Clinical trial NCT00478426
Conditions: Endometrial Adenocarcinoma Endometrial Endometrioid Adenocarcinoma Endometrial Serous Adenocarcinoma Recurrent Uterine Corpus Carcinoma Stage IVA Uterine Corpus Cancer AJCC v7 Stage IVB Uterine Corpus Cancer AJCC v7 Uterine Carcinosarcoma Uterine Corpus Carcinosarcoma
Sponsor: National Cancer Institute (NCI)
Start date: 2007-04-30; Completion date: 2019-02-12
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well sunitinib malate works in treating patients with endometrial cancer that has come back after a period of improvement (recurrent) or has spread to other places in the body (metastatic). Sunitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the objective response rate of recurrent or metastatic endometrial cancer to sunitinib (sunitinib malate).

II. To assess the frequency of prolonged stable disease (as defined by percentage \[%\] of patients alive and free from progressive disease at 6 months) in patients with recurrent or metastatic endometrial cancer treated with sunitinib.

SECONDARY OBJECTIVES:

I. To assess time-to- progression, median overall survival, and rate of one-year survival in patients with recurrent or metastatic endometrial cancer treated with sunitinib.

II. To assess the toxicity associated with sunitinib in patients with recurrent or metastatic endometrial cancer.

OUTLINE:

Patients receive sunitinib malate orally (PO) once daily (QD) on days 1-28. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

After the completion of study treatment, patients are followed up at 4 weeks and then every 3 months until relapse.

Arms: arm 1: Patients receive sunitinib malate PO QD on days 1-28. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Sunitinib Malate
Intervention descriptions: intervention 1: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
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i 
SUMMARY OF CHANGES 
 
For Protocol Amendment #17 to Amendment #18 
NCI Protocol #: 7713 
Local Protocol #: PHL-062 
 
Protocol Version Date: February 26, 2016; Amendment 18  
 
# 
Section 
Page(s) 
Change 
1. 
7.1 
36-40 
Rationale: As per the Request for Rapid Amendment (RRA) dated February 9, 
2016 from Dr. Pamela Harris (harrispj@mail.nih.gov) Section 7.1 has been 
amended to reflect the updated safety information. 
 
Approved Text: CAEPR Version 2.11 dated January 10, 2014 
 
Proposed Text: CAEPR Version 2.12 dated January 14, 2016.  Added new 
risks:  
• 
Added New Risk: 
• 
Less Likely: Gastroesophageal reflux disease; Paresthesia 
• 
  Rare but Serious: Cardiac disorders - Other (cardiomyopathy); 
Endocrine disorders - Other (thyroidism); Heart failure; 
Hyperthyroidism; Infections and infestations - Other (necrotizing 
fasciitis); Musculoskeletal and connective tissue disorder -  Other 
(rhabdomyolysis); Myocardial infarction; Nervous system disorders 
- Other (cerebral infarction);  Renal and urinary disorders - Other 
(nephrotic syndrome); Skin and subcutaneous tissue disorders - 
Other (pyroderma gangrenosum); Toxic epidermal necrolysis; 
Transient ischemic attacks; Wound complication 
• 
Reported but With Insufficient Evidence for Attribution: 
Hemorrhoids 
 
• 
Increase in Risk Attribution:  
• 
Changed to Likely from Less Likely: Constipation; Dyspepsia; 
Palmar-plantar erythrodysesthesia syndrome 
• 
Changed to Less Likely from Reported but With Insufficient 
Evidence for Attribution: Bronchopulmonary hemorrhage; 
Depression; Gastrointestinal hemorrhage; Intracranial hemorrhage; 
Laryngeal hemorrhage; Mediastinal hemorrhage; Ovarian 
hemorrhage; Pharyngeal hemorrhage; Pleural hemorrhage; Prostatic 
hemorrhage; Pruritus; Renal hemorrhage; Spermatic hemorrhage; 
Testicular hemorrhage; Uterine hemorrhage; Vaginal hemorrhage 
• 
Changed to Rare But Serious from Reported but With Insufficient 
Evidence for Attribution: Allergic reaction; Cholecystitis; 
Esophagitis; Pancreatitis 
 
• 
Provided Further Clarification: 
• 
Bronchopulmonary hemorrhage, Gastrointestinal hemorrhage, 
Intracranial hemorrhage, Laryngeal hemorrhage, Mediastinal 
hemorrhage, Ovarian hemorrhage, Pharyngeal hemorrhage, Pleural 


NCI 7713; PHL062 
February 26, 2016; A18 
 
ii 
# 
Section 
Page(s) 
Change 
hemorrhage, Prostatic hemorrhage, Renal hemorrhage, Spermatic 
cord hemorrhage, Testicular hemorrhage, Uterine hemorrhage, and 
Vaginal hemorrhage (All listed under Reported but With 
Insufficient Evidence for Attribution) are now reported as Vascular 
disorders - Other (hemorrhage). 
• 
Blood and lymphatic system disorders - Other (thrombotic 
microangiopathy (e.g., thrombotic thrombocytopenic purpura [TTP] 
or hemolytic uremic syndrome [HUS]) (under Rare but Serious) is 
now being reported as Hemolytic uremic syndrome (Under Rare 
but Serious) and Thrombotic thrombocytopenic purpura (Under 
Rare but Serious). 
• 
Footnote #3 on the previous CAEPR, “Gastrointestinal fistula 
includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal 
fistula, Gastric fistula, Gastrointestinal 
fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, Pancreatic 
fistula, Rectal fistula, and Salivary gland fistula under the 
GASTROINTESTINAL DISORDERS SOC” has been deleted. 
• 
Footnote #4 on the previous CAEPR, “Gastrointestinal hemorrhage 
includes Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, 
Esophageal varices hemorrhage, Gastric 
hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-
abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal 
hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal 
hemorrhage, Retroperitoneal hemorrhage, and Upper 
gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC” has been deleted. 
• 
Footnote #5 on the previous CAEPR, “Infection includes all 75 
sites of infection under the INFECTIONS AND INFESTATIONS 
SOC” has been deleted. 
• 
A new footnote #3 has been added: “Allergic reactions observed 
include anaphylaxis and angioedema.” 
• 
A new footnote #4 has been added: “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.” 
 
• 
Deleted Risk:  
• 
Reported but With Insufficient Evidence for Attribution: Acute 
coronary syndrome; Cardiac troponin I increased; Edema face; 
Gastrointestinal fistula; Infection; Ischemia cerebrovascular 
 
 


NCI 7713; PHL062 
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NCI Protocol #: 
7713 
Local Protocol #: 
PHL-062 
 
TITLE:  A Phase 2 Study of Sunitinib Malate in Recurrent or Metastatic Endometrial 
Carcinoma 
 
Coordinating Center: 
 
Princess Margaret Hospital Phase II Consortium 
 
*Principal Investigator: 
 
Dr. Amit M. Oza  
Division of Medical Oncology,  
Princess Margaret Hospital 
5-700, 610 University Avenue 
Toronto, ON, Canada.  M5G 2M9 
Tel: (416) 946-2818 
Fax:(416) 946-2082 
E-mail: amit.oza@uhn. ca 
 
Co-Investigators: 
 
Dr. Hal Hirte 
 
 
Juravinski Cancer Centre  
 
 
 
 
699 Concession St. 
 
 
Hamilton, ON, Canada L8V 5C2 
 
 
Tel: (905) 387-9495 
 
 
Fax: (905) 575-6326 
E-mail: hal.hirte@hrcc.on.ca 
 
Dr. Michael Fung Kee Fung 
Ottawa Hospital, General Division 
501 Smyth Road 
Ottawa, ON, Canada K1H 8L6 
Tel: (613) 737-8560 
Fax: (613) 737-8828 
E-mail: mfung@ottawahospital.on.ca 
 
Dr. Jim Biagi 
Cancer Centre of Southeastern Ontario at Kingston 
25 King Street West 
Kingston, ON, Canada K7L 5P9 
Tel: (613) 544-2630 
Fax: (613) 546-8209 
E-mail: jim.biagi@krcc.on.ca 
 
Dr. Paul Hoskins  
BC Cancer Agency 
600 West Tenth Avenue 
Vancouver, BC, Canada V5Z 4E6 
Tel: (604) 877-6000 


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2 
Fax: (604) 877-6179 
E-mail: phoskins@bccancer.bc.ca 
 
Dr. Helen Steed 
Cross Cancer Institute, Department of Medicine 
11560 University Avenue, 2nd Floor 
Edmonton, AB, Canada  T5G 1Z2 
Tel: (780) 432-8284 
Fax: (780) 432-8888 
 
 
E-mail:  helenste@cancerboard.ab.ca 
 
Dr. Al Covens, 
 
 
Toronto Sunnybrook Regional Cancer Centre 
 
 
2075 Bayview Avenue, T2 051 
Toronto, ON, Canada.  M4N 3M5 
Tel: (416) 480-4026 
Fax:(416) 480-6002 
 
 
E-mail: al.covens@sunnybrook.ca 
 
 
 
Dr. Robert Morgan 
 
 
California Cancer Consortium 
 
 
City of Hope National Medical Center 
 
 
1500 E. Duarte Road 
 
 
Duarte, CA 91010 
Tel: (626) 256-4673, ext. 62830 
Fax: (626) 301-8973 
E-mail: rmorgan@coh.org 
 
 
 
Dr. Gini Fleming  
 
 
University of Chicago Consortium 
 
 
University of Chicago Medical Center 
 
 
5841 South Maryland Avenue, MC2115 
 
 
Chicago, IL 60637-1470 
Tel: (773) 702-6712 
Fax: (773) 702-0963 
E-mail: gfleming@medicine.bsd.uchicago.edu 
 
Dr. Susie Lau 
Jewish General Hospital 
McGill University 
3755 Cote Ste-Catherine, Room E-727 
Montreal, QC, Canada   H3T 1E2 
Tel: (514) 340-8222 ext. 3114 
Fax: (514) 340-8619 
E-mail: slau@surg.jgh.mcgill.ca 
 


NCI 7713; PHL062 
February 26, 2016; A18 
3 
Dr. Mark McNamera 
City of Hope Medical Group Inc.  
50 Bellafontaine Street 
Pasadena, CA, USA   91105 
Tel: (626) 396-2900   
Fax:  (626) 396-2911 
E-mail: MMcNamera@coh.org 
  
Dr. Solomon Hamburg 
Tower Cancer Research Foundation 
9090 Wilshire Blvd., 2nd Floor 
Beverly Hills, CA, USA   90211 
Tel:  (310) 285-7427 
Fax:  (310) 285-7298 
Email:  hamburghs@toweroncology.com 
  
Dr. Sidney Scudder 
University of California, Davis Cancer Center 
4501 X Street, Room 3016 
Sacramento, CA, USA   95817 
Tel: (916) 734-3772   
Fax: (916) 734-7946 
Email: sidney.scudder@ucdmc.ucdavis.edu 
  
Dr. Lynda Diane Roman 
University of Southern California / Norris Comprehensive 
Cancer Center  
120 N Mission Road, Room 1L4 
Los Angeles, CA, USA   90033 
Tel: (323) 226-3405 
Fax: (323) 865-0089 
Email: lroman@usc.edu 
 
Central Office  
 
Senior Investigator  
Dr. Amit Oza 
 
Princess Margaret Hospital 
 
610 University Avenue 
 
Toronto, ON, Canada.  M5G 2M9 
 
Tel: 416-946-2818 
 
 
 
Fax: 416-946-2082 
 
 
E-mail: Amit.Oza@uhn. ca 
 
Program Manager:  
Chantale Blattler  
 
 
Princess Margaret Hospital  
610 University Avenue 


NCI 7713; PHL062 
February 26, 2016; A18 
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Toronto, ON, Canada  M5G 2M9 
Tel: 416-946-4501 x 3692 
Fax: 416-946-2016 
E-mail: chantale.blattler@uhn. ca 
 
Study Coordinator: 
 
Robert Halford 
 
 
Princess Margaret Hospital  
610 University Avenue 
Toronto, ON, Canada  M5G 2M9 
Tel: 416-946-4501 x 3476 
Fax: 416-946-2016 
E-mail: robert.halford@uhn. ca  
 
Dr. Athanassios Argiris 
University of Pittsburgh Cancer Institute Hillman Cancer 
Center 
UPMC Cancer Pavilion 
5150 Centre Avenue, Fifth Floor 
Pittsburgh, PA, USA   15232 
Tel: (412) 623-4083 
Fax: (412)-647-7678 
E-mail: argirisae@upmc.edu 
 
Statistician: 
 
Lisa Wang 
 
 
Princess Margaret Hospital 
610 University Avenue 
Toronto, ON, Canada. M5G 2M9 
Tel: 416-946-4501 ext.4883 
Fax: 416-946-2048 
E-mail: lwang@uhnres.utoronto.ca 
 
NCI Supplied Agent: 
Sunitinib malate (NSC 736511; IND 74019) 
 
University of Chicago Consortium Co-Investigators: 
 
Gini Fleming, MD 
University of Chicago Medical Center 
5841 Maryland Ave.,  
Chicago, IL 60637 
(773) 702-4400 
Maha Hussain, M. D. 
mahahuss@umich.edu 
University of Michigan Comprehensive Cancer 
Center 
7314 CCGC, 1500 East Medical Center Drive,  
Ann Arbor, MI  48109-0946 
(734) 936-8906 
Martin Edelman, M.D. 
medelman@umm.edu 
University of Maryland Greenebaum Cancer 
Center 


NCI 7713; PHL062 
February 26, 2016; A18 
5 
22 S. Greene Street, Baltimore, MD 21201-1595 
(410) 328-2703 
Stuart J. Wong, M.D. 
swong@mcw.edu 
Medical College of Wisconsin  Division of 
Neoplastic Diseases and Related Disorders  
9200 W. Wisconsin Avenue, Milwaukee, WI 
53226 
(414) 805-4603 
Patrick Stiff, M.D.          Joseph Clark, M.D. 
pstiff@lumc.edu             jclark@lumc.edu 
Ellen Gaynor, M.D.        John Godwin, M.D. 
egaynor@lumc.edu         jgodwin@lumc.edu 
Kathy Albain, M.D. 
kalbain@lumc.edu   
Loyola University Medical Center 
2160 S. First Ave., Maywood, IL 60153 
(708) 327-3300 
Edem Agamah, M.D.                                    
ihdn@aol.com 
Central Illinois Hem/Onc Center 
319 E. Madison Suite F 
Springfield, IL 62701 
(217) 525-2500 
James L. Wade III, M.D.  
JLWADE3@aol.com   
John Godwin, M.D., M.S. 
jgodwin@siumed.edu 
Krishna A. Rao, M.D., Ph.D. 
krao@siumed.edu                  
Decatur Memorial Hospital 
2300 N. Edward St. 
Decatur, IL 62526 
(217) 876-6600 
Southern Illinois University School of Medicine 
PO Box 19678, 415 North Ninth Street 
Springfield, IL  62794-9678 
(217) 545-5817 
 
Phone (217) 545-5817 
 
Bruce Brockstein, M.D. 
b-brockstein@northwestern.edu 
Evanston Northwestern Healthcare 
2650 Ridge Ave., Evanston, IL 60201 
(847) 570-2515 
Sreenivasa Nattam, M.D. 
David F. Sciortino, M.D. 
(no email)   
Fort Wayne Oncology/Hematology  
4402 East State Blvd., Fort Wayne, IN 46815-
5099 
(260) 484-8830 
Mark Kozloff, M.D. 
mfkozloff@aol.com 
S. Yalavarthi, M.D. 
sulochana2001@hotmail.com 
Ingalls Hospital  
1 Ingalls Dr. Harvey, IL 60430-1144 
(708) 339-4800 
Sanjiv Modi, M.D. 
smodi@jolietoncology.com 
Joliet Hematology Associates, Ltd. 
2420 Glenwood Ave., Joliet, IL 60435 
(815)725-1335 
David A. Taber, M.D. 
Rafat H. Ansari, M.D. 
lwiseman@memorialsb.org 
Northern Indiana Cancer Research Consortium 
100 Navarre Place, Ste 5550, South Bend, IN 
46601     
(574) 647-7370                         


NCI 7713; PHL062 
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Eric Lester, M.D.     
oncology@parrett.net 
Oncology Care Associates 
820 Lester Ave., Suite 119, St. Joseph, MI 49085 
(269) 985-0029 
Sachdev P. Thomas, M.D. 
sthomas@ohaci.com   
James A. Knost, M.D. 
jknost@ohaci.com 
Oncology/Hematology Associates     
8940 N. Wood Sage Road, Peoria, IL  61615-7828 
(309) 243-3605 
Bethany G. Sleckman, M.D. 
slecbg@stlo.mercy.net 
Saint John's Mercy Medical Center 
607 S. New Ballas Road, Ste 3425, St. Louis, 
MO 63141 
(314) 251-7057 
 
Protocol Version Date:  March 20, 2006 
 
Addendum 1:  
August 11, 2006 
Addendum 2:  
August 25, 2006 
Addendum 3:  
September 26, 2006 
Addendum 4:  
February 14, 2007 
Addendum 5:  
May 22, 2007 
Addendum 6:  
August 24, 2007 
Addendum 7:  
November 23, 2007 
Amendment 8:  
January 3, 2008 
Amendment 9:  
February 4, 2009 
Amendment 10: 
August 26, 2009 
Amendment 11: 
 September 08, 2009 
Amendment 12: 
March 01, 2010 
Amendment 13: 
October 04, 2010 
Amendment 14: 
June 15, 2011 
Amendment 15: 
November 15, 2011 
Amendment 16: 
July 01, 2013  
Amendment 17: 
April 28, 2014 
Amendment 18: 
February 26, 2016 


NCI 7713; PHL062 
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SCHEMA 
 
 
 
Recurrent or metastatic endometrial 
cancer 
ECOG PS 0-2 
 1 prior chemotherapy 
Baseline imaging 
Screening bloodwork 
Sunitinib malate 
One cycle = 
50 mg PO QD x 4 weeks 
Rest period x 2 weeks 
Repeat x 2 cycles 
Repeat imaging 
Off study 
Continue treatment 
Stopping rules: 
Stage I:  15 evaluable patients; stop if ORR < 1/15, proceed to stage II if ORR  1/15. 
If ORR < 1/15 but  4 /15 patients have prolonged SD*, request will be made to continue accrual 
to stage II. 
Stage II:  15 further evaluable patients; consider interesting if ORR  4/30 and inactive if ORR < 
4/30. 
 
* prolonged SD = alive and free from progressive disease at 6 months from registration 
CR, PR, SD 
PD or unacceptable toxicity 


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TABLE OF CONTENTS 
SUMMARY OF CHANGES ........................................................................................................... i 
SCHEMA 
7 
1. 
OBJECTIVES ............................................................................................10 
1.1 
Primary Objectives.................................................................................................10 
1.2 
Secondary Objectives.............................................................................................10 
2. 
BACKGROUND .......................................................................................10 
2.1 
Endometrial Cancer ...............................................................................................10 
2.2 
Sunitinib Malate .....................................................................................................12 
2.3 
Rationale ................................................................................................................21 
3. 
PATIENT SELECTION ............................................................................22 
3.1 
Eligibility Criteria ..................................................................................................22 
3.2 
Exclusion Criteria ..................................................................................................24 
3.3 
Inclusion of Minority Populations .........................................................................26 
4. 
REGISTRATION PROCEDURES ...........................................................27 
4.1 
General Guidelines.................................................................................................27 
4.2 
Registration Process ...............................................................................................27 
5. 
TREATMENT PLAN ................................................................................28 
5.1 
Sunitinib Malate Administration............................................................................28 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................29 
5.3 
Duration of Therapy ...............................................................................................30 
5.4 
Duration of Follow Up ...........................................................................................31 
6. 
DOSING DELAYS/DOSE MODIFICATIONS .......................................31 
6.1 
Management of Treatment-Emergent Hypertension .............................................31 
6.2 
Left ventricular systolic dysfunction / CHF...........................................................32 
6.3 
Other Hematologic and Non-Hematologic Adverse Events ..................................34 
6.4 
Management of Other Clinically Significant AEs (not specifically 
addressed above) ...............................................................................................35 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ....36 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Sunitinib Malate (NSC 736511) ............................................................................36 
7.2 
Adverse Event Characteristics ...............................................................................40 
7.3 
Expedited Adverse Event Reporting ......................................................................40 
7.4 
Routine Adverse Event Reporting .........................................................................42 
7.5 
Secondary AML/MDS ...........................................................................................42 
8. 
PHARMACEUTICAL INFORMATION ..................................................42 
9. 
STUDY CALENDAR ...............................................................................46 


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10. 
MEASUREMENT OF EFFECT................................................................47 
10.1 
Definitions..............................................................................................................47 
10.2 
Guidelines for Evaluation of Measurable Disease .................................................48 
10.3 
Response Criteria ...................................................................................................49 
10.4 
Confirmatory Measurement/Duration of Response ...............................................50 
10.5 
Progression-Free Survival ......................................................................................51 
10.6 
Response Review ...................................................................................................51 
11. 
DATA REPORTING / REGULATORY CONSIDERATIONS ...............51 
11.1 
Data Reporting .......................................................................................................51 
11.2 
CTEP Multicenter Guidelines ................................................................................52 
11.3 
Cooperative Research and Development Agreement (CRADA)/Clinical 
Trials Agreement (CTA) ........................................................................................52 
12. 
STATISTICAL CONSIDERATIONS.......................................................54 
12.1 
Study Design/Endpoints.........................................................................................54 
12.2 
Sample Size/Accrual Rate ......................................................................................55 
12.3 
Analysis of Secondary Endpoints ..........................................................................55 
12.4 
Reporting and Exclusions ......................................................................................55 
REFERENCES 
56 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................60 
APPENDIX B 
NEW YORK HEART ASSOCIATION CLASSIFICATION OF 
CARDIAC DISEASE ................................................................................61 
APPENDIX C 
DRUGS KNOWN TO BE METABOLIZED BY SELECTED CYP450 
ISOENZYMES ..........................................................................................62 
APPENDIX D 
PATIENT’S MEDICATION DIARY .......................................................64 
APPENDIX E 
PATIENT’S BLOOD PRESSURE DIARY ..............................................65 
APPENDIX F 
MANAGEMENT OF SUNITINIB-INDUCED HYPERTENSION .........66 
APPENDIX G 
COLLECTION/RECORDING OF BLOOD PRESSURE 
INFORMATION........................................................................................68 
APPENDIX H 
DATA MANAGEMENT GUIDELINES ..................................................71 
APPENDIX I 
CTEP MULTICENTER GUIDELINES ....................................................73 
APPENDIX J 
MEDICATIONS THAT MAY CAUSE QTC PROLONGATION ..........75 
 


NCI 7713; PHL062 
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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
• To assess the objective response rate of recurrent or metastatic endometrial cancer to 
sunitinib. 
• 
To assess the frequency of prolonged stable disease (as defined by % of patients alive 
and free from progressive disease at 6 months) in patients with recurrent or metastatic 
endometrial cancer treated with sunitinib. 
 
1.2 
Secondary Objectives 
 
• To assess time-to progression, median overall survival, and rate of one-year survival 
in patients with recurrent or metastatic endometrial cancer treated with sunitinib. 
• To assess the toxicity associated with sunitinib in patients with recurrent or metastatic 
endometrial cancer.  
 
2. BACKGROUND 
 
2.1 
Endometrial Cancer 
 
Endometrial carcinoma is the most common malignancy of the female reproductive system, with 
an estimated 40, 000 women newly diagnosed in 2005, according to the American Cancer 
Society 1.  The majority of these patients have early-stage disease that is curable with surgery.  
In the minority of patients who present with advanced or metastatic disease, or who have 
recurrent disease, effective treatment options are limited.  The 5-year overall survival rate for 
patients with distant metastatic endometrial cancer is approximately 26%.   
 
Hormonal therapy is considered for treatment of patients with advanced, low-grade endometrial 
cancer, as response rates to medroxyprogesterone acetate in this patient population is as high as 
37%.  Patients with high-grade or hormone-receptor-negative disease demonstrate significantly 
lower rates of response and have a poorer prognosis overall 2. 
 
A recent systematic review of chemotherapy for advanced endometrial cancer has recently been 
published 3.  Historically, doxorubicin and cisplatin have been the most extensively used agents 
in clinical practice.  Response rates to cisplatin (P) or doxorubicin (A) as monotherapy in 
prospective clinical trials are approximately 20%4-6.  Although higher response rates have been 
demonstrated with the combination of doxorubicin and cisplatin (AP) over single agent therapy, 
this difference has not been reflected in an overall survival advantage 4,6.  AP chemotherapy 
improves progression-free and overall survival when compared to whole abdominal radiation in 
the primary treatment of advanced endometrial cancer, although this improvement is at the 
expense of increased toxicity 7.  Paclitaxel (T) is also an active agent in the treatment of 
advanced endometrial cancer 8.  The addition of T to AP chemotherapy has improved response 
rates (57% versus 34%) and median survival (15.3 versus 12.3 months) 9, but the three-drug 
regimen is associated with significant toxicity, particularly hematological.  The TAP regimen in 


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11 
the trial by Fleming et al. mandated the use of G-CSF for hematologic support.  The combination 
of carboplatin (C) / paclitaxel has shown promising efficacy in large phase II trials, with 
acceptable toxicity 10 11, prompting a prospective comparison of TAP versus CT in patients 
with advanced endometrial cancer. 
 
Clinical trials involving molecularly targeted therapies in advanced endometrial cancer have 
been undertaken recently, with impressive results.  Erlotinib is a small molecule inhibitor of the 
epidermal growth factor receptor (EGFR), which is overexpressed in 60-80% of endometrial 
cancers.  A phase II study of erlotinib in endometrial cancer has recently completed, reporting a 
12.5% overall response rate 12.  Temsirolimus (CCI-779) is an inhibitor of the mammalian target 
of rapamycin (mTOR), a key regulator of intracellular protein translation.  mTOR activation is 
associated with increased protein translation, progression through G1 of the cell cycle, and 
increased cell growth.  Preliminary results of an ongoing phase II trial of CCI-779 as weekly 
treatment of patients with recurrent or advanced endometrial cancer have been reported in 
abstract form.  Among the first 23 patients treated, a response rate of 31% has been demonstrated 
13.   
 
Whereas combination chemotherapy is the first-line treatment of choice for patients with 
advanced endometrial cancer with adequate organ function and performance status, there is no 
clear standard second-line treatment regimen.  Evidence is available from small phase II trials to 
guide clinical management in this setting (see table 1).  With the exception of one phase II trial 
of paclitaxel in previously-treated patients (RR=28%, median PFS = 4.2 months 14), second-line 
chemotherapy for advanced endometrial cancer has been minimally effective 15-19 20 21 22. 
Response rates are universally less than 20% (often less than 10%) and the majority of patients 
have progressive disease within 3 months. 


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12 
Table 1.  Phase II trials of single-agent chemotherapy in the management of advanced 
endometrial cancer. 
 
* RR for all patients in bold.  RR depending on prior chemotherapy in parentheses (no prior 
chemotherapy / prior chemotherapy) 
PLD = pegylated liposomal doxorubicin, Cyclo = cyclophosphamide, Ifos = ifosfamide, NR = 
not reported 
 
2.2 
Sunitinib Malate 
 
Please provide background     Sunitinib malate (sunitinib; SU11248; SU011248; Sutent®) is a 
novel, multi-targeted, small molecule inhibitor of the receptor tyrosine kinases (RTKs) involved 
in tumor proliferation and angiogenesis, including vascular endothelial growth factor receptor-1 
(VEGFR-1), -2, and -3, platelet-derived growth factor receptor (PDGFR) - and -, stem cell 
factor receptor (KIT), the tyrosine kinase (TK) receptor encoded by the ret proto-oncogene 
(RET; rearranged during transfection), and fms-like tyrosine kinase 3 (Flt3) (Investigator’s 
Brochure SU011248, 2005).  Sunitinib selectively and potently inhibits the class III and class IV 
split-domain RTKs 14. 
 
Sunitinib shows significant antitumor and antiangiogenic activity in a number of human tumor 
xenograft and angiogenesis models in mice as well as in phase 1 and 2 studies in patients with a 
variety of tumor types 15.  To date, over 3500 cancer patients have received sunitinib, including 
Agent (n) 
Prior 
chemo 
RR* 
PFS 
OS 
Reference 
Paclitaxel 
(15) 
Yes 
27% 
NR 
NR 
(14) 
Flavopiridol 
(26) 
Yes 
0 
3.2 mo 
NR 
(15) 
PLD 
(46) 
Yes 
9.5% 
NR 
8.2 mo 
(16) 
Irofulven 
(25) 
Yes 
4% 
2.0 mo 
9.4 mo 
(18) 
Cyclo (29) 
Ifos (32) 
Yes / no 
7% (0 / 14) 
12% (0 / 25) 
2.0 mo 
1.7 mo 
NR 
NR 
(17) 
Carboplatin 
(64) 
Yes / no 
13%  
(0 / 24) 
2.8 mo 
8.7 mo 
(19) 
Docetaxel 
(33) 
Yes / no 
31% 
(23 / 37) 
3.9 mo 
17.8 mo 
(21) 
Paclitaxel 
(23) 
Yes / no 
30.4% 
(8 / 60) 
NR 
NR 
(22) 
PLD 
(52) 
No 
11.5% 
NR 
10.9 mo 
(20) 
Erlotinib 
(25) 
No 
13% 
NR 
NR 
(12) 
CCI-779 
 (23) 
No 
26% 
NR 
NR 
(13) 


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13 
patients with renal cell carcinoma (RCC) and those with gastrointestinal stromal tumors (GIST).  
In phase 2 studies in cytokine-refractory metastatic RCC, sunitinib produced objective responses 
in 40% of patients with a median time to progression (TTP) of 8.7 months 16, while data from a 
phase 3 trial in patients with imatinib-resistant GIST indicate that sunitinib is highly superior to 
placebo (p<0.00001) with respect to time-to-progression (TTP) and overall survival (OS) 17.  
 
Sunitinib was granted approval on January 26, 2006 by Food and Drug Administration (FDA) 
for the treatment of gastrointestinal stromal tumor (GIST) after disease progression on or 
intolerance to imatinib mesylate and advanced renal cell carcinoma (RCC).  Approval for 
advanced renal cell carcinoma is based on partial response rates and duration of response. 
 
Mechanism of Action 
 
Tumor VEGF expression has been associated clinically with disease prognosis in many different 
types of malignancies.  VEGF expression is increased by diverse stimuli including proto-
oncogene activation and hypoxia, with the hypoxic state frequently arising in solid tumors 
because of inadequate perfusion.  In addition to its angiogenic role, VEGF also profoundly 
increases the permeability of the vasculature thereby potentially contributing to tumor 
progression.  A leaky tumor endothelium enhances nutrient and catabolite exchange and 
represents less of a barrier to tumor cell migration and intravasation during metastasis.  Two 
high-affinity receptors for VEGF with associated TK activity have been identified on human 
vascular endothelium, VEGFR-1/Flt-1 and VEGFR-2/kinase insert domain-containing receptor 
(KDR).  Although the relative contributions of KDR and Flt-1 signaling in mediating tumor 
progression have not been elucidated, a number of studies suggest that KDR performs a 
predominant role. 
 
In addition to VEGF receptor signaling, increasing evidence implicates PDGFR signaling in 
tumor angiogenesis.  Recent nonclinical evidence suggests that inhibition of PDGFR signaling 
augments the antitumor and antiangiogenic effects of VEGFR inhibitors.  In addition, PDGF 
signaling is implicated in the autocrine growth of tumor cells and in the recruitment and 
regulation of tumor fibroblasts. 
 
Upon chronic oral dosing, sunitinib is expected to inhibit PDGF- and VEGF-driven angiogenesis 
and as a consequence, limit solid tumor growth.  Because angiogenesis is necessary for the 
growth and metastasis of solid tumors, and VEGF is believed to have a pivotal role in this 
process, sunitinib treatment may have broad-spectrum clinical utility 18.  Sunitinib also exerts 
direct anti-tumor activity on cells that express target RTKs associated with tumor cell 
proliferation, such as KIT, PDGFR and RET.  The clinical activity of sunitinib in patients with 
advanced GIST is an example of this anti-tumor effect. 
 
Nonclinical Specificity and Efficacy Studies 
 
In vitro studies have demonstrated the specificity of sunitinib for inhibition of the Class 3 and 
Class 5 RTKs including receptors for VEGF (VEGFR), KIT and Flt-3, and PDGFR 
(Investigator’s Brochure SU011248, 2005).  Specifically, receptor phosphorylation inhibition 
studies have shown that sunitinib inhibits KIT-ligand-induced phosphotyrosine levels in a dose-


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dependent manner with IC50 values of 0.001-0.01 mcM in vitro and reduced PDGFR-β 
phosphotyrosine levels in vivo 19.  Sunitinib also selectively inhibited proliferation of human 
umbilical vein endothelial cells (HUVEC) stimulated with VEGF (IC50=0.04 mcM) compared 
to FGF-stimulated proliferation (IC50=0.7 mcM) 14. 
 
In animal efficacy studies, sunitinib showed broad antitumor activity in mouse xenograft models 
against a variety of human tumor cell lines including colorectal cancer (HT-29, Colo205), non-
small cell lung cancer (H460), breast cancer (MDA-MB-435), melanoma (A375), epidermoid 
cancer (A431), and glioma (SF763T) 14.  Sunitinib has also demonstrated antitumor activity 
against other breast cancer models (MMTV-v-Ha-ras transgenic mouse mammary carcinoma and 
dimethylbenzanthracene [DMBA]-induced rat mammary carcinomas) 20.  In an animal model of 
KIT-expressing small cell lung cancer (SCLC; NCI-H526), sunitinib administration resulted in 
greater tumor growth inhibition than did imatinib 19. 
 
Combination studies of sunitinib with docetaxel, 5-fluorouracil (5-FU), or doxorubicin resulted 
in significantly enhanced growth inhibition of human MX-1 breast cancer xenografts compared 
to levels of inhibition with either sunitinib or the cytotoxic agent alone 20.   Moreover, the 
combination therapies each led to a significantly increased survival compared to either single 
agent alone 20.  Significantly delayed tumor growth has also been demonstrated in combination 
studies of sunitinib and cisplatin in NCI-H526 SCLC xenografts 19. 
 
Additional nonclinical in vitro and in vivo studies are summarized in Sakamoto, 2004. 
 
Nonclinical Toxicology Studies 
 
Single- and multiple-dose toxicology studies were conducted in mice, rats, dogs, and monkeys 
(Investigator’s Brochure SU011248, 2005).  The acute oral maximally-tolerated dose (MTD) for 
mice, rats, and dogs was greater than the maximum dose of 500 mg/kg.  The MTD in monkeys 
was greater than the 1200 mg/kg maximum dose tested, but emesis occurred at doses ≥ 50 
mg/kg.  Treatment-related effects in the hemolymphopoietic system, adrenal glands, and bone 
growth plate were seen in rat repeat dose studies with gastrointestinal tract, reproductive organ, 
kidney, pancreas, and pituitary effects reported at the highest dose.  Gastrointestinal disturbances 
(diarrhea, loss of appetite, emesis) as well as hematologic disturbances also occurred in an 8-
week study in female monkeys.  Other monkey toxicities seen included mild elevations in AST, 
ALT, and creatinine kinase (CK), adrenal gland cortex hemorrhage, acinar degranulation of the 
salivary glands, decreased erythropoiesis in the bone marrow, and lymphoid atrophy.  Possible 
impairment of immune function in the highest dose group was manifested as cytomegalovirus 
and bacterial infections.  There is an indication that repeated high doses of sunitinib may lead to 
cardiac function/contractility changes as confirmed by altered ECG and MUGA or 
echocardiographic parameters and increased cTnI and/or T in single animals that died or were 
euthanized early due to a moribund condition.  These changes appear to be primarily functional 
and reversible.  It is not clear whether these changes are due to treatment with sunitinib, or 
resulted from the poor clinical condition of the animals. 
 
Sunitinib was found to be negative for genotoxicity in vivo and in vitro.  
 


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Nonclinical Pharmacokinetics and Pharmacology 
 
Single-dose pharmacokinetics (PK) was evaluated in mice, rats, and monkeys at oral doses of 40, 
20, and 6 mg/kg, respectively.  At these doses, the respective Tmax in these species was 1.0, 3.0-
6.0, and 6.0 hours, while Cmax was 1070, 838, and 131 ng/mL, respectively.  In monkeys, t1/2, 
t1/2, and t1/2were 5.5, 15, and 173 hours, respectively.  Repeated dose PK studies indicated 
that increases in exposure were not consistently proportional to dose.  Steady state plasma 
concentrations were reached after 28 days of dosing with little change in levels thereafter. 
 
The major metabolite of sunitinib in mouse, rat, and monkey plasma is the N-desethyl derivative, 
SU12662, an active metabolite with activity comparable to that of sunitinib.  Sunitinib and its 
major metabolite are highly (90-95%) protein bound in monkey and human plasma.  IC50 values 
measured in vitro are expected to be reached with the currently recommended 50 mg dose. 
 
Clinical Experience 
 
As of December 2005, over 3500 subjects had received sunitinib in various clinical trials, with 
nearly 400 subjects having received the agent for at least 6 months (Company Communication 
2005).  In phase 1 studies, sunitinib demonstrated single-agent activity in patients with RCC, 
GIST, non-GIST sarcomas, NSCLC, colorectal cancer, neuroendocrine tumors (NET), 
melanoma, prostate cancer, and thyroid cancer.  Sunitinib has also been studied in the phase 1 
setting in patients with acute myeloid leukemia (AML).  Phase 2 development thus far has 
focused on single-agent trials in metastatic RCC (MRCC), imatinib-resistant GIST, metastatic 
breast cancer (MBC), NSCLC, and carcinoid and islet cell NETs.  Pivotal trials of sunitinib in 
imatinib-resistant GIST (a placebo-controlled phase 3 trial) and MRCC (single-arm, non-
randomized, multicenter, open-label trial) and supporting trials in each disease have completed 
accrual and were submitted in support of the NDA after appropriate follow up and completion.  
In addition, there are several ongoing company-sponsored single agent and combination clinical 
trials for a variety of other indications 
 
Phase 1 Experience 
 
In an early phase 1 study designed to investigate dosing regimen and scheduling (in human 
subjects, the results of clinical pharmacology studies demonstrate that Cmax and AUC increased 
in a proportional manner after single doses of 50 to 350mg as well as after multiple does of 25 to 
100 mg), 41 patients with a variety of advanced solid tumors received sunitinib administered on 
a schedule of 2 weeks of treatment followed by 2 weeks off (2/2 schedule) or 4 weeks on with 2 
weeks off (4/2 schedule) 21.  Doses evaluated on the 2/2 schedule (n=23) included 50 mg every 
other day (n=3), 50 mg daily (n=15), or 75 mg daily (n=5); the 18 patients enrolled in the 4/2 
schedule received 25 mg daily (n=3) or 50 mg daily (n=15).  The most frequent adverse events 
(AEs) were constitutional (fatigue/asthenia), gastrointestinal (nausea, vomiting, diarrhea) and 
hematologic (neutropenia, thrombocytopenia).  Most of the AEs were grade 1 or 2, although at 
75 mg daily, grade 3 and 4 fatigue/asthenia were dose limiting but readily reversible on 
discontinuation of treatment.  There were 4 partial responses (PRs) assessed by RECIST and 22 
patients with stable disease (SD) among the 41 patients. 
 


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A phase 1 dose-escalation study in 28 patients with advanced tumors evaluated sunitinib doses of 
30 mg/m2 every other day, and doses of 30, 42, or 59 mg/m2 daily on the 4/2 schedule 22.  
Grade 3 fatigue and hypertension were dose limiting at 59 mg/m2 as well as grade 2 bullous skin 
toxicity, and the MTD was defined as 42 mg/m2 daily.  Based on these and other reversible AEs 
in the 12 patients treated at the MTD, the recommended phase 2 dose on the 4/2 schedule was 
determined to be 50 mg/day.  Responses determined by RECIST were seen in 6 of 23 evaluable 
patients (RCC, NET, gastrointestinal stromal tumors, and unknown primary).  Tumor responses 
in patients treated at higher doses were often associated with reduced intratumoral 
vascularization and central tumor necrosis, leading to organ perforation in one patient and fistula 
in another.  These observations suggest the possible necessity for careful tumor density 
monitoring to detect early evidence of necrosis. 
 
Two phase 1 studies have been conducted in AML, the first with the primary endpoint of 
evaluation of the inhibition of FLT3 phosphorylation 23 and the second designed as a 
conventional dose-escalation study 24.  O’Farrell and colleagues studied FLT3 phosphorylation 
in 29 AML patients who received a single dose of sunitinib at doses ranging from 50 to 350 mg.  
Over 50% of patients showed strong inhibition of Flt3 phosphorylation at doses of 200 mg and 
higher.  As anticipated from nonclinical data, patients with FLT3 internal tandem duplication 
(ITD) mutations were more sensitive than those with wild-type Flt3 (FLT3-WT) as shown by 
100% inhibition in FLT3-ITD compared to 50% in FLT3-WT.  This study also gave evidence of 
downstream signal inhibition (STAT5 and ERK pathways), with STAT5 levels reduced 
primarily in FLT3-ITD patients while ERK inhibition occurred in the majority of patients 
independently of FLT3 inhibition.  The dose-escalation study enrolled 15 patients with refractory 
or resistant AML who were treated with sunitinib on either the 4/2 or 4/1 schedule at a starting 
dose of 50 mg/day 24.  Dose-limiting AEs (grade 4 fatigue and hypertension) occurred in both 
patients treated at 75 mg/day, and one of these patients (who had received prior mitoxantrone) 
developed cardiac failure.  The 75 mg dose level was therefore terminated and 50 mg/day was 
considered to be the MTD.  All four patients with FLT3 mutations had morphologic or partial 
responses compared to 2 of 10 evaluable patients with wild-type FLT3.  Responses, although 
longer in patients with mutated FLT3, were of short duration. 
 
Phase 2 and 3 Experience 
 
Results have been published on 63 patients with MRCC treated on a phase 2 study of sunitinib at 
a daily dose of 50 mg on the 4/2 schedule 16.  Among these 63 patients, 25 (40%) achieved a PR 
(as determined by RECIST), an additional 17 (27%) had SD for > 3 months, and the remaining 
21 patients either had progressive disease (PD) or maintained SD for less than 3 months.  Of the 
25 PRs, 15 patients progressed, 2 were removed from the study because of AEs, and 8 patients 
have remained progression-free for at least 21 to 24 months (from the start of therapy to the time 
of analysis).  The median time-to-progression (TTP) for the 63 patients was 8.7 months and 
median survival was 16.4 months.  Tumor shrinkage was seen in sites of local recurrence as well 
as metastatic sites.   
 
The promising results in phase 1 trials and the involvement of KIT, PDGFR-α and two of the 
sunitinib target RTKs in GIST led investigators to undertake a phase 1/2 trial in patients with 
GIST refractory or intolerant to imatinib to determine an appropriate dose and regimen for phase 


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17 
2 development of sunitinib in this disease.  Patients received up to 75 mg sunitinib daily on the 
2/2, 4/2, or 2/1 schedule, with 50 mg daily on the 4/2 schedule being selected for continued 
study.  In all, 75 patients were treated on the trial.  Among 41 patients treated for at least 6 
months, 6 had an objective response (OR; RECIST criteria) and an additional 16 had cessation of 
disease progression and minor responses for >6 months.  Overall, 54% of the 41 patients had 
evidence of clinical benefit (OR or progression free survival; PFS) 25.  Determination of the 
GIST genotype in these 41 patients showed that clinical benefit had been achieved in several 
secondary mutational variants that conferred imatinib resistance 26.  Fifty-three of the GIST 
patients treated on this trial subsequently underwent serial 18FDG-PET imaging where 
qualitative responses were graded as good in 33/53 patients, mixed in 15/53, and poor in 5/53 27.  
Correlation with clinical response (Fisher’s exact p=0.03) showed that 22 of 33 patients graded 
as good by 18FDG-PET imaging had clinical benefit (OR or SD ≥ 6 months) after 6 months of 
therapy while 4 of 15 patients graded as mixed had benefit as did 2 of 5 patients graded as poor.  
 
Preliminary data from a pivotal multinational, randomized (2:1), double-blind, placebo-
controlled phase 3 trial in over 300 patients with imatinib-resistant GIST were presented at a 
national meeting in May 2005 17.  Patients on the active treatment arm received sunitinib at a 
dose of 50 mg daily on the 4/2 schedule   At the time of the interim analysis, the study was 
unblinded based on the independent core laboratory efficacy assessment of the primary endpoint 
(TTP).  The median TTP for the treatment arm (n=207) was 27.3 weeks compared to a median of 
6.4 weeks for placebo (n=105) (p<0.001) (Investigator’s Brochure SU011248, 2005).  
 
In addition to patients with RCC and GIST, 106 patients with NET were treated on a phase 2 
protocol with 50 mg sunitinib daily on schedule 4/2 28.  Among the 52 evaluable patients with 
islet cell NET, there were 7 PRs (1 unconfirmed), 40 SD, and 3 PD, while among the 39 
evaluable carcinoid NET patients, there were 2 PRs (1 unconfirmed), 36 SD, and 1 PD.  
Sunitinib is also under phase 2 evaluation in MBC, with 38 patients enrolled thus far 29.  There 
have been 4 PR, 5 SD, and 14 PD among the 23 evaluable MBC patients on this ongoing trial.  
 
Safety Profile 
 
The most frequent adverse events (AEs) seen following sunitinib treatment are constitutional 
(fatigue/asthenia), gastrointestinal (nausea, vomiting, diarrhea, abdominal pain, anorexia, 
stomatitis, dysgeusia) and hematologic (neutropenia, thrombocytopenia) as well as skin 
discoloration (Investigator’s Brochure SU011248, 2005).  Most of the AEs are grade 1 or 2, but 
at 75 mg daily on an early phase 1 trial, grade 3 and 4 fatigue/asthenia were dose-limiting but 
readily reversible on discontinuation of treatment 21.  These investigators noted that the 
frequency and severity of AEs appeared to correlate with higher drug exposure or with lower 
performance status of the patients.  In another phase 1 study, grade 3 fatigue and hypertension 
were dose limiting at 59 mg/m2 and the MTD was defined as 42 mg/m2 daily 30.  Tumor 
responses in patients treated at higher doses on this study were often associated with reduced 
intratumoral vascularization and central tumor necrosis which led to organ perforation in one 
patient and fistula in another.  These observations indicate the necessity for careful tumor density 
monitoring to detect early evidence of necrosis.  Rapid destruction of bulky solid tumors can 
occur following sunitinib treatment, with pneumothorax, intestinal fistulae, or intestinal 
perforation each occurring at an incidence of less than 1.5% of patients.  Across all patient 


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18 
populations, fatigue, hematologic AEs, and lipase elevations were the most common grade 3 and 
4 events.   
 
In addition to the frequent AEs noted above and those which are infrequent but severe, the 
following events have occurred:  grade 2 edema and oral ulceration in AML 24; transient grade 3 
and 4 hypertension, asymptomatic lipase increases (with or without amylase elevations), skin 
irritation in imatinib-resistant GIST 25; and grade 3/4 glossodynia in the NET trial 28.  
Additional reports from the manufacturer include anemia, pyrexia, and dyspnea in AML; and 
abdominal pain, dyspepsia, skin discoloration, headache, constipation, dermatitis, increased 
lipase, limb pain, and taste disturbance in various solid tumor patients (Investigator’s Brochure 
SU011248, 2005).  Of interest, dyspepsia, dysgeusia, and stomatitis were reported twice as often 
in MRCC as in GIST, although these events occurred in both populations.  
 
Fatal bleeding possibly related to their disease occurred in two patients with AML (one from 
concomitant lung cancer, the other from a cerebral bleed) 24.  Both of the AML patients treated 
at the 75 mg dose level on this trial experienced dose-limiting AEs including grade 4 fatigue and 
hypertension; one of these patients (who had received prior mitoxantrone) developed cardiac 
failure.  Other hemorrhagic events have occurred among patients receiving sunitinib for MRCC 
and GIST (SUTENT package insert).  Although epistaxis was the most common hemorrhagic 
AE reported, bleeding events also occurred in several other organ systems.  Tumor-related 
hemorrhage can occur with sunitinib and in the case of pulmonary tumors, may present as severe 
and life-threatening hemoptysis or pulmonary hemorrhage. 
 
The incidence of cardiac AEs in patients receiving sunitinib has been investigated by the 
pharmaceutical company (Company Communication, December 2005):   
 
• 
Evaluation of data from 1356 subjects with solid tumors exposed to sunitinib for whom 
there are AE data(as of June 2005) shows a combined incidence of 0.4% for cardiac 
events [including cardiac failure, cardiac failure NOS, cardiac failure congestive, or left 
ventricular failure as described by the NCI Common Toxicity Criteria (CTC) 2.0].  
 
• 
In an early dose-escalation study of sunitinib involving 32 subjects with AML, three 
cases of congestive heart failure were reported.  Each subject had received high sunitinib 
doses (75 or 100 mg daily), and two of the three subjects had previously received 
anthracycline-based chemotherapy (cytarabine, idarubicin, daunorubicin, 
cyclophosphamide, and mitoxantrone). 
 
• 
After LV monitoring was implemented in sunitinib trials (including echocardiogram or 
multiple gated acquisition scans, cardiac enzyme measurements, and AE rates), a review 
of the data from the GIST and RCC clinical studies was subsequently conducted to 
identify whether changes in the LVEF (left ventricular ejection fraction) correlated with 
the clinical diagnosis of heart failure (congestive heart failure, cardiac failure, or LV 
failure) as reflected in reported AEs.  In two MRCC studies (N=169), twenty-five 
patients (15%) had decreases in left ventricular ejection fraction (LVEF) to below the 
lower limit of normal (LLN).  In a placebo-controlled, phase 3 GIST study (N=312), 22 
patients (11%) receiving sunitinib and 3 receiving placebo (3%) had treatment-emergent 


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LVEF values below the LLN.  Nine of 22 GIST patients on sunitinib recovered without 
intervention, and 5 patients had documented LVEF recovery following intervention (dose 
reduction - 1 patient, addition of antihypertensive or diuretic medication - 4 patients).  Six 
patients went off study without documented recovery.  Additionally, 3 patients (1%) on 
sunitinib had Grade 3 reductions in left ventricular systolic function to LVEF < 40%; two 
of these patients died without receiving further study drug.  No GIST patients on placebo 
had Grade 3 decreased LVEF.  One (<1%) patient on sunitinib and one (1%) patient on 
placebo died of diagnosed heart failure; two (1%) patients on sunitinib and two (2%) 
patients on placebo died of treatment-emergent cardiac arrest. 
 
• 
Cardiac enzymes CK-MB, cTnT, or cTnI were measured in over 200 subjects receiving 
sunitinib with the expectation that an elevation in cTn accompanying a decline in LVEF 
would suggest a drug-induced myocardial injury.  In contrast, lack of correlation with 
cTn would be expected from conditions that induce (1) transient effects on LVEF, such 
as altered preload resulting from dehydration or (2) effects on myocardial contractility 
without significant myocardial cell injury.  Viewed in the aggregate, the composite 
clinical data showed no consistent correlation between cTn elevations and decreases in 
LVEF, suggesting that LVEF declines associated with sunitinib treatment were not 
indicative of a drug-induced myocardial injury. 
 
• 
In summary, intensive and prospective cardiac monitoring in 288 subjects receiving 
sunitinib has not identified major clinical cardiac AEs at the starting daily dose level of 
50 mg (Schedules 2/2 or 4/2).  While 8 (2.8%) of these 288 subjects developed 
significant decreases in LVEF, the evaluation of causality was confounded by 
comorbidities and the lack of a control population.  None of these 8 events was of Grade 
4 severity or associated with a fatal outcome.  In addition, a correlation between LVEF 
decreases and drug exposure could not be established.  Follow-up extending to 6 or more 
cycles in over 170 subjects showed no trend in cardiac AEs or cardiotoxicity serum 
biomarkers to suggest a cumulative or long-term adverse effect of sunitinib on cardiac 
function.  Taken together, these findings suggest no increased risk of significant clinical 
cardiac toxicity for subjects with solid malignant tumors who will be receiving sunitinib 
treatment in future clinical studies.  Moreover, serial and routine LVEF measurements do 
not appear justified except for patients with known risk factors for cardiac AEs (e.g., 
NYHA Class II dysfunction at entry or with a history of Class II dysfunction, prior 
anthracycline exposure, or central thoracic irradiation). 
 
• 
Additional information received from Pfizer Global Pharmaceuticals Safety Report July 
2006 revealed the following case summary:   A 47-year-old male with renal cell 
carcinoma received sunitinib malate at 50 mg daily. On day 11 of treatment, he 
developed diarrhea, followed by recurrent vomiting on day 12. On day 13, he presented 
to the hospital with nausea, vomiting, and lower right quadrant pain, and was found to be 
in ventricular tachycardia consistent with Torsade de pointes. He suffered cardiac arrest 
and was resuscitated. He also experienced an episode of focal seizures (shaking of right 
limb) on the same day. An echocardiogram showed new pericardial effusion (with 
possible tamponade) causing blood pressure fluctuations. His concomitant therapy 
included gabapentin, morphine sulfate for epigastric pain, fluoxetine for depression, and 


NCI 7713; PHL062 
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20 
zopiclone for sleeplessness. The patient’s vomiting, pain, diarrhea, ventricular 
tachycardia, and cardiac arrest were considered by the physician to be related to sunitinib 
malate. No causality assessment was reported for the episode of Torsade de pointes; 
however, a causal relationship cannot be excluded.   
 
Nonclinical evidence of adrenal toxicity following sunitinib exposure led the company to 
perform specialized safety assessments in clinical studies, including computed tomography or 
MRI in 365 subjects (as of July 2005) to specifically identify any change in adrenal gland 
structure or the presence of adrenal gland hemorrhage (Investigator’s Brochure SU011248, 
2005).  Neither event was observed. Based on available clinical AE safety data and radiologic 
and laboratory test results in patients treated with sunitinib, a total of, 6 of 1439 had AEs of 
adrenal insufficiency but without definitive causal relationship to the agent.  Furthermore, no 
cases of drug-related hypocorticism requiring corticosteroid replacement therapy have been 
observed in clinical studies.  However, based on the nonclinical findings, patients receiving 
sunitinib should be clinically followed for signs and symptoms of adrenal insufficiency, 
especially (1) patients with comorbidities associated with adrenal dysfunction, (2) patients with 
preexisting adrenal insufficiency (primary or secondary), and (3) patients with concomitant stress 
(e.g., fever, infection, bleeding, serious accident, surgery) that may precipitate overt adrenal 
insufficiency in the presence of subclinical sunitinib-induced adrenal toxicity. 
 
Many of the kinase inhibitors including sunitinib, sorafenib, imatinib, and the epidermal growth 
factor receptor (EGFR) inhibitors produce a variety of cutaneous side effects that, while not life-
threatening, can be very troublesome to the patient 31.  As presented in this review, hair 
depigmentation, splinter subungual hemorrhages, acral erythema, and facial edema (occasional) 
are some of the dermatologic adverse effects seen with sunitinib.  Because the severity of certain 
cutaneous effects appears to correlate with antitumor response in the case of the EGFR 
inhibitors, there is interest in further elucidating the mechanisms whereby kinase inhibitors 
produce these effects and in the potential for identification of predictive factors. 
 
Clinical Pharmacokinetics, Pharmacology, and Pharmacodynamics 
Clinical pharmacology studies of sunitinib demonstrate that Cmax and AUC increase in a 
proportional manner after single doses of 50-350 mg, as well as after multiple doses of 25-100 
mg (Investigator’s Brochure SU011248, 2005).  Cmax ranged from 26.0-48.7 ng/mL for the 
parent compound and from 4.3-8.9 ng/mL for the major metabolite, SU12662.  AUC0-24 ranged 
from 389-819 ng•hour/ml for sunitinib and 52-140 ng•hour/mL for SU12662.  Peak plasma 
concentrations of the metabolite were much lower than those of sunitinib but declined more 
slowly.  The terminal elimination half-lives of sunitinib and SU12662 are approximately 40 
hours and 80 hours, respectively.  After 28 days of dosing, the AUC0-24 for sunitinib increased 
2.5- to 3.5-fold, while AUC0-24 of SU12662 increased 4- to 12-fold compared to day 1.  Plasma 
concentrations of sunitinib and SU12662 typically reach steady-state levels after 1 to 2 weeks of 
dosing.  Concentrations of parent drug and metabolite measured through 3 cycles of therapy have 
shown that Cmax, AUC0-24, and trough plasma drug concentrations during cycle 2 or cycle 3 
were not increased above those observed in cycle 1. 
 
The major in vitro studies on metabolism enzymology have been conducted in human liver 
microsomes, human hepatocytes, and expressed human CYP enzymes.  Sunitinib is primarily 


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21 
metabolized in human liver microsomes by cytochrome P450 (CYP) isoform 3A4 but appears to 
have minimal potential to inhibit CYP3A4-mediated metabolism, and studies in human 
hepatocytes indicated that neither sunitinib nor SU12662 induced CYP3A4.  These studies 
suggest that sunitinib and SU12662 are unlikely to have any clinically relevant drug-drug 
interactions with drugs that are substrates for CYP3A4.  Concurrent administration of sunitinib 
and ketoconazole, a potent CYP3A4 inhibitor, resulted in less than a 2-fold increase in sunitinib 
exposure (based on Cmax and AUC) and a small decrease in SU12662 exposure (Washington et 
al., 2003).  However, concurrent administration of sunitinib and rifampin (a potent CYP3A4 
inducer) in healthy male Caucasian and Asian volunteers resulted in a 4-fold reduction in 
sunitinib plasma exposure (AUC) and a 2.5-fold reduction in plasma Cmax compared with 
sunitinib alone in both ethnic groups 32.  
 
The effect of sunitinib on Flt3 phosphorylation was studied in three patients with AML treated 
with 50 mg/day sunitinib 24.  Results showed that although there was no dramatic change in Flt3 
protein levels, Flt3 phosphorylation decreased to 24-65% of baseline at a time point 6 hours after 
dosing on day 1.  Plasma levels of Flt3 ligand and VEGF increased dramatically in these 
patients.  However, no correlation with response or other clinical events was apparent.  In a study 
in AML patients where single doses of sunitinib were administered, strong inhibition of Flt3 
phosphorylation was reached in the 200 mg and higher dose cohorts with inhibition occurring in 
50% of patients with wild-type Flt3 and 100% of patients with mutant Flt3 23. 
 
Biomarker analysis was performed on plasma samples taken predose on days 1 and 28 of each 
cycle from 63 patients with MRCC treated with 50 mg sunitinib daily on the 4/2 schedule 33.  
After the first cycle, VEGF increased 3-fold in 24 of 54 patients compared to baseline, PIGF 
increased greater than 3-fold in 22 of 55 patients, and sVEGFR2 levels decreased by 30% in 50 
of 55 patients.  In addition, longitudinal decreases in sKIT were observed in most cases.  Results 
from this study indicate that analysis of circulating proteins may be of utility as 
pharmacodynamic biomarkers of sunitinib activity. 
 
Proposed Dose and Schedule for Phase 2 Clinical Trials 
Starting doses in multiple-dose studies were 25, 50, 75, and 100 mg administered orally once 
daily with the majority of patients receiving the 50-mg dose.  Patients in sunitinib studies have 
been treated on four different schedules: schedules 4/1 and 4/2 comprised 4 consecutive weeks of 
daily dosing followed by a 1- or 2-week rest period, respectively, while schedules 2/1 and 2/2 
comprised 2 consecutive weeks of daily dosing followed by a 1- or 2-week rest period, 
respectively.  The majority of subjects were treated on schedules 4/2 or 2/2 in phase 1 studies.  
Schedule 4/2 has been well tolerated with generally mild to moderate adverse effects at a 50 mg 
daily dose.  Therefore, the recommended starting dose of sunitinib for DCTD, NCI-sponsored 
studies is 50 mg daily administered on schedule 4/2 (daily for 4 consecutive weeks on followed 
by 2 weeks off).  Continuous dosing is currently being evaluated and recommendations will be 
provided for use in hematological malignancies. 
 
2.3 
Rationale 
 
There is an urgent need for effective agents to improve the therapeutic ratio for patients with 
advanced or recurrent endometrial cancer.  Given the central role of protein tyrosine kinases in 


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tumor proliferation and angiogenesis, inhibitors of tyrosine kinases would be of great interest. 
 
Targeting angiogenesis and vascular endothelial growth factor (VEGF) receptor represents a 
promising approach to treat highly vascular tumors, such as endometrial cancer.   VEGF 
overexpression has been consistently demonstrated in endometrial cancer, and the degree of 
expression correlates with poor outcome in many reports 34-37.  Angiogenesis is a key factor in 
the growth and metastasis of solid tumours and is regulated by a host of endogenous factors, with 
VEGF being the most potent and specific pro-angiogenic factor identified to date.   VEGF 
expression and angiogenesis appears to be sex hormone-dependent in some uterine cancers 38, 
and linked to loss of p53 mutation 39.  In particular, flt-4 (VEGFR-3) overexpression has 
independent prognostic significance in endometrial cancer 37, suggesting a greater role for this 
receptor among the other VEGF receptors in the pathogenesis of endometrial cancer.  
 
Since sunitinib has affinity for multiple VEGF receptors, particularly VEGFR-3, it is seen as an 
attractive antiangiogenic agent.  Given the emerging preclinical data regarding the importance of 
VEGF in endometrial cancer, a prospective clinical trial to determine the efficacy and tolerability 
of sunitinib in patients with recurrent or advanced endometrial cancer is warranted. 
 
The advent of antiangiogenic drugs among the arsenal of chemotherapeutic agents has begun to 
challenge the notion of the necessity for tumor shrinkage to provide clinical benefit 40.  Based 
on their mechanism of action, one might expect agents such as sunitinib to be more tumoristatic 
rather than tumoricidal.  In a disease such as endometrial cancer, where cytotoxic chemotherapy 
is associated with short-lived responses, a novel agent that can induce long-term stability of 
disease is of clinical interest.  As such, we intend to evaluate a clinical benefit endpoint (rate of 
prolonged stable disease), in addition to the traditional endpoint of objective response rate, in this 
phase II clinical trial. 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed endometrial cancer. 
Adenocarcinoma (endometrioid and serous / papillary serous) and carcinosarcoma (ie. 
malignant mixed mullerian tumor (MMMT) of the uterus will be investigated.  Patients 
with other histologies (eg. squamous cell carcinoma or leiomyosarcoma) are excluded. 
 
3.1.2 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as >20 
mm with conventional techniques or as >10 mm with spiral CT scan.  See section 10.2for 
the evaluation of measurable disease.  Indicator lesions must not have been previously 
treated with surgery, radiation therapy or radiofrequency ablation. 
 
3.1.3 Previously treated patients must have evidence of progressive disease, either clinically or 
radiographically, as assessed by the investigator. 
 
 


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3.1.4 Eligible patients may have received no more than one prior cytotoxic chemotherapy 
regimen for recurrent, locally-advanced, or metastatic disease.  If the prior chemotherapy 
was an anthracycline, they may have received no more than 6 cycles (or less than 450 
mg/m2 doxorubicin).  Patients must have completed any previous chemotherapy a 
minimum of 4 weeks (or 6 weeks if the regimen contained BCNU or mitomycin) prior to 
study registration.  Prior investigational treatment is permissible (as long as such 
treatment completed 4 weeks prior to registration). 
 
3.1.5 Because no dosing or adverse event data are currently available on the use of sunitinib in 
patients <18 years of age, children are excluded from this study but will be eligible for 
future pediatric single-agent trials, if applicable. 
 
3.1.6 Life expectancy of greater than 3 months. 
 
3.1.7 ECOG performance status < 2 (Karnofsky > 60%; see Appendix A). 
 
3.1.8 Patients must have normal organ and marrow function as defined below: 
 
 
leukocytes  
 
>3,000/mcL 
 
absolute neutrophil count 
>1,500/mcL 
 
platelets 
 
 
>100,000/mcL 
 
hemoglobin  
 
>100 g/L 
 
serum calcium  
<12.0 mg/dL (<3.0 mmol/L) 
 
total serum bilirubin 
within normal institutional limits 
 
AST(SGOT)/ALT(SGPT) 
< 2.5 X institutional upper limit of 
 
   
 
 
 
normal 
 
creatinine 
 
 
within normal institutional limits 
 
 
OR 
 
creatinine clearance 
>60 mL/min/1.73 m2 for patients with                              
   
 
creatinine levels above institutional                                  
   
 
normal 
 
serum lipase / 
< 1.5 x institutional upper limit of 
 
   
 
serum amylase  normal 
 
TSH / T3 / T4  
within normal institutional limits 
X  Magnesium  
 
 
 
 
 
 
 
>0.5 mmol/L 
 
3.1.9 Patients must have QTc < 500 msec. 
 
3.1.10 The following groups of patients are eligible provided they have normal baseline cardiac 
function (as determined by estimate of left ventricular ejection fraction (LVEF) on 
echocardiogram or MUGA: 
• those with a history of congestive heart failure, provided they are no greater than 
NYHA class I on treatment at baseline 
• those with prior anthracycline exposure 


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• those who have received central thoracic radiation that included the heart in the 
radiotherapy port. 
 
3.1.11 The effects of sunitinib on the developing human fetus at the recommended therapeutic 
dose are unknown.  For this reason and because antiangiogenic agents are known to be 
teratogenic, women of childbearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry and for the duration of study participation.  All women of childbearing potential 
must have a negative pregnancy test prior to receiving sunitinib.  Should a woman 
become pregnant or suspect she is pregnant while participating in this study, she should 
inform her treating physician immediately. 
 
3.1.13  Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered 
from adverse events due to agents administered more than 4 weeks earlier.  At least 4 
weeks must have elapsed since any major surgery. 
 
3.2.2 Patients may not be receiving any other investigational agents. 
 
3.2.3 Patients who have received prior treatment with any other antiangiogenic agent (e.g., 
bevacizumab, sorafenib, pazopanib, AZD2171, PTK787, VEGF Trap, etc.) are ineligible. 
 
3.2.4 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to sunitinib. 
 
3.2.5 Patients who have a history of serious ventricular arrhythmias (VT or VF equal to or 
greater than 3 beats in a row), QTc prolongation (defined as a QTc interval equal to or 
greater than 500 msec) or other significant ECG abnormalities are excluded. 
 
3.2.6 Patients with poorly controlled hypertension (systolic blood pressure of 140 mmHg or 
higher or diastolic blood pressure of 90 mmHg or higher) are ineligible. 
 
3.2.7 Patients who require use of therapeutic doses of coumarin-derivative anticoagulants such 
as warfarin are excluded, although doses of up to 2 mg daily are permitted for 
prophylaxis of thrombosis.  Note: Low molecular weight heparin is permitted provided 
the patient’s PT INR is <1.5.  
 
3.2.8 Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to 
take oral medication or a requirement for IV alimentation, prior surgical procedures 
affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow 
and retain sunitinib tablets are excluded. 
 


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3.2.9 Patients with any of the following conditions are excluded: 
• Serious or non-healing wound, ulcer, or bone fracture. 
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess 
within 28 days of treatment. 
• Any history of cerebrovascular accident (CVA) or transient ischemic attack within 12 
months prior to study entry. 
• History of myocardial infarction, cardiac arrhythmia, stable/unstable angina, 
symptomatic congestive heart failure, or coronary/peripheral artery bypass graft or 
stenting within 12 months prior to study entry. 
• History of pulmonary embolism within the past 12 months. 
• Class III or IV heart failure as defined by the NYHA functional classification system 
(see Appendix B). 
• Pre-existing adrenal insufficiency (primary or secondary) 
 
3.2.10 Because sunitinib is metabolized primarily by the CYP3A4 liver enzyme, the eligibility 
of patients taking medications that are potent inducers or inhibitors of that enzyme will be 
determined following a review of their case by the Principal Investigator.  (A list of 
potent CYP3A4 inducers or inhibitors can be found in Section 5.2.)  Every effort should 
be made to switch patients taking such agents or substances to other medications, 
particularly patients who are taking enzyme-inducing anticonvulsant agents.  A 
comprehensive list of medications and substances known or with the potential to alter the 
pharmacokinetics of sunitinib through CYP3A4 is provided in Appendix C. 
 
3.2.11 Patients with a pre-existing thyroid abnormality who are unable to maintain thyroid 
function in the normal range with medication are ineligible. 
 
3.2.12 Patients with known brain metastases should be excluded because of their poor prognosis 
and because they often develop progressive neurologic dysfunction that would confound 
the evaluation of neurologic and other adverse events. 
 
3.2.13 Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infections or psychiatric illness/social situations that would limit compliance with 
study requirements are ineligible. 
 
3.2.14 Pregnant women are excluded from this study because sunitinib is an antiangiogenic 
agent with the potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with sunitinib, breastfeeding should be discontinued if the mother is treated 
with sunitinib malate. 
 
3.2.15 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with sunitinib.  In addition, these patients are at 
increased risk of lethal infections when treated with marrow-suppressive therapy.  
Appropriate studies will be undertaken in patients receiving combination antiretroviral 
therapy when indicated. 
 


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26 
3.3 
Inclusion of Minority Populations 
 
Women of all ethnic groups are eligible for this phase II trial.  This study is designed to 
include minorities as appropriate.  However, the trial is not designed to measure 
differences in intervention effects.  The population of Canada is ethnically diverse and 
the proportions of different ethnic groups in the community are provided in the table 
below. Universal access to health care will ensure that there is no discrimination on the 
basis of race or gender Guide to Canadian Human Rights Act: 
www.chrc-ccdp.ca/public/guidechra.pdf). 
Individual hospital registries and databases do not routinely collect racial data, under the 
direction of the Canadian Human Rights Code. 
 
The population demographics and distribution of minorities in various regions of Canada 
is included in the table 1 below: 
 
Table 2: Visible minority population by Consortium Provinces  (2001 Census)  
  
British 
Columbia 
Alberta 
Ontario 
Nova 
Scotia 
Total 
Total population of 
province 
3,868,870 
2,941,150 
11,285,550 
897,570 
18,993,140 
Visible Minorities 
Populati
on 
% 
Populati
on 
% 
Populati
on 
% 
Populat
ion 
% 
Populati
on 
% 
Black 
25,465 
1% 31,390 1% 411,095 4% 19,670 2% 487,620 3% 
Asian 
768,435 
20
% 
268,660 9% 1,513,825 13% 12,630 1% 
2,563,55
0 
13
% 
Latin American 
(Hispanic) 
23,880 
1% 18,745 1% 106,835 1% 520 
0% 149,980 1% 
Visible minority, not 
included elsewhere 
4,195 
0% 4,220 
0% 78,915 
1% 1,170 
0% 88,500 
0% 
Multiple visible 
minority 
14,465 
0% 6,910 
0% 42,375 
0% 535 
0% 64,285 
0% 
Total Visible minority 
population 
836,440 
22
% 
329,925 
11
% 2,153,045 19% 34,525 4% 
3,353,93
6 
18
% 
Source: Statistics Canada, Census of Population.  
 
We have compiled some data from our consortium of representation of 
minorities on previous clinical trials, and the distribution is as follows: 
 
 
 
Table 3:  Population Percentage of Minority 
and Gender of entering PMHC Trials 
 
2002 
2003 
2004 
Visible Minorities 
 
 
 
Black 
3.6 
0 
2.8 
Asian 
7.2 
9.0 
8.4 


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27 
 
 
 
 
 
 
 
 
 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 72 hours.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled. The Central Office Study Coordinator should be notified of cancellations as 
soon as possible. 
 
Each participating institution will order DCTD-supplied agents directly from the Pharmaceutical 
Management Branch (PMB) of CTEP.  Agents may be ordered by a participating site only after 
the initial IRB approval for the site has been forwarded by the Coordinating Center to the CTEP 
PIO (PIO@ctep.nci.nih.gov) except for Group studies.  In the event of any problems or issues 
with product supply, PMB must be contacted directly. 
 
4.2 
Registration Process 
 
• 
Prior to registering a patient, each institution must have submitted all necessary 
regulatory documentation to the PMH Phase II Consortium Central Office.  CRFs will 
only be sent once this has been received.   
 
• 
No patient can receive protocol treatment until registration with the Central Office has 
taken place.  All eligibility criteria must be met at the time of registration.  There will be 
no exceptions.  Any questions should be addressed with the Central Office prior to 
registration.  
 
• 
The eligibility checklist must be completed, and signed by the investigator prior to 
registration.  
 
• 
Sites will fax in the signed, completed eligibility checklist to the central office at 416-
946-2016.  The central office will then review the checklist and once eligibility has been 
confirmed fax back a confirmation sheet indicating the unique study number for the 
subject and confirmation of entry into the trial. Only after this faxed confirmation sheet 
has been received back from central office, can the patient receive the study drug. 
Hispanic 
2.4 
3.0 
1.7 
Total  
13.2 
12 
12.9 
Women 
44.6 
49.3 
46.9 


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28 
 
• 
To ensure immediate attention is given to the faxed checklist, each site is advised to also 
call the study coordinator listed on the front sheet or call the central office at 416-946-
4501 ext 4724 or page the program manager at 416-790-8163.  Patient registration will be 
accepted between the hours of 9 am to 5 pm Monday to Friday, excluding Canadian 
statutory holidays when the central office will be closed. 
 
5. TREATMENT PLAN 
 
5.1 
Sunitinib Malate Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications for sunitinib are described in 
Section 6.  No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient’s malignancy. 
 
• Patients will take sunitinib once daily in the morning, with or without food, as 
desired.  Patients take one 50-mg capsule of sunitinib daily for 4 consecutive weeks 
followed by 2 weeks of rest (drug holiday) with no sunitinib.  This 6-week period 
constitutes one cycle of treatment. 
 
• Patients will be provided with a Medication Diary for sunitinib (Appendix D), 
instructed in its use, and asked to bring the diary with them to each appointment.  A 
new copy of the Medication Diary will be given to patients whose dose is reduced 
due to adverse events. 
 
• Because hypertension is a known and potentially serious but rare adverse event 
associated with sunitinib malate treatment, patients will have their blood pressure 
monitored and recorded weekly during the first cycle of therapy, either at the doctor’s 
office or using any calibrated electronic device (such as those found at a local drug 
store or pharmacy).  Patients will be provided with a Blood Pressure Check Diary 
(Appendix E).  An increase in blood pressure of >20 mmHg (systolic) and 10 mmHg 
(diastolic) should be reported to the treating physician immediately.  (See Section 6.1 
for hypertension management and dose reduction guidelines.) 
 
• Routine monitoring for cardiac function (echocardiogram / MUGA) should be 
performed every other cycle of treatment in the following groups of patients:  (1) 
those with a history of Class congestive heart failure who no greater than NYHA 
Class I (see Appendix B) on treatment at baseline, and (2) those previously exposed 
to anthracyclines or, (3) those previously treated with thoracic irradiation if the heart 
was included in the radiotherapy port.  Routine cardiac monitoring is not required in 
patients with no known cardiac dysfunction at entry or in the absence of clinically 
observed adverse cardiac events. 
 
• Although adrenal gland insufficiency is rarely seen with sunitinib treatment, patients 
should be clinically followed for the signs and symptoms of this complication, 


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especially (1) patients with comorbidities associated with adrenal dysfunction, (2) 
patients with pre-existing adrenal insufficiency (primary or secondary), and (3) 
patients with concomitant stress (e.g., fever, infection, bleeding, serious accident, 
surgery) that may precipitate overt adrenal insufficiency in the presence of subclinical 
sunitinib-induced adrenal toxicity.  If clinically indicated, objective testing for adrenal 
gland function should be conducted. 
 
• Patients with bulky solid tumors should be monitored closely for pneumothorax, 
intestinal fistulae, or intestinal perforation in the event of rapid tumor destruction. 
 
• Patients should be alerted to the possibility that sunitinib capsules can cause a yellow 
discoloration of the skin on direct contact.  If this happens, the patient should wash 
immediately with soap and water. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
The case report form (CRF) must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies including herbal supplements, specifically, St. John’s wort.  
The Principal Investigator should be alerted if the patient is taking any agent known to affect or 
with the potential to affect selected P450 isoenzymes.  (A comprehensive list of CYP3A4-
interactive agents is provided in Appendix C.)  
 
5.2.1 Concomitant Medications 
 
• Use of agents with proarrhythmic potential (terfenadine, quinidine, procainamide, 
disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide, and 
flecainide) is not permitted during the study.  A comprehensive list of agents with 
proarrhythmic potential can be found at http://torsades.org.  Refer to Appendix J. 
 
• Sunitinib is primarily metabolized by liver enzymes, particularly CYP3A4.  Co-
administration of potent inhibitors or inducers of this enzyme can result in significant 
changes in exposure to sunitinib (e.g., a mean 1.8-fold increased exposure with 
ketoconazole and a mean 4-fold decrease with rifampin) .  For this reason, use of the 
following agents is not permitted before or during the study: 
 
Inhibitors – prohibited 7 days before dosing and during study. 
azole antifungals 
(ketoconazole, itraconazole) 
verapamil 
clarithromycin 
HIV protease inhibitors 
(indinavir, saquinavir, 
ritonavir, atazanavir, 
nelfinavir) 
erythromycin 
delavirdine 
diltiazem 
 
Inducers – prohibited 12 days before dosing and during study. 
rifampin  
phenytoin 


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rifabutin 
St. John’s wort 
carbamazepine 
efavirenz 
phenobarbital 
tipranavir 
 
A comprehensive list of CYP3A4 inhibitors, inducers, and substrates is provided in 
Appendix C. 
 
• Steroid use is not recommended during sunitinib treatment unless absolutely 
necessary (e.g., for treatment of adverse events or protocol-required premedication) 
because many steroids (e.g., prednisone, prednisolone, dexamethasone, etc.) 
effectively lower sunitinib exposure through CYP3A4 interactions. 
 
• The use of coumarin-derivative anticoagulants such as warfarin (Coumadin®) is not 
recommended, although doses of up to 2 mg daily are permitted for prophylaxis of 
thrombosis. 
 
5.2.2 Supportive Care 
 
• Nausea/vomiting:  Patients with treatment-related nausea should be treated initially 
with a phenothiazine (prochlorperazine – 10 mg every 8 hours orally as needed, or 
promethazine – 12.5-25 mg IV every 6 hours as needed).  If this is inadequate, a 
benzodiazepine should be added until acute nausea is controlled or toxicity is 
limiting.  Should this prove inadequate acutely, a steroid may be added (e.g., 
dexamethasone 4 mg every 6 hours as needed). 
 
• After acute nausea has resolved, consideration should be given to initiation of 
prophylactic antiemetic therapy.  If nausea recurs despite reasonable medical 
intervention (as outlined above), dose reduction will be needed as described in 
Section 6. 
 
• Diarrhea should be managed with loperamide:  4 mg at first onset, then 2 mg every 
2-4 hours until diarrhea is controlled (maximum = 16 mg loperamide per day).  
 
• Hand-foot syndrome may be treated with topical emollients (such as Aquaphor), 
topical/systemic steroids, and/or antihistamine agents.  Vitamin B6 (pyridoxine; 50-
150 mg orally each day) may also be used. 
 
• Patients with neutropenic fever or infection should be evaluated promptly and 
treated with IV antibiotic therapy or therapeutic colony-stimulating factors as 
appropriate following the ASCO guidelines [J Clin Oncol 18(20):3558-85, 2000]..  
Packed red blood cell and platelet transfusion should be administered as clinically 
indicated.  Erythropoietic agents may be used at the discretion of the treating 
physician. 
 
5.3 
Duration of Therapy 
 


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31 
In the absence of treatment delays due to adverse event(s), treatment may continue indefinitely, 
until one of the following criteria applies: 
 
 Disease progression, 
 Intercurrent illness that prevents further administration of treatment, 
 Unacceptable adverse event(s), 
 Patient decides to withdraw from the study, or 
 General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.4 
Duration of Follow Up 
 
All patients will be seen at 4 weeks after completion of protocol therapy. Thereafter, continued 
follow-up is not required for patients who go off protocol treatment with progressive disease, 
except to document ongoing toxicities (until resolved to < grade 2), late toxicities (including 
second malignancies) and death. For patients who go off protocol treatment with CR, PR, or SD 
ongoing, follow-up will be required every 3 months until relapse. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
The dose levels and the general approach to dose modification of sunitinib on this trial are shown 
below.  Adverse events (AEs) should be treated with the appropriate maximum supportive care, 
and dose reductions should be clearly documented in the case report form (CRF).  All AEs 
should be graded according to the Common Terminology Criteria for Adverse Events (CTCAE 
v3.0). 
 
Sunitinib dose levels  
Dose Level 
Daily Dose 
-2 
25 mg 
(one 25 mg capsule) 
-1 
37.5 mg 
(one 12.5 capsule plus 
one 25 mg capsule) 
0 
50 mg 
(one 50 mg capsule) 
 
6.1 
Management of Treatment-Emergent Hypertension 
 
Increases in blood pressure (BP) and cases of hypertension have been associated with 
many drugs acting on the VEGF pathway.  The proposed mechanism for this increase is 
through inhibition of VEGF-induced peripheral vasodilation.  Hypertension following 
sunitinib treatment has rarely been seen in animal studies or clinical trials.  Specific 
guidelines for management of this adverse event and a table of various antihypertensive 
medications are provided in Appendix F.  In addition, guidance on the collection and 
recording of BP information is provided in Appendix G.  
 


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Management of Hypertension 
BP measurements - 
systolic/diastolic 
 
Treatment/Dose Modification 
Patients not receiving maximal antihypertensive therapy: 
> 140 mmHg (systolic) 
OR 
> 90 mmHg (diastolic) 
 
• Add new or additional antihypertensive meds or increase dose 
of existing meds 
• Increase frequency of monitoring until stabilized (e.g., every 
48-72 hrs) 
• Maintain dose of sunitinib 
> 180 mmHg (systolic) 
OR 
> 110 mmHg (diastolic)1 
• Hold sunitinib 
• Add new or additional antihypertensive meds or increase dose 
of existing meds 
• Monitor patient closely for hypotension (if on antihypertensive 
meds) until sunitinib is restarted. 
• Resume treatment at same dose level when BP falls to <140/90. 
Patients receiving maximal antihypertensive therapy2 (four antihypertensives for 2 weeks 
without dose modification of antihypertensive medications):  diuretics, beta blocker or central 
sympathetic blocker, ACE inhibitor or ARB and vasodilator or calcium channel blocker (CCB) 
• 160 mmHg (systolic) 
OR 
> 105 mmHg (diastolic) 
• Hold sunitinib 
• Maintain antihypertensive meds and monitor patient closely for 
hypotension until sunitinib is restarted. 
• Resume treatment at one lower dose level3 when BP falls to 
<140/90 
1.   Any patient with symptomatic severe hypertension (i.e.,  180 / 110) should have sunitinib 
stopped and treatment initiated as per hypertensive crisis (e.g., hospitalization, monitoring, IV 
therapy) 
2.   Maximal antihypertensive therapy is defined as four antihypertensive medications given for 2 
weeks. 
3.   If hypertension persists despite two dose level reductions, sunitinib must be discontinued.  
 
• While patients are receiving treatment with sunitinib, the early initiation of 
antihypertensive treatment for grade 1 or 2 hypertension to minimize more severe or 
persistent hypertension is not considered a grade 3 adverse event. 
 
• Decisions to hold or decrease the sunitinib dose during treatment must be based on 
BP readings taken in the clinic by a medical professional. 
 
6.2 
Left ventricular systolic dysfunction / CHF 
 
• Symptomatic Cardiac Events 
 
Discontinue sunitinib if: 
o a patient has symptoms of CHF and a diagnosis of CHF is confirmed 


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33 
o a patient has a myocardial infarction 
 
• Asymptomatic Decrease in LVEF 
(Applicable only to patients undergoing routine cardiac monitoring as outlined in Section 
5.1) 
 
The decision to continue or hold sunitinib is based on the ejection fraction as it relates to 
the institution’s LLN and change in ejection fraction from screening (LVEF as measured 
at registration) according to the following table: 
 
Relationship of 
LVEF to 
institution’s LLN 
 
Decrease 
< 10% 
 
Decrease 
10-15% 
 
Decrease 
> 16% 
 
Normal 
Continue 
Continue 
Continue 
Repeat MUGA / 
ECHO in 6 weeks 
1-5% below LLN 
 
Continue 
Repeat MUGA / 
ECHO in 6 weeks 
Continue 
Repeat MUGA / 
ECHO in 6 weeks 
HOLD 
Repeat MUGA / 
ECHO in 6 weeks 
> 6% below LLN 
 
Continue 
Repeat MUGA / 
ECHO in 6 weeks 
HOLD 
Repeat MUGA / 
ECHO in 6 weeks 
HOLD 
Repeat MUGA / 
ECHO in 6 weeks 
 
Discontinue suntinib if: 
• Two consecutive HOLD categories occur 
• Three intermittent HOLD categories occur. (At the discretion of the investigator, 
sunitnib may also be permanently discontinued prior to the occurrence of 3 
intermittent HOLD categories)  
 
IF LVEF is maintained at a “Continue” or improves from a “HOLD” to a “Continue” 
category, additional MUGA scans / echocardiograms prior to the next scheduled MUGA 
/ echo will be at the discretion of the investigator, as clinically indicated.  


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34 
 
6.3 
Other Hematologic and Non-Hematologic Adverse Events 
 
Event 
AE Grade or 
Observation 
Dose modification 
Neutropenia 
Grades 1 and 
2 
Maintain dose 
Grade 3 * 
Hold sunitinib until < grade 2, then resume at same 
dose level 
Grade 4 
Hold sunitinib until < grade 2, then reduce 1 dose 
level and resume treatment 
Thrombocytopenia 
Grades 1 and 
2 
Maintain dose 
Grade 3 * 
Hold sunitinib until < grade 2, then resume at same 
dose level 
Grade 4 
Hold sunitinib until < grade 2, then reduce 1 dose 
level and resume treatment 
Fatigue (lethargy, 
malaise, asthenia) 
Grades 1 and 
2 
Maintain dose 
Grade 3 * 
Hold sunitinib until < grade 2, then reduce 1 dose 
level and resume treatment 
Grade 4 
Hold sunitinib until < grade 2, then reduce 1 dose 
level and resume treatment 
 
 
 
 
 
 
 
QTc Prolongation 
>450 but 
 < 550 msec 
• Review patient’s concomitant medications for 
QT interval-prolonging agents.  Correct any 
electrolyte abnormalities. 
• Continue sunitinib at current dose level. 
> 550 msec 
• Stop sunitinib and any other QT-interval   
      prolonging agents immediately.  Correct any    
      electrolyte abnormalities, then 
1.If there is a plausible explanation for AE 
other than sunitinib treatment, resume 
sunitinib at current dose level. 
2.If sunitinib may have contributed to the AE: 
• Reduce 2 dose levels and restart sunitinib. 
• If QTc remains <500 msec after 14 days at 
reduced dose, increase one dose level and 
continue sunitinib. 
If QTc remains <500 msec after 14 days, original 
dose of sunitinib may be resumed. 
Hand-foot syndrome 
Grades 1 and 
2 
Maintain dose 
Grade 3 
Hold sunitinib until < grade 1, then reduce 1 dose 
level 
Grade 4 
Discontinue treatment 
Serum lipase / 
Grades 1 and 
Maintain dose 


NCI 7713; PHL062 
February 26, 2016; A18 
35 
amylase 
2 
Grades 3 and 
4 
Hold sunitinib until < grade 1, then reduce 1 dose 
level 
ALT / AST / 
Bilirubin 
> Grade 3 
Sunitinib should be dose delayed, may be re-
administered when levels of ALT / AST / bilirubin 
is ≤ grade 2.  Sunitinib should NOT be re-
administered if subjects develop ≥ grade 3 hepatic 
failure (CTCAEv4 definition). 
 
 
• Recurrent grade 3 events require dose reduction. 
 
6.4 
Management of Other Clinically Significant AEs (not specifically addressed 
above) 
 
General Management Guidelines 
Observation 
Action 
AE resolves promptly with supportive care 
Maintain dose level 
Grade 3 or higher non-hematologic related to 
sunitinib despite maximum supportive care for < 
48 hours. 
Hold sunitinib until resolution 
to < grade 2, then reduce by 
one dose level 
AE does not resolve to grade 2 or below after 2 
weeks off sunitinib 
Remove patient from study 
Recurrent grade 3 or higher non-hematologic on 
the lowest dose level (i.e., 25 mg daily). 
Remove patient from study  
 
In general, patients requiring sunitinib malate treatment to be held for greater than 2 weeks 
are to be discontinued from the study; however, in the rare event that a patient requires 
sunitinib malate treatment to be held for greater than 2 weeks in order to receive treatment 
for an unrelated concurrent medical condition, the patient may be permitted to continue 
sunitinib malate treatment on study following treatment of their concurrent medical condition 
if specific requirements are met and if approved by the CTEP drug monitor.  For a patient 
where it is evident that the patient has benefitted, and continues to benefit from treatment 
(i.e., a confirmed partial response or extended stable disease has been determined according 
to RECIST); the re-start of sunitinib malate treatment following an extended sunitinib malate 
treatment holiday may be permissible if the investigator determines that: 
 
• the patient is of sufficient health to continue following the intervention for the 
patient’s concurrent medical condition 
• continued sunitinib malate treatment would not subject the patient to undue harm 
• there exists the possibility of the patient to derive continued benefit from further 
sunitinib malate treatment.   
 
The investigator will assess the patient’s disease and the potential benefit of continued sunitinib 


NCI 7713; PHL062 
February 26, 2016; A18 
36 
treatment before and after the extended drug holiday. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited (via AERS) reporting in addition to routine (via 
CDUS) reporting. See the company’s prescribing information regarding hepatotoxicity at 
www.sutent.com.  
 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Sunitinib Malate 
(NSC 736511) 
The Comprehensive Adverse Events 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. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for further clarification. 
Frequency is provided based on 7115 patients. Below is the CAEPR for Sunitinib malate (SU011248 L-malate). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
Version 2.12, January 14, 20161 
 
 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 4.0 Term) 
[n= 7115] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
 
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 
 
 Hypothyroidism (Gr 2) 
EYE DISORDERS 
  
 
 
Eye disorders - Other (macular 
edema) 
 Eye disorders - Other (macular edema) 
(Gr 2) 


NCI 7713; PHL062 
February 26, 2016; A18 
37 
 
 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 4.0 Term) 
[n= 7115] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
  
 
 
Eye disorders - Other (vision 
deterioration) 
 Eye disorders - Other (vision 
deterioration) (Gr 2) 
 
Papilledema 
 
 Papilledema (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
 Abdominal distension (Gr 2) 
Abdominal pain 
 
 
 Abdominal pain (Gr 3) 
Anal mucositis 
 
 
 Anal mucositis (Gr 2) 
Constipation 
 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
Dyspepsia 
 
 
 Dyspepsia (Gr 2) 
 
 
 Esophagitis 
  
 
Flatulence 
 
 Flatulence (Gr 2) 
 
Gastritis 
 
 Gastritis (Gr 2) 
 
Gastroesophageal reflux disease  
  
 
 
Gastrointestinal perforation2 
  
Mucositis oral 
 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Oral pain 
 
 Oral pain (Gr 2) 
 
 
 Pancreatitis 
  
Rectal mucositis 
 
 
 Rectal mucositis (Gr 2) 
Small intestinal mucositis 
 
 
 Small intestinal mucositis (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 2) 
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 
 
 Alanine aminotransferase increased (Gr 
3) 
 
Alkaline phosphatase increased  
 Alkaline phosphatase increased  
(Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased (Gr 
3) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
CPK increased 
 
  


NCI 7713; PHL062 
February 26, 2016; A18 
38 
 
 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 4.0 Term) 
[n= 7115] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
  
 
Creatinine increased 
 
 Creatinine increased (Gr 3) 
 
 
Electrocardiogram QT corrected 
interval prolonged 
  
 
Lipase increased 
 
 Lipase increased (Gr 4) 
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 2) 
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 4) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 4) 
 
Serum amylase increased 
 
 Serum amylase increased (Gr 2) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hyperuricemia 
 
 Hyperuricemia (Gr 2) 
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 2) 
 
 
Hypoglycemia 
  
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 2) 
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
 
Musculoskeletal and connective 
tissue disorder - Other 
(rhabdomyolysis) 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
 
 
Osteonecrosis of jaw 
  
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
Dysgeusia 
 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
 
Leukoencephalopathy 
  
 
 
Nervous system disorders - Other 
(cerebral infarction) 
  
 
 Paresthesia 
 
  
 
 
Reversible posterior 
leukoencephalopathy syndrome 
  
 
 
Transient ischemic attacks 
  
PSYCHIATRIC DISORDERS 
  
 
Depression 
 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
 
 Acute kidney injury 
  
 
 
 Proteinuria 
  
 
 
 Renal and urinary disorders - Other 
(nephrotic syndrome) 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 


NCI 7713; PHL062 
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39 
 
 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 4.0 Term) 
[n= 7115] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
  
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
 Epistaxis Gr 2) 
Laryngeal mucositis 
 
 
 Laryngeal mucositis (Gr 2) 
Pharyngeal mucositis 
 
 
 Pharyngeal mucositis (Gr 2) 
Tracheal mucositis 
 
 
 Tracheal mucositis (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Erythema multiforme 
  
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
 
 Palmar-plantar erythrodysesthesia 
syndrome (Gr 3) 
 
Pruritus 
 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
 
Skin and subcutaneous tissue 
disorders - Other (hair color 
change) 
 
 Skin and subcutaneous tissue disorders - 
Other (hair color change) (Gr 2) 
 
 
 Skin and subcutaneous tissue 
disorders - Other (pyoderma 
gangrenosum) 
  
 
Skin hypopigmentation 
 
 Skin hypopigmentation (Gr 2) 
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
Vascular disorders - Other 
(hemorrhage)4 
 
  
 
1This 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. 
 
 
2Gastrointestinal 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. 
 
3Allergic reactions observed include anaphylaxis and angioedema. 
 
4The 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 


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40 
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 
 
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. 
 
7.2 
Adverse Event Characteristics  
 
• 
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 3.0.  A copy of the CTCAE 
version 3.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov).  
Please consult the CTEP mapping document of CTCAE version 3.0 to CTCAE 
version 4.0 when determining expectedness and expedited adverse event reporting. 
 
• 
“Expectedness”:  AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) for 
expedited reporting purposes only.  ‘Expected’ AEs (the SPEER) are bold and 
italicized in the CAEPR (Section 7.1). 
 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 


NCI 7713; PHL062 
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41 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP home page (http://ctep.cancer.gov).  The 
reporting procedures to be followed are presented in the “CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements” which can be downloaded from the CTEP home 
page (http://ctep.cancer.gov).  These requirements are briefly outlined in the table below 
(Section 7.3.3). 
 
In the rare event when Internet connectivity is disrupted a 24-hour notification is to be 
made to NCI by telephone at: 301-897-7497, or 301-897-7402 for CIP studies. An 
electronic report MUST be submitted immediately upon re-establishment of internet 
connection 
 
7.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
CTEP-AERS Reporting Requirements for Adverse Events that occur within 30 Days1 of the Last 
Dose of the Investigational Agent on Phase 2 and 3 Trials 
 
 
Phase 2 and 3 Trials 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected  
and Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unex- 
pected  
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
10 Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of 
treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 unexpected events  
 
CTEP-AERS 10 calendar day report: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events 
2 Although a CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report is required as 
outlined in the table. 
December 15, 2004 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
• Expedited AE reporting timelines defined: 


NCI 7713; PHL062 
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42 
➢ “24 hours; 5 calendar days” – The investigator must initially report the AE via 
CTEP-AERS within 24 hours of learning of the event followed by a complete 
CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
➢ “10 calendar days” - A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the event.  
 
• Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported regardless 
of attribution and designation as expected or unexpected with the exception of any 
events identified as protocol-specific expedited adverse event reporting exclusions.   
 
• Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs 
following treatment with an agent under a CTEP IND. 
 
• Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 
 
7.5 
Secondary AML/MDS 
 
All secondary malignancies that occur following treatment with an agent under an NCI IND/IDE 
must be reported via CTEP-AERS.  CTCAE v4.0 has three options available to describe 
treatment-related events: 
• 
Leukemia secondary to oncology chemotherapy, 
• 
Myelodysplastic syndrome,  
• 
Treatment related secondary malignancy.  
If you are reporting in CTCAE v3.0, the event can be reported as: “Secondary malignancy-Other 
(Specify)”. 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with sunitinib malate administered 
in this study can be found in Section 7.1.   
Sunitinib malate (NSC 736511) 
 
Chemical Name: 
5-(5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-
dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-
amide; compound with (S)-2-hydroxy-succinic acid. 
 
Other names: 
SU011248 L-Malate salt; SU010398; PHA-290940AD; Sutent; 
SU011248 
 


NCI 7713; PHL062 
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43 
Classification: 
Receptor tyrosine kinase (RTK) inhibitor 
 
Molecular formula: 
C22H27FN4O2.C4H6O5 
M.W.: 532.57 Daltons 
 
Physical description: 
Yellow to orange powder 
 
CAS registry number: 
341031-54-7 
 
Aqueous solubility:  
Solvent 
Solubility (mg/mL) 
0.1 M HCl 
59.1  
pH 4.5 buffer 
25.4  
pH 7.5 buffer 
37.8  
In water 
4.9  
 
Solubility in various solvents: 
Solvent 
Solubility (mg/mL) 
Tetrahydrofuran 
0.2 
1-Butano:Water (80/20 v:v) 
1.0 
N, N-Dimethylacetamide 
3.0 
 
Mode of Action: 
Sunitinib malate is a receptor tyrosine kinase inhibitor involved 
in tumor proliferation and angiogenesis, specifically inhibiting 
platelet derived growth factor receptor, vascular endothelial 
growth factor receptor, stem cell factor receptor, Fms-like 
tyrosine kinase-3 receptor, and ret proto-oncogene. 
 
How Supplied: 
Sunitinib malate is supplied by Pfizer and distributed by 
DCTD/NCI as 12.5 mg, 25 mg, and 50 mg capsules with 
mannitol, croscarmellose sodium, povidone, and magnesium 
stearate.  Each opaque plastic bottle contains 30 capsules. 
Capsule strength 
              Description 
12.5 mg 
Swedish Orange, Size 4 hard gelatin capsule 
25 mg 
Swedish Orange/Caramel, Size 3 hard gelatin capsule. 
50 mg 
Caramel, Size 2 hard gelatin capsule 
 
Storage: 
Store at controlled room temperature (150 to 300 C), and protect 
from light.  
 
Stability: 
Shelf-life studies for sunitinib capsules are ongoing. 
 
Route of Administration: 
Oral.  Sunitinib malate may be administered without regard to 
meals.  
 
Potential Drug Interaction: Sunitinib malate is metabolized primarily by liver enzymes, 
particularly CYP3A4.  CYP3A4 inducers (e.g., rifampin, 


NCI 7713; PHL062 
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44 
dexamethasone) and CYP3A4 inhibitors (e.g., grapefruit juice, 
ketoconazole) should be avoided, if possible.  Rifampin lowers 
sunitinib malate Cmax concentration by more than 2-fold.  
Ketoconazole increases sunitinib malate Cmax by 1.6 fold.  Dose 
reduction with the CYP3A4 inhibitors is recommended, based on 
clinical symptoms. 
 
Concomitant treatment with dysrhythmic drugs, i.e., terfenadine, 
quinidine, procainamide, sotalol, probucol, bepridil, haloperidol, 
risperidone, and indapamide, is not recommended. 
 
Patient Care Implications: A yellow discoloration of the skin area may result following 
direct contact with the capsules.  Wash the exposed area with 
soap and water immediately. 
 
Availability: 
Sunitinib malate is an investigational agent supplied to 
investigators by the Division of Cancer Treatment and 
Diagnosis (DCTD), NCI. 
 
Sunitinib malate is provided to the NCI under a Collaborative 
Agreement between Pfizer and the DCTD, NCI (see Section 
11.3). 
 
Agent Ordering: 
NCI-supplied agents may be requested by the Principal 
Investigator (or their authorized designees) at each 
participating institution.  Pharmaceutical Management Branch 
(PMB) policy requires that the agent be shipped directly to the 
institution where the patient is to be treated.  PMB does not 
permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).   
 
 
Active CTEP-registered investigators and investigator-
designated shipping designees and ordering designees can 
submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx.  Access to OAOP 
requires the establishment of a CTEP Identity and Access 
Management (IAM) account https://eapps-
ctep.nci.nih.gov/iam/ and the maintenance of an “active” 
account status and a “current” password.  For questions about 
drug orders, transfers, returns, or accountability, call (240) 276-
6575 Monday through Friday between 8:30 am and 4:30 pm 
(ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
Agent Accountability: 
The Investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory 
and disposition of all agents received from DCTD using the 


NCI 7713; PHL062 
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45 
NCI Drug Accountability Record Form.  See the CTEP web 
site for Policy and Guidelines for Accountability and Storage 
of Investigational Drugs 
(http://ctep.cancer.gov/requisition/storage.html), or call the 
PMB at (240) 276-6575. 


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46 
9. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to administration of protocol 
therapy.  Tumor imaging studies must be done 4 weeks prior to the start of therapy.  In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy. 
 
   
Pre-
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
 4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
 13 
Off Study 
 
Sunitinib 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
 
X---------------------------------------------------------------------------------------------------------X 
 
 
Physical exam 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Vital signs 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Performance status 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
CBC w/diff, plts 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
Serum chemistrya 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
Blood pressure measurementb 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
Electrocardiogramc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram or MUGAd 
(as indicated) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Adverse event evaluation 
 
   X -------------------------------------------------------------------------------------------------------X 
X 
 
Tumor measurements 
 
X 
 
Tumor measurements are repeated every 2 cycles.f  Documentation (radiologic) must be 
provided for patients removed from study for progressive disease. 
X 
 
Radiologic evaluation 
 
X 
Radiologic measurements should be performed every 2 cycles.f 
X 
 
B-HCG 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a: 
Albumin, alkaline phosphatase, amylase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, lipase, phosphate, 
potassium, total protein, SGOT[AST], SGPT[ALT], sodium, magnesium, TSH, T3 &  T4. LFTs should be obtained at any time when they are 
clinically indicated 
b: 
Blood pressure measurement may be performed more frequently as dictated by clinical observations. 
c:     All patients must have ECG at baseline.  Follow-up ECGs as clinically indicated 
d:    All patients must have echo or MUGA at baseline.  Echo / MUGA must be repeated every other cycle for high-risk patients only (see sections 
3.1.9 and 5.1) 
e:     Serum pregnancy test (women of childbearing potential). 
f 
In the rare event that sunitinib treatment is discontinued for an extended period to permit treatment of an unrelated concurrent  
medical 
condition radiologic evaluation and tumor measurements are to be repeated prior to re-initiation of treatment if deemed  
necessary by the 
investigator. 
 
 
 


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47 
10. MEASUREMENT OF EFFECT 
 
For the purposes of this study, patients should be reevaluated for response every 2 cycles (1 
cycle = 6 weeks).  In addition to a baseline scan, confirmatory scans should also be obtained 6 
weeks following initial documentation of objective response. 
 
10.1 
Definitions 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000].  Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST criteria. Note:  Lesions are either measurable or non-
measurable using the criteria provided below. The term “evaluable” in reference to measurability 
will not be used because it does not provide additional meaning or accuracy. 
 
10.1.1 Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm with conventional techniques (CT, MRI, 
x-ray) or as >10 mm with spiral CT scan.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
10.1.2 Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with 
conventional techniques or <10 mm using spiral CT scan), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 
 
10.1.3 Target Lesions 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD.  The baseline sum LD will be used as reference 
by which to characterize the objective tumor response. 
 
10.1.4 Non-target Lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline.  Non-target lesions include measurable lesions that exceed the maximum 
numbers per organ or total of all involved organs as well as non-measurable lesions.  
Measurements of these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up. 


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48 
10.2 
Guidelines for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
Note: Tumor lesions that are situated in a previously irradiated area are only considered 
measurable if there has been documented growth of these lesions prior to study.  
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
 
Clinical lesions.  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI.  These techniques should be performed with cuts of 10 mm or less 
in slice thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Head and 
neck tumors and those of extremities usually require specific protocols. 
 
Ultrasound (US).  When the primary endpoint of the study is objective response evaluation, US 
should not be used to measure tumor lesions.  It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules.  
US might also be useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination. 
 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor evaluation 
has not yet been fully and widely validated.  Their uses in this specific context require 
sophisticated equipment and a high level of expertise that may only be available in some centers.  
Therefore, the utilization of such techniques for objective tumor response should be restricted to 
validation purposes in reference centers. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained. 
 
Tumor markers.  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific additional criteria for standardized usage of prostate-
specific antigen (PSA) and CA-125 response in support of clinical trials are being developed. 
 


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49 
Cytology, Histology.  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
10.3 
Response Criteria 
 
10.3.1 Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all target lesions 
 
Partial Response (PR): 
 
At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions, taking as reference the baseline sum 
LD 
 
 
 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded 
since the treatment started or the appearance of one or more 
new lesions 
 
Stable Disease (SD):  
 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started 
 
10.3.2 Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization 
of tumor marker level 
 
Incomplete Response/ 
 
 
 
Stable Disease (SD):  
 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 
Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances the opinion of the treating physician should prevail, and the progression 
status should be confirmed at a later time by the review panel (or study chair). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
 


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50 
10.3.3 Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria (see Sections 10.3.1 and 10.4.1). 
 
 
Target Lesions 
 
Non-Target Lesions 
 
New Lesions 
 
Overall Response 
 
CR 
 
CR 
 
No 
 
CR 
 
CR 
 
Incomplete 
response/SD 
 
No 
 
PR 
 
PR 
 
Non-PD 
 
No 
 
PR 
 
SD 
 
Non-PD 
 
No 
 
SD 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Any 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Any 
 
Yes 
 
PD 
 
Note: 
 
 Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time 
should be classified as having “symptomatic deterioration.”  Every effort 
should be made to document the objective progression, even after 
discontinuation of treatment. 
 
X   In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue.  When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) before confirming the complete response status. 
 
10.4 
Confirmatory Measurement/Duration of Response 
 
10.4.1 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed 6 weeks after the criteria for response are first met.  
In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval 12 weeks (see section 10.3.3). 
 
10.4.2 Duration of overall response 


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51 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
 
10.4.3 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.  The 
maintenance of stable disease or objective response for 6 months or greater is defined as 
prolonged stable disease. 
 
10.5 
Progression-Free Survival 
 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression. 
 
10.6 
Response Review 
 
All responses will be reviewed, independently from the investigators, by a staff radiologist.  Staff 
with the Princess Margaret Hospital Phase II Consortium will conduct a simultaneous review of 
the patients’ files and radiological images. 
 
11. DATA REPORTING / REGULATORY CONSIDERATIONS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
11.1 
Data Reporting 
 
11.1.1 Method 
 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  
Reports are due January 31, April 30, July 31, and October 31.  Instructions for 
submitting data using the CDUS can be found on the CTEP web site 
(http://ctep.cancer.gov/reporting/cdus.html).  
 
11.1.2 Responsibility for Submissions 
 
Study participants are responsible for submitting CDUS data and/or data forms to the 
Coordinating Center quarterly by  January 31, April 30, July 31, and October 31 to allow 
time for Coordinating Center compilation, Principal Investigator review, and timely 
submission to CTEP (see Section 11.1.1.).  Please refer to Appendix H, Data 


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52 
Management Guidelines, for further details regarding data submission requirements. 
 
The Coordinating Center is responsible for compiling and submitting CDUS data to 
CTEP for all participants and for providing the data to the Principal Investigator for 
review.   
 
11.2 
CTEP Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix I. 
 
The Principal Investigator/Coordinating Center is responsible for distributing all IND Action 
Letters or Safety Reports received from CTEP to all participating institutions for submission to 
their individual IRBs for action as required. 
 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP.  Agents may be ordered by a participating site only after the initial 
IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) except for Group studies. 
 
11.3 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) 
 
The agent(s), supplied by CTEP, DCTD, NCI, used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA) between the Pharmaceutical Company(ies) 
[hereinafter referred to as ACollaborator(s)@] and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines, in addition to the provisions in the 
AIntellectual Property Option to Collaborator@ (http://ctep.cancer.gov/industry) contained 
within the terms of award, apply to the use of Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators.  The protocol documents for 
studies utilizing investigational agents contain confidential information and should 
not be shared or distributed without the permission of the NCI.  If a copy of this 
protocol is requested by a patient participating on the study or patient’s family 
member, the individual should sign a confidentiality agreement.  A suitable model 
agreement can be downloaded from http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different collaborative 
agreements, the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as "Multi-
Party Data”.): 


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53 
 
a. NCI must provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NIH, the design of the proposed combination protocol, and the existence of 
any obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow 
said other Collaborator to develop, obtain regulatory approval, or 
commercialize its own investigational agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use 
the Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own investigational agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a collaborative 
agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order.  Additionally, all Clinical Data and Results and Raw Data will be collected, 
used and disclosed consistent with all applicable federal statutes and regulations for 
the protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164.   
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
 
5. Any data provided to Collaborator(s) for phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
for immediate delivery to Collaborator(s) for advisory review and comment prior to 
submission for publication.  Collaborator(s) will have 30 days from the date of receipt 
for review.  Collaborator shall have the right to request that publication be delayed for 
up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three 
(3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings.  Press releases and other media presentations must 
also be forwarded to CTEP prior to release.  Copies of any manuscript, abstract, 
and/or press release/ media presentation should be sent to: 


NCI 7713; PHL062 
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54 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
6130 Executive Boulevard, Suite 7111 
Rockville, MD  20892 
FAX 301-402-1584 
E-mail: anshers@ctep.nci.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/proprietary information. 
 
12. STATISTICAL CONSIDERATIONS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Design/Endpoints 
 
The primary endpoint of the study is objective response rate (ORR).  ORR is defined as the rate 
of complete or partial response as defined by the RECIST criteria (see section 10.3).  Secondary 
endpoints will include prolonged stable disease (as defined in sections 1 and 11.4.3) overall 
survival, toxicity and time to progression. 
 
A two-stage design has been adopted for this study that judges the agent as promising based on 
tumor response rate.  An objective response rate of 20% would be considered of interest, 
whereas a rate of 5% would be deemed uninteresting.  For this design we will set α≈0.05 and 
β≈0.20. 
• In the first stage, 15 patients will be accrued.  If no objective responses are observed 
among the initial 15 evaluable patients, the study would be terminated early and 
declared negative.   
• If there are 1 or more objective responses, the trial will continue on to a second stage, 
accruing an additional 15 patients.   
• If at least 4 objective responses (at least 13%) are observed among the 30 evaluable 
patients, this agent would be considered worthy of further testing in this disease. 
 
This design yields 86.5% (type II error=0.135) power to detect a true objective response rate of 
at least 20% and 0.942 (type I error=0.058) probability of a negative result if the true objective 
response rate is no more than 5%.  The probability of stopping at the end of the first stage is 
approximately 0.46 and the expected sample size is 23.05 if the true objective response rate is 
5%. 
 
Data from clinical trials of single-agent chemotherapy in the salvage setting for endometrial 
cancer suggest a median progression-free survival from 1.8 – 3.2 months (see section 2).  
Assuming exponential survival, this equates to an approximate 6-month progression-free 
survival rate of 10-25%. Based on these statistics, we consider 6-month stable disease rate of 
greater than 25% (or 4 out of the first 15 patients) to be of interest, even in the absence of 


NCI 7713; PHL062 
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55 
objective response. 
 
If, at the end of stage I, no objective responses are seen, but at least 4 patients demonstrate 
prolonged stable disease (i.e. best response of stable disease that is maintained for at least 6 
months), consideration would be given to continuing accrual to the second stage.  In this 
circumstance, a decision to continue to stage II would only be made in consultation with CTEP. 
12.2 
Sample Size/Accrual Rate 
 
Sample size: 15 (minimum) to 30 (projected maximum) 
Anticipated accrual rate: 2 patients per month 
 
12.3 
Analysis of Secondary Endpoints 
 
Survival statistics will be estimated using the Kaplan-Meier method.  Patients will be evaluated 
for response according to the RECIST criteria.  Standard descriptive statistics, such as the mean, 
median, range and proportion, will be used to summarize the patient sample and to estimate 
parameters of interest.  Adverse events will be described using the CTCAE v3 (as described in 
section 7) and will be summarized in tabular form, describing all adverse events, and sub-tables 
describing all attributable (possibly, probably or definitely related) and all serious (grade 3 or 
higher) adverse events will also be constructed.  All tests will be two-sided and a p-value of 0.05 
or less will be considered statistically significant.  95% confidence intervals will be provided for 
estimates of interest where possible. 
 
12.4 
Reporting and Exclusions 
 
12.4.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with sunitinib. 
 
12.4.2 Evaluation of response.  All patients included in the study will be assessed for response 
to treatment, even if there are major protocol treatment deviations or if they are ineligible.  
Each patient will be assigned one of the following categories:  1) complete response, 2) 
partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data). 
 
All of the patients who meet the eligibility criteria (with the possible exception of those 
who received no study medication) will be included in the main analysis of the response 
rate.  Patients in response categories 4-9 will be considered to have a treatment failure 
(disease progression).  Thus, an incorrect treatment schedule or drug administration will 
not result in exclusion from the analysis of the response rate.   
 
All conclusions will be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 


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56 
subanalyses will not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis will be clearly reported.  
  
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therapy for the disease. Blood 105:986-993, 2005 
 
 
25. Desai J, Maki R, Heinrich MC, et al: Activity and tolerability of the multi-targeted tyrosine 
kinase inhibitor SU011248 in patients (pts) with metastatic gastrointestinal stromal tumor (GIST) 
refractory to imatinib mesylate. Proc Am Soc Clin Oncol Gastrointestinal Cancers 
Symposium:abstract 7, 2004 
 
26. Demetri GD, Desai J, Fletcher JA, et al: SU11248, a multi-targeted tyrosine kinase inhibitor, 
can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) 
with metastatic gastrointestinal stromal tumor (GIST). J Clin Oncol (Meeting Abstracts) 
22:3001-, 2004 
 
27. Dileo P, Van Den Abbeele A, Manola J, et al: Qualitative assessment of 18FDG-PET 
correlates with clinical benefit in patients (pts) with imatinib mesylate (IM)-resistant GIST 
treated with the multi-targeted tyrosine kinase inhibitor SU11248. Proc Am Soc Clin Oncol 
Gastrointestinal Cancers Symposium:abstract 8, 2005 
 
28. Kulke M, Lenz HJ, Meropol NJ, et al: A phase 2 study to evaluate the efficacy and safety of 
SU11248 in patients (pts) with unresectable neuroendocrine tumors (NETs). J Clin Oncol 
(Meeting Abstracts) 23:4008-, 2005 
 
29. Miller KD, Burstein HJ, Elias AD, et al: Phase II study of SU11248, a multitargeted receptor 
tyrosine kinase inhibitor (TKI), in patients (pts) with previously treated metastatic breast cancer 
(MBC). J Clin Oncol (Meeting Abstracts) 23:563-, 2005 
 
30. Raymond E, Faive S, Vera K: Final results of a phase I and pharmacokinetic study of 
SU11248, a novel multi-targeted tyrosine kinase inhibitor, in patients with advanced cancers. 
Proc Am Soc Clin Oncol 22:192s, 2003 
 
31. Robert C, Soria J-C, Spatz A, et al: Cutaneous side-effects of kinase inhibitors and blocking 
antibodies. The Lancet Oncology 6:491-500, 2005 
 
32. Bello C, Houk B, Sherman L, et al: Effect of rifampin on the pharmacokinetics of SU11248 
in healthy volunteers. J Clin Oncol (Meeting Abstracts) 23:3078-, 2005 
 
33. Deprimo SE, Bello C, Smeraglia J, et al: Soluble protein biomarkers of pharmacodynamic 
activity of the multi-targeted kinase inhibitor SU 11248 in patients with metastatic renal cell 
cancer. Proc Amer Assoc Cancer Res 46:abstract 464, 2005 
 
34. Giatromanolaki A, Sivridis E, Brekken R, et al: The angiogenic "vascular endothelial growth 
factor/flk-1(KDR) receptor" pathway in patients with endometrial carcinoma: prognostic and 
therapeutic implications. Cancer 92:2569-77, 2001 
 
35. Seki N, Kodama J, Hongo A, et al: Vascular endothelial growth factor and platelet-derived 
endothelial cell growth factor expression are implicated in the angiogenesis of endometrial 


NCI 7713; PHL062 
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59 
cancer. Eur J Cancer 36:68-73, 2000 
 
36. Talvensaari-Mattila A, Soini Y, Santala M: VEGF and its receptors (flt-1 and KDR/flk-1) as 
prognostic indicators in endometrial carcinoma. Tumour Biol 26:81-7, 2005 
 
37. Yokoyama Y, Sato S, Futagami M, et al: Prognostic significance of vascular endothelial 
growth factor and its receptors in endometrial carcinoma. Gynecol Oncol 77:413-8, 2000 
 
38. Fujimoto J, Toyoki H, Jahan I, et al: Sex steroid-dependent angiogenesis in uterine 
endometrial cancers. J Steroid Biochem Mol Biol 93:161-5, 2005 
 
39. Mazurek A, Pierzynski P, Kuc P, et al: Evaluation of angiogenesis, p-53 tissue protein 
expression and serum VEGF in patients with endometrial cancer. Neoplasma 51:193-7, 2004 
 
40. Michaelis LC, Ratain, M.J.: Measuring response in a post-RECIST wolrd: from black and 
white to shades of grey. Nature Reviews Cancer 6:409-414, 2006 
 
 


NCI 7713; PHL062 
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60 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 


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61 
 
APPENDIX B 
NEW YORK HEART ASSOCIATION CLASSIFICATION OF 
CARDIAC DISEASE 
 
 
 
 
 


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62 
 
APPENDIX C 
DRUGS KNOWN TO BE METABOLIZED BY SELECTED CYP450 
ISOENZYMES 
 
CYP3A4 
 
 
SUBSTRATES 
 
INHIBITORS 
 
INDUCERS 
Generic Name 
Trade Name 
Generic Name 
Trade Name 
Generic Name 
Trade 
Name 
Anti-neoplastics: e.g. 
    Docetaxel 
    Gefitinib 
    Irinotecan 
 
Taxotere 
Iressa 
Camptosar 
Anti-arrhythmics: e.g. 
    Amiodarone 
    Diltiazem 
    Quinidine 
 
Cordarone, Pacerone 
Cardizem, Dilacor XR 
Cardioquin 
Aminoglutethimide 
Cytadren 
Anti-virals: e.g. 
    Amprenivir 
    Rifampin 
 
Agenerase 
Rifadin 
 
 
Anti-virals: e.g. 
    Amprenavir 
    Indinavir 
    Nelfinavir 
    Ritonavir 
 
Agenerase 
Crixivan 
Viracept 
Norvir 
Antibiotics: e.g. 
    Rifabutin 
    Rifampin 
 
Rifadin 
Mycobutin 
 
 
Anxiolytics: e.g. 
    Diazepam 
    Sertraline 
 
Valium 
Zoloft 
Cimetadine 
Tagamet 
Anticonvulsants: e.g.   
    Carbamazapine 
    Phenytoin 
    Pentobarbital 
    Phenobarbital 
 
Tegretol 
Dilantin 
Nembutal 
Luminal 
Cyclosporine 
Sandimmune 
Cyclosporine 
Sandimmune 
Hypericum perforatum (2) 
St. John’s Wort 
Anti-infectives: e.g. 
    Erythromycin 
    Tetracycline 
 
Erythrocin 
Sumycin 
Antibiotics: e.g. 
    Ciprofloxacin 
    Clarithromycin 
    Doxycycline 
    Enoxacin 
    Isoniazid 
    Telithromycin 
 
Cipro, Ciloxan 
Biaxin 
Adoxa, Periostat 
Penetrex 
Nydrazid, INH 
Ketek 
 
 
Steroids: e.g. 
    Estrogens, conjugated 
    Estradiol 
    Progesterone 
 
Premarin 
Climara 
Crinone 
Imatinib 
Gleevec 
  
 
Haloperidol 
Haldol 
Haloperidol 
Haldol 
 
 
Cardiovascular agents: e.g. 
    Digitoxin 
    Quinidine 
 
Crystodigin 
Cardioquin 
Diclofenac 
Cataflam, Voltaren 
 
 
Anti-hypertensives: e.g. 
    Nicardipine 
    Verapamil 
 
Cardene 
Calan, Chronovera 
Vasodilators: e.g. 
    Nicardipine 
    Verapamil 
 
Cardene 
Calan, Chronovera 
 
 
Anesthetics: e.g. 
    Ketamine 
    Lidocaine 
 
Xylocaine 
Diprivan 
Anesthetics: e.g. 
    Lidocaine 
    Propofol 
 
Xylocaine 
Diprivan 
 
 
Nefazodone 
     
Serzone 
Anti-depressants: e.g. 
    Nefazodone 
    Sertraline 
 
Serzone 
Zoloft 
 
 
Cocaine 
 
Anti-fungals: e.g. 
    Itraconazole 
    Ketoconazole 
   Miconazole 
 
Sporanox 
Nizoral 
Lotrimin, Monistat 
 
 
Ketoconazole 
Nizoral 
Caffeine 
 
 
 
Sildenafil 
Viagra 
Grapefruit juice (1) 
 
 
 
Albuterol 
Ventolin 
 
 
 
 
Carbamazapine 
Tegretol 
 
 
 
 
Lovastatin 
Mevacor 
 
 
 
 
 
When drugs classified as ‘substrates’ are co-administered with (Sunitinib Malate), there is the potential for higher concentrations of the 
‘substrate’. When  (Sunitinib Malate) is co-administered with compounds classified as ‘inhibitors’, increased plasma concentrations of 
(Sunitinib Malate) is the potential outcome. The coadministration of ‘inducers’ would potentially lower plasma  (Sunitinib Malate) 
concentrations. 


NCI 7713; PHL062 
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63 
CYP3A4 
Inhibitors 
Acetominophen 
Acetazolamide 
Amioderone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffiene 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetadine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Cyclophosphamide 
Cyclosporine 
Danazol 
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit juice 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Isoniazid 
Isradapine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan 
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nitrendipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarpine 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapimil 
Vinblastine 
Vincristine 
Vinorelbine 
Zafirlukast 
Ziprasidone 
 
 
 
Inducers 
Aminoglutethimide 
Carbamazapine 
Fosphenytoin 
St. John’s wort 
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin 
Rifampin 
Rifapentine 
 
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In: Lacy CF, Armstrong LL, Goldman MP, Lance 
LL eds. Drug Information Handbook 12TH ed. Hudson, OH; LexiComp Inc. 2004: 1619-1631.) 
 
(1)  Malhorta et al. (2000). Clin Pharmacol Ther. 69:14-23 
 
(2)  Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249 
      Frye et al. (2004). Clin Pharmacol Ther. 76:323-329 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
__________________.  This clinical trial is sponsored by the NCI.  
__________________ interacts with drugs that are processed by your 
liver.  Because of this, it is very important to: 
➢ 
Tell your doctors if you stop taking regular medicine 
or if you start taking a new medicine. 
➢ 
Tell all of your prescribers (doctor, physicians’ 
assistant, nurse practitioner, pharmacist) that you are taking part in a 
clinical trial. 
➢ 
Check with your doctor or pharmacist whenever you 
need to use an over-the-counter medicine or herbal supplement. 
__________________ interacts with a specific liver enzyme called 
CYP______, and must be used very carefully with other medicines 
that interact with this enzyme.  
➢ Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP______.” 
➢ Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/ for a list of drugs 
to avoid, or contact your study doctor.   
➢ Your study doctor’s name is ______________ and can be 
contacted at ______________.  


NCI 7713; PHL062 
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64 
 
APPENDIX D 
PATIENT’S MEDICATION DIARY 
 
Today’s date ____________________ Agent ____Sunitinib_____ 
Patient Initials__________________ Patient Study ID ______________________________________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each 4 week-period while you take sunitinib. 
2. 
You will take your dose of sunitinib each day in the morning for 4 weeks.  You will take ____12.5 mg capsules,  
 
____ 25 mg capsules, and _____ 50 mg capsules every morning.  You may take the capsules with or without food as you wish. 
3. 
Record the date, the number of capsules of each size you took, and when you took them.   
4. 
If you have any comments or notice any side effects, please record them in the Comments column.   
5. 
Please return this form to your physician when you go for your next appointment. 
 
Day 
 
Date 
Time of 
daily dose 
# of capsules taken 
Comments 
 
12.5 mg 
25 mg 
50 mg 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
Physician’s Office will complete this section: 
1. 
Date patient started protocol treatment_____________________________________________________ 
2. 
Date patient was removed from study_____________________________________________________  
3. 
Patient’s planned total daily dose____________________________________________________________ 
4. 
Total number of capsules taken this month (each size)___________________________________________ 
Physician/Nurse/Data Manager’s Signature ________________________ 
 
CTEP-assigned Protocol # _____________ 
 
Local Protocol # ______________________ 


NCI 7713; PHL062 
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65 
 
APPENDIX E 
PATIENT’S BLOOD PRESSURE DIARY 
 
Today’s date ______________________ Agent _____Sunitinib ______ 
Patient Initials_____________________  Patient Study ID _____________________________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Your blood pressure readings have two numbers.  The first number is the pressure in your blood vessels during a heart beat 
(systolic), and the second number is the pressure in the vessels when the heart rests in between beats (diastolic).  These numbers 
are usually written with a slash in between them (for example, 110/85). 
2. 
Record the date and time of each blood pressure reading. 
3. 
If you take your blood pressure at other times of the day, please record the numbers and time under “Other readings”. 
4. 
If your systolic pressure is greater than 140 or your diastolic blood pressure is greater than 90 twice in a row measured several 
hours apart, please contact your doctor’s office at _______________________________ for instructions. 
5. 
Please bring this form to every clinic visit or appointment. 
Date 
Time 
Blood 
Pressure  
Other readings (include 
time of day) 
Date 
Time 
Blood 
Pressure  
Other readings (include time 
of day) 
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
 
Physician’s Office will complete this section: The above information has been reviewed with the patient. 
 _________________________________ 
____________________________________________________________ 
 
Date of this clinic visit 
Physician/Nurse/Data Manager’s Signature    
 


NCI 7713; PHL062 
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66 
 
APPENDIX F 
MANAGEMENT OF SUNITINIB-INDUCED HYPERTENSION 
 
Oral Antihypertensive Medications 
 
Agents in bold characters are suggested as optimal choices to avoid or minimize potential 
drug-interactions with sunitinib 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 / 
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 


NCI 7713; PHL062 
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67 
fosinopril 
10 mg 
daily 
20 mg daily 
40 mg daily Yes (CYP450 
unknown) 
perindopril 
4 mg 
daily 
none 
8 mg daily 
Yes, but not 
CYP450 
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 
 


NCI 7713; PHL062 
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68 
 
APPENDIX G 
COLLECTION/RECORDING OF BLOOD PRESSURE 
INFORMATION 
 
1.0 
General Guidelines 
1.1 
Frequency of monitoring.  Blood pressure (BP) should be monitored weekly during the first cycle of 
sunitinib therapy, then at least every 2 weeks for the duration of treatment.  More frequent monitoring 
may be considered on a study by study basis, particularly during the first two cycles of sunitinib 
therapy. 
 
1.2 
Data recording.  All required data should be recorded in the appropriate CRF or on the patient’s blood 
pressure monitoring diary, as appropriate.  The following data are required at baseline and at each 
subsequent assessment: 
• 
Assessment date and time 
• 
Pulse 
• 
Systolic and diastolic BP (2 readings/assessment taken 5 minutes apart while patient sitting) 
 
1.3 
Risk factors for hypertension (assess and record data in baseline history/physical CRF) 
• 
Diabetes (type 1 or type 2) 
• 
Renal disease (specify on CRF) 
• 
Endocrine condition associated with HTN (specify on CRF) 
• 
Use of steroids or NSAIDs (specify all concomitant meds) 
• 
Underlying cardiovascular condition – specify (i.e., ischemic heart disease) 
 
2.0 
Baseline data collection  (at study entry) 
2.1 
All patients 
• 
Current BP 
• 
Proteinuria, if present 
 
2.2 
Patients with preexisting hypertension (i.e., those for whom “hypertension” is entered as a concomitant 
condition at study entry, or those who are currently receiving therapy with antihypertensive 
medication) – also record: 
• 
Date of HTN diagnosis (original) 
• 
Type HTN (essential or secondary) 
• 
CTCAE v3.0 grade of HTN (at time of study entry) 
• 
Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of the following: 
- 
Antihypertensive agents taken at study entry 
- 
Antihypertensive agents taken in past (e.g., discontinued for toxicity, lack of efficacy) 
 
3.0 
Follow up BP data collection (during study) 
3.1 
All patients (at each clinic visit) 
• 
Current BP 
• 
Proteinuria, if present 
 
3.2 
Patients with treatment-emergent hypertension [defined as BP increase of >20 mmHg (diastolic) OR 
BP >150/100 (if previously within normal limits)] – record at time of hypertension diagnosis and at all 
subsequent clinic visits: 
• 
BP changes from baseline (or from previous assessment) (specify CTCAE v3.0 grade 
changes) 
• 
Hypertension-related symptoms as reported by patient (e.g., headache) 
• 
Other relevant changes associated with development of hypertension (e.g., ECG 
abnormalities) 
• 
Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of currently 
prescribed antihypertensive agents 


NCI 7713; PHL062 
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69 
 
3.3 
Patients with preexisting hypertension at study entry – record at each clinic visit 
• 
BP changes from previous clinic visit (specify CTCAE v3.0 grade changes) 
• 
Hypertension-related symptoms reported by patient (e.g., headache) 
• 
Other relevant changes associated with development of hypertension (e.g., ECG 
abnormalities) 
• 
Changes in antihypertensive medications since last assessment (e.g., dose change, 
add/discontinue drug) 
 
Classes of antihypertensive drugs include ACE inhibitors, calcium channel blockers, alpha blockers, beta blockers, 
diuretics, angiotension II receptor antagonists. 


NCI 7713; PHL062 
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70 
Management of Sunitinib-Induced Hypertension* 
 
 
 
 
 
Mild Hypertension 
140-149 / 90-99   
Persistent Moderate Hypertension 
140-179 / 90-109 
Persistent Severe Hypertension 
>180 / >110 
Consider long-acting DHP CCB at initial 
dose. 
→  partial or no control, ↑  dose in 
stepwise fashion until BP control 
Start/add a long-acting DHP CCB at intermediate 
dose.  If partial or no control,, ↑ to maximum dose 
until BP control (at least down to mild 
hypertension) 
WORSENS 
No Control 
WORSENS 
Asymptomatic 
SYMPTOMATIC 
Add 2nd /additional drug (BB, ACEI, ARB, or ABB) 
→  partial or no control, ↑  dose in stepwise fashion 
until BP control. 
No Control 
WORSENS 
• Hold sunitinib 
• Start / add 2-drug combination (DHP CCB, 
BB, ACEI, or ARB) 
• ↑  dose(s) in stepwise fashion until BP control 
• When BP controlled, may start sunitinib per 
protocol 
No Control and 
Asymptomatic 
No Control AND 
SYMPTOMATIC 
Add 3rd and 4th drug at initial 
dose 
↑ dose(s) in stepwise fashion 
Add 3rd and 4th additional drug (BB, ACEI, ARB, or ABB) 
→  partial or no control, ↑ dose in stepwise fashion until BP control 
OR 
Hold sunitinib and restart when BP controlled per protocol. 
No Control and 
Asymptomatic 
No Control 
WORSENS 
↓ sunitinib by one further 
dose level 
OR 
Stop sunitinib 
↓ sunitinib by one dose level 
OR 
Stop sunitinib 
• Stop sunitinib 
• Consider hospitalization for 
close monitoring and IV 
therapy 
• Treat as hypertensive crisis. 
PLEASE NOTE: 
• These are guidelines only 
• Investigators should use them  at their 
own discretion 
• 24-48 hrs are suggested as an elapsed 
time between decision steps unless 
persistent severe hypertension occurs. 
DHP CCB (Dihydropyridine Calcium-Channel Blockers); BB (selective Beta blockers); ACEIs (Angiotensin Converting Enzyme Inhibitors); ARBs (Angiotensin II Receptor Blockers);  ABB (alpha and beta blocker) 
* This appendix contains 
additional information on 
hypertension management and a 
list of oral antihypertensive 
medications 


NCI 7713; PHL062 
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71 
 
APPENDIX H 
DATA MANAGEMENT GUIDELINES 
 
Case Report Form Submission Schedule 
 
Data required for the study will be collected in Case Report Forms provided by the PMH Phase 2 
Consortium Central Office.  The form submission schedule is outlined below. 
 
Case Report Form 
Submission Schedule 
Eligibility Checklist 
At the time of registration 
Baseline Form 
Within 3 weeks of on study date 
On Treatment Form 
Within 3 weeks of the end of each 
cycle of treatment 
Off Treatment Form 
Within 3 weeks of the patient 
coming off-study 
Short Follow-up Form 
Within 3 weeks of the patient 
coming to clinic.  Required every 
3 months until death. 
Final Report Form 
Within 3 weeks of the patient's 
death being known to the 
investigator unless this constitutes 
a reportable adverse event when it 
should be reported according to 
CTEP-AERS guidelines 
 
Case Report Form Completion 
 
Case Report Forms must be completed using black ink.  Any errors must be crossed out so that 
the original entry is still visible, the correction clearly indicated and then initialed and dated by 
the individual making the correction. 
 
Case Report Forms will be submitted to the PMH Phase 2 Consortium Central Office along with 
relevant supporting documentation such as scans, progress notes, nursing notes, bloodwork, 
pathology reports etc.  All patient names or other identifying information will be removed prior 
to being sent to the Central Office and the documents labeled with patient initials, study number 
and the protocol number.  
 
Monitoring 
 
Central data monitoring will take place throughout the trial at the Central Office.  On- site 
monitoring will be performed generally at least once a year at some participating sites. 
 
Once data has been checked and quality assurance performed, it will be entered into an Oracle 
based relational database by Central Office staff.  Further data quality checks will be performed 
and then the required information will then be submitted to CDUS quarterly. 


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Patient Registration 
 
Prior to registering a patient, each institution must have submitted all necessary regulatory 
documentation to the PMH Phase 2 Consortium Central Office.  CRF's will only be sent once 
this has been received. 
No patient can receive protocol treatment until registration with the Central Office has taken 
place. 
Each site should call the PMH Phase 2 Consortium Central Office to register the patient.  Please 
call the study coordinator on the front page or 416-946-4501 ext. 4724 or pager # 416-790-8163.   
The eligibility checklist must be completed and signed by the investigator prior to registration 
and faxed into the Central Office at 416-946-2016.   
There will be no exceptions to eligibility criteria allowed at the time of registration.  Any 
possible exceptions must be discussed in advance with the program manager and the Principal 
Investigator. 
Upon receipt of the completed eligibility checklist the Central Office will confirm registration 
and dose level and issue a study number. This will then be confirmed in writing. 
 
Regulatory Requirements 
 
Please submit all required documents to the PMH Phase 2 Consortium Central Office. 
Principal investigators must submit a completed Qualified Investigator Undertaking. 
All principal investigators must submit a completed FDA form 1572. 
All investigators must have an NCI investigator number on file with the PMH Phase 2 
Consortium Central Office. 
All investigators must have an up-to-date CV on file with the PMH Phase 2 Consortium Central 
Office. 
Laboratory certification/accreditation and normal ranges are required 
Confirmation of all investigators having undergone training in the Protection of Human Research 
Subjects is required.  It is preferred that other staff involved in the trial also undergo such 
training. 
OPRR assurance numbers for each institution are required 
Consent forms must be reviewed by the Central Office before submission to the local ethics 
regulatory board (REB/IRB) and must include a statement that 1. information will be sent to and 
2. medical records will be reviewed by the PMH Phase 2 Consortium Central Office. 
A Membership list of the local ethics board is required. 
A copy of the initial approval letter from the ethics board for the trial. 
Continuing approval will be obtained at least yearly until follow-up on patients is completed and 
no further data is being obtained for research purposes. 


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APPENDIX I 
CTEP MULTICENTER GUIDELINES 
 
If an institution wishes to collaborate with other participating institutions in performing a 
CTEP sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
•  Prior to the activation of the protocol at each participating institution, an OHRP form 
310 (documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports.  There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the 
Coordinating Center who in turn report to CTEP.  The Coordinating Center will submit 
AE reports to the Protocol Chair for timely review. 


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• Audits may be accomplished in one of two ways:  (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites.  If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 
 
Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
➢ The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
➢ The Coordinating Center must be designated on the title page. 
➢ Central registration of patients is required.  The procedures for registration must be 
stated in the protocol. 
➢ Data collection forms should be of a common format.  Sample forms should be 
submitted with the protocol.  The frequency and timing of data submission forms to 
the Coordinating Center should be stated. 
➢ Describe how AEs will be reported from the participating institutions, either directly 
to CTEP or through the Coordinating Center. 
➢ Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions.  
 
Agent Ordering 
• 
Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the CTEP PIO. 


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APPENDIX J 
MEDICATIONS THAT MAY CAUSE QTC PROLONGATION