about treatment for these patients) will be based on a 
global evaluation of toxicity, response, PFS, and overall survival.  Analysis of 
overall survival will be descriptive, using Kaplan-Meier survival estimates, and 
will be conducted separately for each arm. 
9.4 
Toxicity 
All patients who receive at least one dose of treatment, regardless of eligibility, 
will be included in the safety analysis population. Safety will be evaluated 
separately on the two arms. If 45 patients are treated with the combination of 
gemcitabine/sunitinib, the maximum width of a 90% confidence interval on the 
rate of severe toxicity will be no wider than 26% (+/- 13%). The probability of 
observing at least one rare toxicity (true rate of 5%) is approximately 90%.  If 40 

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patients are treated with single agent sunitinib, the maximum width of a 90% 
confidence interval on the rate of severe toxicity will be no wider than 28% (+/- 
14%). The probability of observing at least one rare toxicity (true rate of 5%) is 
approximately 87%. 
Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN 
studies. Reports of these analyses are sent to the ECOG-ACRIN Principal 
Investigator or Senior Investigator at the participating institutions. Expedited 
reporting of certain adverse events is required, as described in Section 5.2. 
9.5 
Gender and Ethnicity  
Based on previous data from E8802 the anticipated accrual in subgroups defined 
by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
2 
3 
Not Hispanic or Latino 
34 
48 
82 
Ethnic Category: Total of all subjects 
35 
50 
85 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
1 
0 
1 
Black or African American 
5 
1 
6 
Native Hawaiian or other Pacific 
Islander 
0 
0 
0 
White 
29 
49 
78 
Racial Category: Total of all subjects 
35 
50 
85 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
 

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10. 
Pathology Review 
Diagnostic tumor specimens and related reports are to be submitted from all patients for 
central diagnostic review and classification. The review will include the confirmation of 
the sarcomatoid features and documentation of other pathological parameters. This 
central review is a retrospective assessment required to establish a consistent pathology 
evaluation of the tumor status of all patients on the trial for purposes of the trial only. 
Because the review is retrospective, the results of the central review will not affect 
patient participation on the trial. 
Submission of pathologic materials for diagnostic review is mandatory in order for the 
patient to be considered evaluable. Failure to submit pathologic materials may render 
the case unevaluable. Submission guidelines for the submitting pathologist and clinical 
research associate are also provided in Appendix II (Pathology Submission Guidelines).  
NOTE: ECOG-ACRIN requires that all biological samples submitted be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System (STS). An STS 
shipping manifest form must be generated and shipped with the sample 
submissions.  See Section 10.5.  
10.1 
The pathology materials required for this protocol are: 
10.1.1 
Forms: Must be submitted with every tissue submission 
10.1.1.1 
A copy of the surgical pathology report 
10.1.1.2 
Immunological study reports, if available 
10.1.1.3 
STS Shipping Manifest 
10.1.2 
Biological Material Submission  
If blocks are unavailable for submission, contact the ECOG-ACRIN 
CBPF (844-744-2420, eacbpf@mdanderson.org) to obtain a 
description of alternative submission requirements. 
10.1.2.1 
Central Pathology Review (MANDATORY) 
• 
Representative H&E slides from ALL tumor blocks are 
to be submitted. After cursory review by the CBPF, the 
site will then be instructed to submit the required 
appropriate blocks containing Sarcomatoid and non-
sarcomatoid (clear cell, papillary, chromophobe, other) 
primary tumor or metastatic lesions. A representative 
block from a core needle biopsy may be submitted if 
resected specimens are unavailable. 
NOTE: If a requested block is unavailable for 
submission, contact ECOG-ACRIN CBPF 
(844-744-2420, eacbpf@mdanderson.org) to 
discuss possible alternative submission 
requirements. 
• 
Immunological study slides (if performed) 
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10.1.2.2 
Additional Materials for Banking  
One or more additional tumor blocks, if available, are 
requested from patients who have consented to allow their 
specimens to be banked for future research. Note: If a 
block is unavailable for submission, contact ECOG-ACRIN 
CBPF (844-744-2420, eacbpf@mdanderson.org) to obtain 
alternative specimen submission requirements. 
10.2 
Shipping Procedures  
The pathology materials are to be submitted within one month following 
randomization. 
Access to the shipping account for specimen shipments to the ECOG-ACRIN 
CBPF at MD Anderson Cancer Center can now only be obtained by logging into 
fedex.com with an account issued by the ECOG-ACRIN CBPF. For security 
reasons, the account number will no longer be given out in protocols, over the 
phone, or via email. If your site needs to have an account created, please contact 
the ECOG-ACRIN CBPF by email at eacbpf@mdanderson.org. 
Ship to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 844-744-2420 (713-745-4440 Local or International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
An STS shipping manifest form must be generated and shipped with all sample 
submissions.  
10.3 
Central Biorepository and Pathology Facility: Sample processing and Routing  
Tumor tissue blocks and slides will be processed and the appropriate diagnostic 
materials, including the pathology reports, will be forwarded to Dr. Michael Pins 
for the central review.  
From patients who have consented to allow the retention of specimens for 
research, the tissue will be processed to maximize the utility of the specimens. 
Processing may include, but not be limited to, the construction of TMAs and the 
extraction of DNA, RNA, and proteins.  
10.4 
Histologic Confirmation    
Histologic subtype is a strong prognostic indicator, as well as a determinant of 
response to therapy (2,3,4). The following pathological parameters (beyond TNM 
assignment) have been demonstrated to have prognostic relevance in renal cell 
carcinoma. As such, uniform documentation of these parameters is essential in 
any study measuring outcomes. 
1. RCC Subtypes:  The 2004 WHO classification system recognized over 50 
different tumors of the kidney. For practical purposes, the carcinoma 
subtypes fall into five major categories, including clear cell, papillary, 
chromophobe, collecting duct, and renal cell carcinoma, unclassified.  
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Increasingly, rarer subtypes, such as renal medullary carcinoma, 
translocation carcinomas (Xp11.2/TFE3 fusions, for example), mucinous 
tubular and spindle cell carcinoma, multilocular cystic renal cell carcinoma, 
mixed epithelial stromal tumor and others are increasingly recognized.  Each 
of these common and rarer subtypes have characteristic molecular genetic 
abnormalities, which in turn correlate with biological behavior and likely 
correlate with response to adjuvant therapy.  While subclassification based 
upon rigorous application of histopathological criteria is usually straight-
forward, a significant subset of cases are problematic for the pathologist.  For 
example, the occasional tumor with eosinophilic features may be 
misclassified as eosinophilic variant of clear cell carcinoma, papillary 
carcinoma (type 2), eosinophilic variant of chromophobe carcinoma, benign 
oncocytoma, or epithelioid angiomyolipoma. The correct subclassification is 
not only critical from a molecular-genetic standpoint, but also from a 
prognostic standpoint as several studies have demonstrated the prognostic 
significance of the tumor subtype (5,6,7). 
2. Sarcomatoid component:  The 2004 WHO classification discarded the term 
“sarcomatoid carcinoma” in favor of the term “[subtype] with sarcomatoid 
change” recognizing that most renal cell carcinomas with sarcomatoid 
elements have associated, conventional (clear cell, papillary, or chromphobe) 
subtypes.  Those tumors that lack a conventional subtype are categorized as 
RCC, unclassified.  Several studies have shown that presence of 
sarcomatoid change is associated with a bad prognosis (8, 9). It is currently 
accepted that the presence of any sarcomatoid component portends a bad 
prognosis; however, the significance of the histopathological features of the 
sarcomatoid component or the relative amount of the sarcomatoid component 
has not been rigorously analyzed. 
3. Fuhrman Grade:  The Fuhrman system is the most widely used nuclear 
grading system for renal cell carcinoma of clear cell histology. The Fuhrman 
nuclear grade is widely accepted as a significant prognostic variable. 
Although the criteria for grades 1 to 4 are fairly rigidly defined, its 
reproducibility between pathologists appears to be low, with studies showing 
Kappa values ranging from 0.19 to 0.44, reflecting only poor to moderate 
reproducibility (27,28,29).  In addition, the applicability of the Fuhrman 
grading sytem may vary between the subtypes. Specifically, a four-tiered 
system (Fuhrman grades 1, 2, 3 and 4) correlates with prognosis in clear cell 
tumors, a two-tiered system (“low-grade” [combining Fuhrman grades 1 and 
2] and “high-grade” [combining Fuhrman grades 3 and 4] better stratifies 
prognosis of papillary tumors, and Fuhrman grading probably does not 
prognostically stratify chromophobe tumors.  Finally, renal cell carcinomas 
are often heterogeneous containing areas of tumor with more than one 
Fuhrman grade.  By convention, the tumor is graded based upon the highest 
Fuhrman grade present; however, this approach has not been seriously 
validated; a tumor with a small focus of Fuhrman grade 4 very likely will not 
behave as badly as a tumor with mostly Fuhrman grade 4 - yet both would be 
classified as grade 4. 
4. Necrosis:  The presence of coagulative tumor necrosis has recently been 
shown to be an adverse prognostic variable (30).  Similar to the presence of a 

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sarcomatoid component, the amount of coagulative necrosis may also show 
prognostic significance. 
5. TNM:  Accurate assignment of TNM status is important in renal cell 
carcinoma.  As such, tumor size, extension beyond the renal capsule 
(perinephric fat, Gerota fascia, adrenal, other), renal vein (or vena cava) 
invasion, renal sinus involvement, and lymph node (hilar, periaortic, distant, 
etc) involvement (if sampled by the surgeon or pathologist) must be 
documented in a uniform manner via Central Pathology Review. 
10.5 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst 
Important: 
Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using 
the software.  A user manual and interactive demo are available by 
clicking this link: http://www.ecog.org/general/stsinfo.html. Please 
take a moment to familiarize yourself with the software prior to 
using the system. 
An STS generated shipping manifest should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to ecog-
acrin.tst@jimmy.harvard.edu 
10.5.1 
Study Specific Notes 
If STS is not available at time of shipment, submit the specimens with 
the appropriate documentation, a completed ECOG-ACRIN Generic 
Specimen Submission Form (#2981), and notify the CBPF of the 
shipment by phone. (844-744-2420) or fax a copy of the Specimen 
Submission Form to 713-563-6506. Retroactively enter all specimen 
collection and shipping information when STS is available. 
10.6 
Banking  
Specimens submitted, including residual materials from the central review, will be 
retained at the ECOG-ACRIN Central Repository for possible use in future 
ECOG-ACRIN approved studies. Any residual blocks will be available for 
purposes of individual patient management on specific written request. If future 
use is denied or withdrawn by the patient, the samples will be removed from 
consideration for use in any future study. 
10.7 
Sample Inventory Submission  
A report of all samples received, used, and stored must be submitted monthly or 
upon request to the ECOG-ACRIN Operations Office – Boston.  The report must 
include residuals or derivatives of the original materials received.  Upon 
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completion of the study, a final study inventory must be submitted.  Any changes 
to the inventory of any stored material must be submitted at the time of the 
change and upon request by the ECOG-ACRIN Operations Office – Boston. 
Inventories must be submitted via secure electronic submission in the 
appropriate pre-approved format to the ECOG-ACRIN Operations Office – 
Boston. 
10.8 
Lab Data Transfer Guidelines 
The data collected and generated on the above mentioned studies will be 
submitted electronically to the ECOG-ACRIN Operations Office – Boston by the 
investigating laboratories on a quarterly basis as per agreement. The quarterly 
cut-off dates are March 31, June 30, September 30, and December 31. Data is 
due at the ECOG-ACRIN Operations Office – Boston 1 week after these cut-off 
dates.  
 
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11. 
Records to Be Kept 
Please refer to the E1808 Forms Packet for the forms submission schedule and copies 
of all forms. The E1808 Forms Packet may be downloaded by accessing the ECOG 
World Wide Web Home Page (http://www.ecog.org). Forms must be submitted to the 
ECOG-ACRIN Operations Office – Boston, FSTRF, 900 Commonwealth Avenue, 
Boston, MA 02215 (ATTN: DATA). 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. 
12. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 

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Version Date: February 22, 2016 
 
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13. 
References 
1. 
Chow WH, Devesa SS, Warren JL, Fraumeni JF Jr. Rising incidence of renal cell 
cancer in the United States.JAMA. 1999 May 5;281(17):1628-31. 
2. 
Gettman MT, Blute ML, Spotts B, Bryant SC, Zincke H. Pathologic staging of renal 
cell carcinoma: significance of tumor classification with the 1997 TNM staging 
system. Cancer. 2001 Jan 15;91(2):354-61. PMID: 11180082  
3. 
Tsui KH, Shvarts O, Smith RB, Figlin RA, deKernion JB, Belldegrun A. Prognostic 
indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the 
revised 1997 TNM staging criteria. J Urol. 2000 Apr;163(4):1090-5. PMID: 
10737472  
4. 
Amin MB, Tamboli P, Javidan J et al: Prognostic impact of histologic subtyping of 
adult renal epithelial neoplasms:an experience of 405 cases. Am J Surg Pathol 
26:281-291, 2002. 
5. 
Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of outcome 
and prognostic features among histologic subtypes of renal cell carcinoma. Am J 
Surg Pathol. 2003 May;27(5):612-24. 
6. 
Ficarra V, Prayer-Galetti T, Novella G, et al: Incidental detection beyond 
pathological factors as prognostic predictor of renal cell carcinoma. Eur Urol 
43:663-669, 2003. 
7. 
Patard JJ. Leray E., et al. Prognostic value of histologic subtypes in renal cell 
carcinoma: a multicenter experience. J Clin Oncol. 23(12):2763-71, 2005. 
8. 
Cheville JC, Lohse CM, Zincke H, et al. Sarcomatoid Renal Cell carcinoma:an 
examination of underlying histologic subtype and an analysis of associations with 
patient outcome. Am J Surg Pathol. 2004 28:435-41. 
9. 
de Peralta-Venturina M, Moch H, Amin M, et al. Sarcomatoid differentiation in renal 
cell carcinoma:a study of 101 cases. Am J Surg Pathol. 2001:25:275-84. 
10. 
Jones TD, Eble JN, Wang M, et al. Clonal Divergence and Genetic Heterogeneity 
in Clear Cell Renal Cell Carcinomas with Sarcomatoid Transformation. 
Cancer.2005 104:1195-1203. 
11. 
Wu JJ, Caliendo G, Hu X-P, et al.: Impact of histology on the treatment outcome of 
metastatic or recurrent renal cell cancer. Med Oncol 15:44-49, 1999. 
12. 
Tomera KM, Farrow GM, Lieber MM: Sarcomatoid renal cell. J Urol 130:657-
659,1983. 
13. 
A. R. Golshayan, S. George, D. Heng, et al. Metastatic renal cell carcinoma 
(mRCC) with sarcomatoid component treated with VEGF-targeted therapy. 2008 
ASCO Genitourinary Cancers Symposium 348 
14. 
Haas N, Manola J, Pins M, Liu G, McDermott D, Nanus D, Heath E, Wilding G, 
Dutcher J.ECOG 8802: Phase II trial of doxorubicin and gemcitabine in metatstaic 
renal cell carcinoma with sarcomatoid features. 2009 ASCO Genitourinary Cancers 
Symposium 285. 
15. 
Nanus DM, Garino A, Milowsky MI, et al.: Active chemotherapy for sarcomatoid 
and rapidly progressing renal cell carcinoma. Cancer. 2004 Oct 1;101(7):1545-51. 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
61 
16. 
Langner C, von Wasielewski R, Ratschek M, et al. Biological significance of p27 
and Skp2 expression in renal cell carcinoma. A systematic analysis of primary and 
metastatic tumour tissues using a tissue microarray technique. Virchows Arch. 
2004 Dec;445(6):631-6. 
17. 
Ishizaki H, Yano H, Tsuneoka M, et al.Overexpression of the myc target gene 
Mina53 in advanced renal cell carcinoma. Pathol Int. 2007 Oct;57(10):672-80. 
18. 
Visapää H, Seligson D, Huang Y,et al. Ki67, gelsolin and PTEN expression in 
sarcomatoid renal tumors. Urol Res. 2003 Feb;30(6):387-9. 
19. 
Gordon JD, Lal P, Letrero R, et al. HIF- expression distinguishes two subtypes of 
sporadic VHL-deficient clear cell renal carcinoma: differential effects on c-Myc and 
replication stress. 2008 submitted. 
20. 
Mertz KD, Demichelis F, Kim R, et al. Automated immunofluorescence analysis 
defines microvessel area as a prognostic parameter in clear cell renal cell cancer. 
Hum Pathol. 2007 Oct;38(10):1454-62. 
21. 
Tickoo SK, Alden D, Olgac S, et al: Immunohistochemical expression of hypoxia 
inducible factor-1alpha and its downstream molecules in sarcomatoid renal cell 
carcinoma. J Urol 177:1258-1263, 2007 
22. 
Tamboli P, Prieto VG, Bekele BN, et al: The tyrosine kinase receptor c-Kit is 
overexpressed in sarcomatoid renal carcinomas. Proc Am Soc Clin Oncol 22:408a, 
2003 (abstr 1641) 
23. 
Escudier B, Droz JP, Rolland F, et al.Doxorubicin and ifosfamide in patients with 
metastatic sarcomatoid renal cell carcinoma: a phase II study of the Genitourinary 
Group of the French Federation of Cancer Centers. J Urol. 2002 Sep;168(3):959-
61. 
24. 
Siu LL, Awada A, Takimoto CH, et al. Phase I trial of sorafenib and gemcitabine in 
advanced solid tumors with an expanded cohort in advanced pancreatic cancer. 
Clin Cancer Res. 2006 Jan 1;12(1):144-51. 
25. 
M. Michaelson, A. Schwarzberg, D. Ryan, et al. A phase I study of sunitinib in 
combination with gemcitabine in advanced renal cell carcinoma and other solid 
tumors. 2008 ASCO Genitourinary Cancers Symposium 362 
26. 
Pandya SS, Mier JW, Cho D, and McDermott, D The Role of adding gemcitabine 
at time of sunitinib resistance in patients with metastatic RCC. 2008 ASCO 
Genitourinary Cancers Symposium 380. 
27. 
Al-Aynati M. Chen V., et al.  Interobserver and intraobserver variability using the 
Fuhrman grading system for renal cell carcinoma. Arch Pathol Lab Med. 
127(5):593-6, 2003. 
28. 
Lang H. Lindner V., et al. Multicenter determination of optimal interobserver 
agreement using the Fuhrman grading system for renal cell carcinoma: 
Assessment of 241 patients with > 15-year follow-up. Cancer. 103(3):625-9, 2005. 
29. 
Ficarra V. Martignoni G., et al. Original and reviewed nuclear grading according to 
the Fuhrman system: a multivariate analysis of 388 patients with conventional 
renal cell carcinoma. Cancer.103(1):68-75, 2005. 
30. 
Sengupta S. Lohse CM, et al.  Histologic coagulative tumor necrosis as a 
prognostic indicator of renal cell carcinoma aggressiveness.  Cancer. 104(3):511-
20, 2005. 

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A Randomized Phase II Trial of Sunitinib/Gemcitabine or Sunitinib in Advanced Renal 
Cell Carcinoma with Sarcomatoid Features 
 
Appendix I 
 
Informed Consent Template for Cancer Treatment Trials 
(English Language) 
[Deleted in Update #2] 
 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I was removed from the protocol document in Update #2 and is posted as a 
separate document on the ECOG website. This was removed from the protocol to comply 
with NCI formatting guidelines. 
 

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A Randomized Phase II Trial of Sunitinib/Gemcitabine or Sunitinib in Advanced Renal 
Cell Carcinoma with Sarcomatoid Features 
 
Appendix II 
 
Pathology Submission Guidelines 
The following items are included in Appendix II: 
1. 
Guidelines for Submission of Pathology Materials (instructional sheet for Clinical 
Research Associates [CRAs]) 
2. 
List of Required Materials for E1808 
3. 
Instructional memo to submitting pathologists 
4. 
ECOG-ACRIN Generic Specimen Submission Form (#2981) 
 
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Guidelines for Submission of Pathology Materials 
 
The following items should always be included when submitting pathology materials to the 
ECOG-ACRIN Central Biorepository and Pathology Facility: 
• 
Institutional Surgical Pathology Report 
• 
Pathology materials (see attached List of Required Material) 
Instructions: 
1. Provide the following information: 
Patient's name (last, first) 
Protocol number 
Protocol case number (the patient's ECOG-ACRIN sequence number) 
The institutional identification numbers for the materials provided 
Institution 
Affiliate (if appropriate) 
2. Complete blank areas of the pathologist's instructional memo and forward it, along with the 
List of Required Material to the appropriate pathologist.  
3. The pathologist should return the required pathology samples and surgical pathology 
reports, along with additional required information. If any other reports are required, they 
should be obtained from the appropriate department at this time. 
4. Keep a copy of the STS shipping manifest or Specimen Submission Form (#2981) for your 
records. 
5. Double-check that ALL required forms, reports and pathology samples are included in the 
package to the Central Biorepository and Pathology Facility.  
Pathology specimens submitted WILL NOT be processed by the Central Biorepository 
and Pathology Facility until all necessary items are received. 
6. Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
If you have any questions concerning the above instructions or if you anticipate any problems in 
meeting the pathology material submission deadline of one month, contact the Pathology 
Coordinator at the ECOG-ACRIN Central Biorepository and Pathology Facility by telephone 
844-744-2420 or by email eacbpf@mdanderson.org. 
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LIST OF REQUIRED MATERIAL 
 
E1808: A Randomized Phase II Trial of Sunitinib/Gemcitabine or Sunitinib in Advanced 
Renal Cell Carcinoma with Sarcomatoid Features 
Pre-Treatment 
1. Institutional pathology report (must be included with EVERY pathology submission). 
2. Required path materials. 
• 
Representative sarcomatoid and nonsarcomatoid diagnostic tumor blocks  
• 
Immunological study slides 
• 
Additional tumor blocks, if available, are requested from patients who have consent to 
allow specimens to be submitted for banking for future research. 
NOTE: If blocks are not available, see Section 10 for guidance for alternative 
submissions. 
NOTE: Since blocks are being used for laboratory studies, in some cases the material 
may be depleted and, therefore, the block may not be returned. 
 
 
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66 
MEMORANDUM 
TO:  
___________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair ECOG-ACRIN Laboratory Science and Pathology 
Committee 
DATE:  
____________________________ 
SUBJECT: 
Submission of Pathology Materials for E1808: (A Randomized Phase II Trial of 
Sunitinib/Gemcitabine or Sunitinib in Advanced Renal Cell Carcinoma with 
Sarcomatoid Features 
 
The patient named on the attached request has been entered onto an ECOG-ACRIN protocol 
by ______________________________ (ECOG-ACRIN Investigator).  This protocol requires 
the submission of pathology materials for central pathology review and banking for future 
research. 
Keep a copy for your records and return the completed Submission Form, the surgical 
pathology report(s), the slides and/or blocks and any other required material (see List of 
Required Material) to the Clinical Research Associate (CRA).  The CRA will forward all required 
pathology material to the ECOG-ACRIN Operations Office – Boston. 
Blocks and slides submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future studies.  Paraffin blocks will be returned upon written request for purposes 
of patient management. 
Please note: Since blocks are being used for laboratory studies, in some cases the material 
may be depleted, and, therefore, the block may not be returned. 
If you have any questions regarding this request, please contact the Central Biorepository and 
Pathology Facility at 844-744-2420 or FAX 713-563-6506 or email eacbpf@mdanderson.org. 
The ECOG-ACRIN CRA at your institution is: 
Name: _________________________________________________ 
Address:_________________________________________________ 
Phone: _________________________________________________ 
 
 
Thank you. 
 
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67 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per patient, per time- 
point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all specimens into STS once the system 
is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 
Courier 
Tracking Number    
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
 include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or 
Sample ID 
Anatomic 
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % Lymphocytes % 
 
 
 
 
Study Drug Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
9/12/14 

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Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
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A Randomized Phase II Trial of Sunitinib/Gemcitabine or Sunitinib in Advanced Renal 
Cell Carcinoma with Sarcomatoid Features 
 
Appendix III 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can be 
downloaded from the ECOG web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN and the 
NCI to increase awareness of the importance of clinical trials and improve accrual and follow-
through. We appreciate your help in this effort. 
____________________________________________________________________________ 
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study.  Many questions remain 
unanswered in cancer. With the participation of people like you in clinical trials, we will improve 
treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care.  I and my research staff will maintain 
very close contact with you.  This will allow me to provide you with the best care while learning 
as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank you 
again and look forward to helping you. 
 
 
 
Sincerely, 
 
 
 
[PHYSICIAN NAME] 
 
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Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
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A Randomized Phase II Trial of Sunitinib/Gemcitabine or Sunitinib in Advanced Renal 
Cell Carcinoma with Sarcomatoid Features 
 
Appendix IV 
 
Patient Medication Calendar (Pill Diary) 
 
Patient Name: _______________________________________________________________ 
ECOG-ACRIN Patient Sequence Number: ________________________ 
Patient's Treatment Arm (e.g., "A"): _________ 
Patient's Initials: ____________ 
Protocol Number: E1808 
Cycle ______ of 8 
Start Date of Week (e.g., Monday) for first dose of this cycle: ___________________________ 
Start Date (e.g., 01/01/09) for first dose of this cycle: _______________________ 
NOTE: A cycle is 42 days (6 weeks) 
Directions for Gemcitabine Administration (Arm A only): 
1. Gemcitabine is administered on Days 1, 8, 22 and 29 of each cycle. 
2. The dosage is 1000 mg/m2 IV over 30 minutes. The dose is based on actual (not ideal) body 
weight. 
Directions for Sunitinib Administration (Arm A): 
1. For each cycle, take 3 capsules (12 mg each) orally once daily for 14 days (2 weeks) 
followed by rest for 7 days (1 week). 
2. After the rest period, resume sunitinib for another 14 days (2 weeks) followed by an 
additional rest period of 7 days (1 week). 
3. Repeat for a total of 8 cycles. 
4. Complete the ARM A Patient Medication Calendar (Pill Diary) appropriately based on the 
days you actually took medication during the cycle.  
5. If a dose is forgotten do not take it at a later time. Skip that dose and note in the calendar 
that the dose was missed. 
6. Remember: Do not take medication on a day that has "XXXXX" on the pill calendar/diary. 
NOTE: 
Sunitinib should be taken at the same time each day and is best tolerated in the 
evening with an 8 oz. glass of water. Do not make up skipped, missed or vomited 
doses. 
Directions for Sunitinib Administration (Arm B): 
1. For each cycle, take 4 capsules (12 mg each) orally once daily for 14 days (2 weeks) 
followed by rest for 7 days (1 week). 
2. After the rest period, resume sunitinib for another 14 days (2 weeks) followed by an 
additional rest period of 7 days (1 week). 
3. Repeat for a total of 8 cycles. 

ECOG-ACRIN 
E1808 
Cancer Research Group 
Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
70 
4. Complete the ARM B Patient Medication Calendar (Pill Diary) appropriately based on the 
days you actually took medication during the cycle.  
5. If a dose is forgotten do not take it at a later time. Skip that dose and note in the calendar 
that the dose was missed. 
6. Remember: Do not take medication on a day that has "XXXXX" on the pill calendar/diary. 
NOTE: 
Sunitinib should be taken at the same time each day and is best tolerated in the 
evening with an 8 oz. glass of water. Do not make up skipped, missed or vomited 
doses. 
Note the number of capsules you take each day. If you develop any side effects, please 
record side effects, the date, and anything you would like to tell the doctor on the back of your 
calendar. Bring your bottles and any unused capsules along with your completed 
calendar/diary to your next appointment. 
NOTE: A yellow discoloration of the skin may occur after touching the capsules. Wash hands 
with soap and water immediately. 
Signature of Patient: _________________________________________ 
Date: _________________ 

ECOG-ACRIN 
E1808 
Cancer Research Group 
Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
71 
 
ARM A – E1808 Patient Medication Calendar (Pill Diary)          Patient ID: _______    Cycle #___ 
Cycle 
Day 
Date 
Sunitinib  
Gemcitabine 
 
XX/XX/XXXX 
# of Capsules 
 
1 
 
 
*Administered* 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
*Administered* 
9 
 
 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
 
 
 
14 
 
 
 
15 
 
XXXXXXX 
 
16 
 
XXXXXXX 
 
17 
 
XXXXXXX 
 
18 
 
XXXXXXX 
 
19 
 
XXXXXXX 
 
20 
 
XXXXXXX 
 
21 
 
XXXXXXX 
 
22 
 
 
*Administered* 
23 
 
 
 
24 
 
 
 
25 
 
 
 
26 
 
 
 
27 
 
 
 
28 
 
 
 
29 
 
 
*Administered* 
30 
 
 
 
31 
 
 
 
32 
 
 
 
33 
 
 
 
34 
 
 
 
35 
 
 
 
36 
 
XXXXXXX 
 
37 
 
XXXXXXX 
 
38 
 
XXXXXXX 
 
39 
 
XXXXXXX 
 
40 
 
XXXXXXX 
 
41 
 
XXXXXXX 
 
42 
 
XXXXXXX 
 

ECOG-ACRIN 
E1808 
Cancer Research Group 
Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
72 
ARM B – E1808 Patient Medication Calendar (Pill Diary)          Patient ID: _______    Cycle #___ 
Cycle Day 
Date 
Sunitinib  
 
XX/XX/XXXX 
# of Capsules 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
6 
 
 
7 
 
 
8 
 
 
9 
 
 
10 
 
 
11 
 
 
12 
 
 
13 
 
 
14 
 
 
15 
 
XXXXXXX 
16 
 
XXXXXXX 
17 
 
XXXXXXX 
18 
 
XXXXXXX 
19 
 
XXXXXXX 
20 
 
XXXXXXX 
21 
 
XXXXXXX 
22 
 
 
23 
 
 
24 
 
 
25 
 
 
26 
 
 
27 
 
 
28 
 
 
29 
 
 
30 
 
 
31 
 
 
32 
 
 
33 
 
 
34 
 
 
35 
 
 
36 
 
XXXXXXX 
37 
 
XXXXXXX 
38 
 
XXXXXXX 
39 
 
XXXXXXX 
40 
 
XXXXXXX 
41 
 
XXXXXXX 
42 
 
XXXXXXX 
 
 

ECOG-ACRIN 
E1808 
Cancer Research Group 
Version Date: February 22, 2016 
 
NCI Update Date: March 14, 2013 
73 
A Randomized Phase II Trial of Sunitinib/Gemcitabine or Sunitinib in Advanced Renal 
Cell Carcinoma with Sarcomatoid Features 
 
Appendix V 
 
Oral Antihypertensive Medications 
Agents in bold characters are suggested as optimal choices to avoid or minimize 
potential drug-interactions with study agents through CYP450. 
Agent  
class 
 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine XL 
30 mg daily 
60 mg daily 
90 mg daily 
CYP 3A4 substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate and 
inhibitor 
Selective 
 Blockers 
(BB) 
metoprolol 
25 mg  
twice daily 
50 mg 
twice daily 
100 mg  
twice daily 
CYP 2D6 substrate 
atenolol 
25 mg daily 
50 mg daily 
100 mg daily 
No 
acebutolol 
100 mg  
twice daily 
200-300 mg 
twice daily 
400 mg  
twice daily 
Yes (CYP450 unknown) 
bisoprolol 
2.5 mg daily 
5-10 mg daily 
20 mg daily 
Yes (CYP450 unknown) 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
 
captopril 
12.5 mg 3x daily 
25 mg 3x daily 
50 mg 3x daily 
CYP 2D6 substrate 
enalapril 
5 mg daily 
10-20 mg daily 
40 mg daily 
CYP 3A4 substrate 
ramipril 
2.5 mg daily 
5 mg daily 
10 mg daily 
Yes (CYP450 unknown) 
lisinopril 
5 mg daily 
10-20 mg daily 
40 mg daily 
No 
fosinopril 
10 mg daily 
20 mg daily 
40 mg daily 
Yes (CYP450 unknown) 
Rarely used:    
perindopril 
4 mg daily 
none 
8 mg daily 
Yes, but not CYP450 
Rarely used:    
quinapril 
10 mg daily 
20 mg daily 
40 mg daily 
No 
Angiotensin 
II Receptor 
Blockers 
(ARBs) 
losartan 
25 mg daily 
50 mg daily 
100 mg daily 
CYP 3A4 substrate 
candesartan 
4 mg daily 
8-16 mg daily 
32 mg daily 
CYP 2C9 substrate 
irbesartan 
75 mg daily 
150 mg daily 
300 mg daily 
CYP 2C9 substrate 
telmisartan 
40 mg daily 
none 
80 mg daily 
Yes, but not CYP450 
valsartan 
80 mg daily 
none 
160 mg daily 
Yes, but not CYP450 
 and   
Blocker 
labetolol 
100 mg twice 
daily 
200 mg twice 
daily 
400 mg twice daily 
CYP 2D6 substrate and 
inhibitor