A Phase II Trial In Which Patients With Metastatic Alveolar Soft Part Sarcoma Are Randomized to Either Sunitinib or Cediranib Monotherapy, With Cross-Over at Disease Progression
Phase: PHASE2
Conditions: Sarcoma, Alveolar Soft Part
Sponsor: National Cancer Institute (NCI)

Clinical Center # 11-C-0200 
CTEP # 8875 
 
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A Phase II Trial in Which Patients With Metastatic Alveolar Soft Part Sarcoma Are 
Randomized to Either Sunitinib or Cediranib Monotherapy, With Cross-Over at  
Disease Progression 
 
Abbreviated Title: Ph II Cediranib Sunitinib in ASPS 
 
Coordinating Center: 
 
 
 
 
Participating Centers: 
 
 
 
Principal Investigator:  
 
 
 
 
 
Developmental Therapeutics Clinic 
National Cancer Institute 
10 Center Drive, 12N226 
Bethesda, MD 20892 
 
Santa Monica Oncology Center 
 
 
 
A. P. Chen, MDA-E 
31 Center Drive 
Bldg 31 Room 3A44 
Bethesda, MD 20892 
Phone: (240) 781-3320 
Fax: (240) 541-4515 
chenali@mail.nih.gov 
 
Statisticians:  
 
 
 
 
 
Referral Contact: 
 
Seth M. Steinberg, PhD, BDMS/CCRE 
9609 Medical Center Dr., MSC 9716 
Phone: (240) 276-5563 
steinbes@mail.nih.gov 
 
 
Ashley Bruns, RN, DCTDA,B,E 
10 Center Drive, Bldg 10/Rm 8D53  
Bethesda, MD 20892 
Telephone: (240) 858-3162  
Fax: (301) 451-5625  
ashley.bruns@nih.gov 
 
 
Roles: Aobtains information by intervening or interacting with living individuals for research purposes; Bobtains 
identifiable private information about living individuals; Cobtains the voluntary informed consent of individuals to 
be subjects; Dmakes decisions about subject eligibility; Estudies, interprets, or analyzes identifiable private 
information or data/specimens for research purposes 
 
 
 

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CTEP # 8875 
 
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Participating Sites (open): 
 
 
Santa Monica Oncology Center 
PI: Sant P. Chawla, MD 
Sarcoma Oncology Center 
Santa Monica Oncology Center 
2811 Wilshire Blvd. #414 
Santa Monica, CA 90403 
Phone: (310) 552-9999, Fax: (310) 201-6685 
santchawla@aol.com  
FWA# 00008645 
 
IRB Contact:  
IRB of Record: WIRB 
IRB IORG #: 00000533 
3535 7th Avenue SW, Olympia, WA98502 
Phone: 1.800.562.4789 
clientservices@wirb.com 
 
Research Contact: Victoria S. Chua 
Sarcoma Oncology Center 
2811 Wilshire Blvd, Suite 414, Santa Monica, CA 
90403 
Phone Number: (310) 552-9999 
vchua@sarcomaoncology.com 
 
 
Pharmacy Contact: Kumiko Murata 
Pharma Tech 
2811 Wilshire Blvd, Suite 414, Santa Monica, CA 
90403 
Phone Number: 310.552.9999 
kmurata@sarcomaoncology.com 
 
 
 
NCI-Supplied Agents: 
Cediranib (NSC 732208) 
Sunitinib malate (NSC 736511) 
 
IND number: 
114163 
 
Version date:  
    June 3, 2022 
 
NCT Number: 
    NCT01391962 
 
 

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PRÉCIS 
Background:  
• Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor accounting for less than 1% of soft 
tissue sarcomas.  There is no effective systemic treatment for patients with metastatic ASPS.  Little is 
known with regards to relevant molecular markers as potential therapeutic targets.   
• Cediranib (AZD2171) and sunitinib (SU011248), oral small molecule inhibitors of VEGF receptor 
tyrosine kinases, are showing preliminary evidence of activity in patients with ASPS. 
Objectives:  
• Part I: Determine the objective response rate (ORR) of single-agent cediranib and single-agent 
sunitinib malate in patients with advanced ASPS. 
• Part II: Determine the ORR of cediranib in patients who progress on the sunitinib arm, and determine 
the ORR of sunitinib in patients who progress on the cediranib arm. 
• Determine the progression-free survival (PFS) at 24 weeks for single-agent cediranib and single-agent 
sunitinib malate in patients with advanced ASPS. 
• Perform pharmacokinetic analysis for cediranib. 
Eligibility: 
Status Update: Patients enrolled after Amendment G (version dated 08/16/2013), will be 
evaluated and compared to the first 13 patients by the study statistician and the Principal 
Investigator.  Patients with newly diagnosed ASPS with clinical evidence of disease progression 
will also be assessed separately.  
• Patients aged ≥ 16 years with histologically or cytologically confirmed metastatic ASPS. 
• Patients must show evidence of objective disease progression per RECIST 1 on scans within the 6 
month period immediately preceding enrollment.  Both scans used to determine disease progression 
should have been obtained within this 6-month period.      
• Patients with newly diagnosed, unresectable, measurable, metastatic ASPS who show clinical evidence 
of disease progression will be eligible. 
• Patients must not have received treatment with any VEGF receptor tyrosine kinase inhibitor (e.g., 
cediranib, sunitinib, pazopanib, sorafenib); however, prior treatment with bevacizumab is allowed. 
Design:  
• Two sets of patients will be enrolled and assessed in separate cohorts: a) patients with non-newly 
diagnosed ASPS and b) patients with newly diagnosed ASPS.   
• Part I: Patients will be randomized to receive cediranib (30 mg) or sunitinib malate (37.5 mg) orally, 
once a day in 28-day cycles.  As of Amendment Y (dated May 6, 2019), we have closed the cediranib 
arm of the newly diagnosed ASPS cohort due to inadequate activity per the statistical plan in Section 
13; all newly diagnosed ASPS patients will be assigned to the sunitinib malate treatment arm. 
• Part II: At the time of disease progression, patients will cross over to the other treatment arm after a 2-
week wash-out period.  As of Amendment Y (dated May 6, 2019), patients in the newly diagnosed 
ASPS cohort are not eligible to cross over to the cediranib treatment arm, which was closed due to 
inadequate activity. 
• Appropriate anatomic imaging studies will be performed at baseline and every 2 cycles for restaging.  
• The study will be conducted using an optimal two-stage design to rule out an unacceptably low 15% 
clinical response rate (PR+CR) in favor of a modestly high response rate of 40%.  The study will 
initially enroll 10 evaluable patients in each arm.  If 0 or 1 of the 10 patients has a clinical response, 
then no further patients will be accrued.  If 2 or more the first 10 patients have a response, then accrual 
continues to a total of 22 patients in each arm. 
   

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SCHEMA 
 
As of Amendment Y (dated May 6, 2019), we have closed the cediranib arm of the newly 
diagnosed ASPS cohort due to inadequate activity per the statistical plan in Section 13.  All 
newly diagnosed ASPS patients will be assigned to the sunitinib malate treatment arm; they will 
not cross over to the cediranib treatment arm, which was closed due to inadequate activity. 
 
Part I:  Patients will be randomized to receive cediranib (30 mg) or sunitinib malate (37.5 mg) orally, 
once a day, in 28-day cycles.  Part I is a two-stage design in which 10 patients are initially 
enrolled in each arm.  If 0 or 1 of the 10 patients has a clinical response, then no further 
patients will be accrued.  That treatment arm will be closed to the accrual of new patients 
and the crossover of patients who progressed on the other agent.  If 2 or more the first  
10 patients have a response, then accrual would continue until a total of 22 patients have 
enrolled in that arm.   
Part II: At the time of disease progression (documented by RECIST 1), patients will cross over to 
the other treatment arm after a 2-week wash-out period (unless the other arm has been 
closed due to inadequate activity or unacceptable toxicity).  
 
a Objective disease progression per RECIST 1 must be documented on scans within the 6 month 
period immediately preceding enrollment.  Both scans used to determine disease progression 
should have been obtained within this 6-month period.  Appropriate anatomic imaging studies will 
be performed at baseline (within 28 days prior to enrollment) and every 2 cycles on study for 
restaging. 
b Blood samples for PK analyses will be collected in 4 cc EDTA (purple top) tubes pre-dose, and at 
the following time points prior to drug administration on that day: cycle 1 day 15, C2D1, C3D1, 
and C4D1.  PK analysis will be performed only on samples from patients on cediranib (both as 
upfront therapy and following cross-over).  No PK sampling and analysis will be done for patients 
receiving sunitinib.  
Part I (until disease progression) 
Part II 
Sunitinib 
Cediranib 
Randomizationa 
OR 
Cediranib 
WASHOUT 
Sunitinib 
Restaginga 
PK 
samplingb 

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TABLE OF CONTENTS 
PRÉCIS ............................................................................................................................... 3 
SCHEMA ............................................................................................................................ 4 
TABLE OF CONTENTS .................................................................................................... 5 
1 
STUDY OBJECTIVES .............................................................................................. 8 
1.1 
Primary Objectives ................................................................................................8 
1.2 
Secondary Objectives ............................................................................................8 
2 
BACKGROUND AND RATIONALE ...................................................................... 8 
2.1 
Alveolar Soft Part Sarcoma (ASPS)......................................................................8 
2.2 
Cediranib (AZD2171) .........................................................................................11 
2.3 
Sunitinib Malate ..................................................................................................20 
2.4 
Rationale ..............................................................................................................29 
2.5 
Correlative Studies Background..........................................................................29 
3 
PATIENT SELECTION .......................................................................................... 30 
3.1 
Eligibility Criteria ...............................................................................................30 
3.2 
Exclusion Criteria ................................................................................................32 
3.3 
Research Eligibility Evaluation ...........................................................................33 
3.4 
Inclusion of Women and Minorities ....................................................................33 
4 
REGISTRATION PROCEDURES ......................................................................... 35 
4.1 
Investigator and Research Associate Registration with CTEP ...........................35 
4.2 
Patient Registration .............................................................................................36 
5 
TREATMENT PLAN .............................................................................................. 37 
5.1 
Drug Administration ...........................................................................................39 
5.2 
General Concomitant Medication and Supportive Care Guidelines ...................40 
5.3 
Duration of Therapy ............................................................................................43 
5.4 
Duration of Follow-up .........................................................................................44 
5.5 
Criteria for Removal From Study ........................................................................44 
6 
DOSING DELAYS/MODIFICATIONS ................................................................. 44 
6.1 
Dose Modifications .............................................................................................44 
6.2 
Cediranib .............................................................................................................45 
6.3 
Sunitinib ..............................................................................................................46 
6.4 
Dose Reduction ...................................................................................................48 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .................. 49 
7.1 
Comprehensive Adverse Events and Potential Risks Lists .................................49 
7.2 
CTEP Reporting Requirements ...........................................................................58 
7.3 
NIH IRB Reporting Requirements ......................................................................61 
8 
PHARMACEUTICAL INFORMATION ................................................................ 62 
8.1 
Cediranib (NSC 732208) .....................................................................................62 
8.2 
Sunitinib Malate (NSC 736511) ..........................................................................64 
8.3 
Agent Ordering and Agent Accountability .........................................................65 
9 
CORRELATIVE STUDIES .................................................................................... 66 

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9.1 
Laboratory Contact ..............................................................................................66 
9.2 
Timing of Biopsies ..............................................................................................67 
9.3 
Biopsy Procedure ................................................................................................67 
9.4 
Processing of Patient Tumor Samples For RNA Analysis ..................................68 
9.5 
Processing of Frozen Tumor Samples .................................................................69 
9.6 
Sample Collection and Processing ......................................................................69 
10 
STUDY CALENDAR ............................................................................................. 70 
11 
MEASUREMENT OF EFFECT.............................................................................. 72 
11.1 Antitumor Effect – Solid Tumors ........................................................................72 
12 
DATA REPORTING / REGULATORY REQUIREMENTS ................................. 77 
12.1 Data Reporting ....................................................................................................77 
12.2 Data Safety and Monitoring Plan ........................................................................77 
12.3 Multicenter Guidelines ........................................................................................78 
12.4 Cooperative Research and Development Agreement (CRADA) / Clinical Trials 
Agreement (CTA) ..........................................................................................................79 
12.5 Publication Policy ...............................................................................................81 
13 
STATISTICAL CONSIDERATIONS..................................................................... 82 
13.1 Sample Size/Accrual Rate ...................................................................................83 
14 
HUMAN SUBJECTS PROTECTION .................................................................... 84 
14.1 Rationale for Subject Selection ...........................................................................84 
14.2 Justification for Exclusions .................................................................................84 
14.3 Participation of Children .....................................................................................84 
14.4 Evaluation of Benefits and Risks/Discomforts ...................................................85 
14.5 Consent and Assent Process and Documentation ...............................................85 
14.6 Procedure for Protecting Against or Minimizing Any Potential Risks ...............86 
REFERENCES ................................................................................................................. 88 
Appendix A: Performance Status Criteria ........................................................................ 98 
Appendix B: New York Heart Association Classification of Cardiac Disease ................ 99 
Appendix C: Potential Cytochrome P450 (CYP) Drug Interactions .............................. 100 
Appendix D: Enzyme-Inducing Anticonvulsant Drugs .................................................. 101 
Appendix E: Medications That May Cause QTc Prolongation ...................................... 102 
Appendix F: Eligibility/Pre-Registration Worksheet...................................................... 104 
Appendix G: Study Diary ............................................................................................... 111 
Appendix H: Blood Pressure Collection and Recording ................................................ 117 
Appendix I: Management of Hypertension ..................................................................... 119 
Appendix J: LVEF Dose Modification Table ................................................................. 122 
Appendix K: CTEP Multicenter Guidelines ................................................................... 123 

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Appendix L:  Information on Possible Interactions with Other Agents for Patients and their 
Caregivers and Non-study Health Care Team ................................................................ 125 
Appendix M: Informed Consent Form Template for Cancer Treatment Trials .............. 129 
Appendix N: Shipping Manifest to NCI ......................................................................... 143 
Appendix O: PK Evaluation of Cediranib ...................................................................... 144 

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1 STUDY OBJECTIVES  
1.1 
Primary Objectives 
• 
Part I: Determine the objective response rate (ORR) of single agent cediranib and 
single-agent sunitinib malate in patients with advanced ASPS. 
• 
Part II: Determine the ORR of cediranib in patients who progress on the sunitinib arm, 
and determine the ORR of sunitinib in patients who progress on the cediranib arm. 
1.2 
Secondary Objectives 
• 
Determine the progression-free survival (PFS) at 24 weeks for single-agent cediranib 
and single-agent sunitinib malate in patients with advanced ASPS. 
• 
Evaluate gene expression in tumor biopsies obtained at baseline and after treatment (at 
the Clinical Center, NCI only).  With Amendment H (version dated 11/20/2013), 
biopsies will no longer be performed as part of this study. 
• 
Perform pharmacokinetic analysis for cediranib. 
 
2 BACKGROUND AND RATIONALE 
2.1 
Alveolar Soft Part Sarcoma (ASPS)  
Alveolar soft part sarcoma (ASPS) is a rare tumor accounting for less than 1% of soft tissue 
sarcomas.  The total number of new soft tissue sarcoma cases in the United States in 2010 is 
estimated to be 10,520 (American Cancer Society, 2010), which predicts approximately 100 new 
cases of ASPS in the United States annually.  The rarity of this disease is exemplified by the 
number of cases of ASPS seen at major centers (Daigeler et al., 2008; Lieberman et al., 1989), 
such as 74 cases at MD Anderson from 1959 to 1998 (Portera et al., 2001) and 57 cases from a 
Japanese registry of 27 centers over a period of 25 years (Ogose et al., 2003). 
 
ASPS occurs most frequently in patients between 15 and 35 years of age and is more prevalent in 
females than in males; prognosis is better in patients presenting at a younger age.  The tumors 
present as slow-growing, painless masses involving almost every part of the body but 
predominantly in the trunk and the proximal extremities.  Metastatic disease usually occurs 
earlier than with most other soft tissue sarcomas and is frequently observed at presentation.  On 
the whole, ASPS is poorly circumscribed as it typically grows in an organoid or nest-like 
arrangement.  Lung, brain, and bone are the most common sites of metastasis.  In a retrospective 
study of 11 patients with ASPS (Daigeler et al., 2008), time of tumor growth (in the thigh, lower 
leg, thoracic wall, upper arm, forearm, and foot) before definite diagnoses ranged from 1 month 
to 20 years.  A correlation between the duration of untreated tumor growth and outcome could 
not be detected.  All tumors were located intramuscularly or subfascially and tumor size ranged 
from 2.9 to 13.5 cm.  The tumors grow slowly, with patients remaining asymptomatic for years, 
even with metastatic disease.  However, the ultimate prognosis of this disease is poor (Daigeler 
et al., 2008; Brennan et al., 2001; Reichardt et al., 2003)   

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Median survival time following initial diagnosis is 11.4 years, with acturial overall survival (OS) 
of 74% and 51% at 5 and 10 years, respectively (Lazar et al., 2007).  There is no effective 
treatment including radiation and chemotherapy for patients with metastatic ASPS.  Given the 
rarity of the disease, reports regarding overall prognosis are limited.  One of the largest series 
comes from a retrospective review of 74 patients with ASPS treated at MD Anderson Cancer 
Center (Portera et al. 2001).  The majority (n = 48) of these patients presented with advanced, 
metastatic disease; 33 patients received treatment, of which 26 patients with metastatic disease 
and 3 patients with localized disease received systematic chemotherapy.  Only one of the 33 
patients responded to systemic therapy.  The 5-year overall survival rate for the 33 
patients with metastatic ASPS was 20%.  Median survival was 40 months.  In a Japanese study 
of 47 patients with metastatic ASPS, there were no objective responses to systemic intravenous 
therapy (Ogose et al, Oncology 2003).  Based on the review of the literature which revealed lack 
of observed objective responses to standard chemotherapies and an overall poor prognosis of 
20% overall survival at 5 years for patients with advanced metastatic ASPS, we feel that the 
response rate of 40% targeted in our study is sufficiently high to assess drug activity. 
 
The origin of ASPS remains unclear.  The disease is associated with t(X;17)(p11;q25) 
translocation resulting in ASPL-TFE3 fusion protein, which activates microphthalmia 
transcription factor (MiT), resulting in over-expression of MET.  MET is the receptor for 
hepatocyte growth factor (HGF), affecting cell survival, adhesion, invasion and migration, and 
angiogenesis.  ASPS is a highly vascular tumor as evidenced by radiologic studies and gene 
expression studies showing upregulation of genes involved in angiogenesis (Stockwin et al., 
2009).  Results from a gene expression profiling study performed at the NCI identified several 
transcripts associated with angiogenesis, cell proliferation, metastasis, and myogenic 
differentiation—the latter suggesting muscle as the cellular origin of this disease (Figure 1).  The 
study collected tumor samples from 7 patients with primary or metastatic ASPS and used 
microarray analysis and quantitative RT-PCR to compare levels of patient RNA (reverse 
transcribed to cDNA) with that of a universal reference set from healthy adults (Figure 1) 
(Stockwin et al., 2009).  Among the angiogenesis-associated transcripts were c-MET and 
vascular endothelial growth factor (VEGF), a key angiogenic factor implicated in tumor blood 
vessel formation and in disease progression in a range of solid tumor malignancies (Hicklin et 
al., 2005).   
 
Correlative studies comparing pre- and post-treatment biopsy specimens from individual patients 
with ASPS would therefore be expected to provide invaluable data about the pathogenesis of this 
disease and the mechanism of action of the therapeutic agent.  ASPS has been termed a chemo-
insensitive tumor, and finding an effective treatment for this rare, slow-growing disease remains 
a challenge (Daigeler et al., 2008).  None of the studies with standard chemotherapeutic 
regimens reports a substantial benefit for this disease.  Chemotherapeutic regimens previously 
assessed include cisplatin, carboplatin, etoposide, vincristine, adriamycin, epiadriamycin, 
cyclophosphamide, actinomycin, and ifosfamide (Ogose et al., 2003; Casanova et al., 2000; 
Kayton et al., 2006).  Reichardt et al. (2005) reported that chemotherapeutic regimens used for 
the treatment of other soft tissue sarcomas lack efficacy in ASPS.  Benefit was observed only in 
patients undergoing tumor resection in combination with chemotherapy, radiotherapy, or both, 
and complete surgical resection has been suggested as the therapy of choice (Anderson et al., 
2005).   

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Figure 1: Heatmap of a subset of aberrantly expressed genes from 7 patients with ASPS 
identified by microarray/qRT-PCR analysis (Stockwin et al., 2009).   
 
Interferon alpha-2b treatment of patients with ASPS was shown to be of some benefit (Bisogno 
et al., 2005; Kuriyama et al., 2001; Roozendaal et al., 2003), but the most promising systemic 
treatment was reported in 2006, when a case report indicated tumor regression in a patient with 
disseminated ASPS during antiangiogenic treatment with bevacizumab, an antibody against 
VEGF.  It was concluded that inhibition of the VEGF signaling pathway alone or in combination 

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with drugs targeting other proangiogenic factors could be an important new treatment option for 
patients with ASPS (Azizi et al., 2006). 
 
Approximately 10 clinical trials are currently recruiting patients with ASPS 
[http://clinicaltrials.gov].  These include trials with vorinostat and bortezomib; oral gamma-
secretase inhibitor RO4929097 with or without oral hedgehog antagonist GDC-0449; radiation 
therapy; combination chemotherapy with doxorubicin and ifosfamide, and/or surgery; dasatinib 
(an oral dual BCR/ABL and tyrosine kinase inhibitor); and various combination chemotherapy, 
surgical, and radiotherapy techniques.  Common inclusion criteria for these studies of ASPS 
include progressive, unresectable, recurrent or metastatic histologically confirmed disease that 
has either not been treated or is nonresponsive to standard therapies.   
 
2.2 
Cediranib (AZD2171) 
Cediranib (AZD2171, Recentin™; 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-
pyrrolidin-1-ylpropoxy) quinazoline maleate; AZD2171 maleate) is a member of an emerging 
class of novel orally-administered small molecule VEGF receptor tyrosine kinase (TK) inhibitors 
with anti-angiogenic properties (Hennequin et al., 1999; Wedge et al., 2005). 
 
Mechanism of Action 
VEGF is a key angiogenic factor, and has been implicated in tumor blood vessel formation and 
in disease progression in a range of solid tumor malignancies (Hicklin and Ellis, 2005).  Two 
high-affinity VEGF transmembrane receptors (VEGFRs) with associated TK activity have been 
identified on human vascular endothelium, VEGFR-1 (also known as fms-like tyrosine kinase 1 
or Flt-1) and VEGFR-2 (also known as kinase insert domain-containing receptor or KDR) 
(Ferrara et al., 2003).  VEGFR-1 and VEGFR-2 signaling help mediate tumor progression.  
Cediranib has been developed as a potent inhibitor of VEGFR-1 and VEGFR-2 (Wedge et al., 
2005).  Cediranib also has activity against VEGFR-3 and c-Kit (Jurgensmeier et al., 2005).  
Cediranib is expected, with chronic oral dosing, to inhibit VEGF-driven angiogenesis and as a 
result prevent the progression and metastasis of solid tumors, and may have broad-spectrum 
clinical utility.   
 
Nonclinical Efficacy 
The effect of cediranib was studied in athymic nu/nu mice bearing established subcutaneous 
human tumor xenografts of diverse histologies [SW620 (colon), PC-3 (prostate), Calu-6 (lung), 
SKOV-3 (ovarian), and MDA-MB-231 (breast)].  Animals were administered cediranib orally 
(PO) at doses from 0.75-6 mg/kg/day (2.25-18 mg/m2/day) in a constant volume of 0.1 mL/10 g 
body weight for 24-28 days.  Cediranib produced a statistically significant inhibition of tumor 
growth in all human tumor types examined when dosed at 1.5 mg/kg/day (4.5 mg/m2/day) or 
higher.   
 
The murine renal cell carcinoma (RENCA) model, which rapidly (generally within 10 days) 
metastasizes to the lung and abdominal lymph nodes, has also been used for efficacy studies 
(Drevs et al., 2004).  In experiments incorporating a vehicle control, cediranib (at a dose of 

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6.3 mg/kg/day PO) reduced primary tumor growth, metastasis, and microvessel density more 
potently than any other previously studied VEGF RTK inhibitor reported in the literature. 
 
Using a transgenic mouse model in which multiple mammary tumors spontaneously develop 
after two pregnancies, investigators studied the temporal effects of cediranib administration 
(Klinowska et al., 2004).  When dosed with cediranib (0.75-6 mg/kg/day PO) at the time early 
lesions start to develop, the number of tumor foci was not affected, but their growth was 
inhibited.  When tumors were well established before cediranib was given (at doses of 3 and 
6 mg/kg/day), dose-dependent growth inhibition occurred as well as tumor regression. 
 
Further details of the non-clinical efficacy of cediranib can be found in Section 4.1 of the 
Investigator’s Brochure (2009). 
 
Nonclinical Pharmacology and Toxicology 
Nonclinical pharmacology and toxicology company-sponsored studies have been conducted in 
rats, dogs, and cynomolgus monkeys.  In rats and dogs, oral bioavailability is high, but 
absorption is relatively slow, with peak plasma concentration (Cmax) of the agent seen 4-6 hours 
after oral dosing.  Plasma concentrations and exposure are generally linear over the dose ranges 
studied in rats.  Cediranib is excreted in the feces (>70% of the dose) of rats, dogs, and 
cynomolgus monkey after both oral and intravenous administration.  Elimination was rapid in 
rats and monkeys with over 75% of the dose being recovered in the first 48 hours; in dogs, 
excretion was slightly slower but again substantially complete by 7 days. 
 
Over the dose ranges examined in the rat, plasma concentrations and exposure generally 
increased in proportion to dose; however, in monkeys, plasma cediranib concentration-time 
profiles obtained following a single oral dose indicated that systemic exposure increased in a 
greater than dose-proportional manner over the dose range 0.05-2.5 mg/kg. 
 
Protein binding of cediranib (90-95%) was relatively high across all species examined and was 
independent of concentration (range: 0.03-10 mcg/mL) and gender.  Cediranib was 
approximately 95% bound to human plasma proteins, with human serum albumin and α1-acid 
glycoprotein accounting for most of this binding.   
 
VEGF has three major biological activities in endothelial cells of rats and primates of the age 
groups used in the nonclinical studies.  It is an important angiogenic factor, a potent 
physiological mediator of vascular tone (specifically of vasodilation), and a potent modulator of 
capillary permeability inducing endothelial cell fenestrations.  VEGF receptor inhibition was 
therefore considered to be the cause of many of the pathophysiological changes encountered. 
 
Vascular (myocarditis, choroid plexus) and renal (glomerulosclerosis and tubular degeneration) 
pathologies have been seen in rat, dog, and primate dosed with cediranib which are considered to 
be consistent with lesions induced by hypertension, although a direct effect by cediranib on these 
tissues cannot be excluded.  Pathological findings were also seen in the adrenal glands 
(degenerative cortical changes), pancreas (acinar epithelial cell necrosis), thyroid (follicular 
epithelial cell atrophy), liver (hepatocyte necrosis), and biliary system (cholangitis and bile duct 

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proliferation and bile duct cholangitis) of the rat.  In addition, in the primate, changes were seen 
in the gallbladder (mucosal hypertrophy) and bile duct (hyperplasia/hypertrophy). 
 
Cediranib did not induce rat hepatic microsomal P450 activity but caused a 40-60% reduction in 
CYP1A activity at the 5 mg/kg dose level.  This may indicate suppression of CYP1A or be 
related to decreased liver weight.  This change was not considered significant.  Inhibition studies 
in vitro using human hepatic microsomal protein gave IC50 values for cediranib against CYP2D6, 
CYP3A4 testosterone, and CYP3A4 midazolam of 32.9, 16.2, and 21.4 mcg/mL, respectively; 
these concentrations were in excess of those found in current clinical studies and would therefore 
not be expected to cause clinically significant drug interactions through inhibition of P450-
mediated metabolism of co-administered agents.  For CYP1A2, CYP2A6, CYP2C8, CYP2C9, 
CYP2C19, and CYP2E1, the IC50 values were outside the concentration range of cediranib 
examined.  
 
Further details of the nonclinical pharmacology and toxicity of cediranib can be found in 
Sections 4.2 and 4.3 of the Investigator’s Brochure (2009), respectively. 
 
Clinical Pharmacology 
Preliminary pharmacokinetics (PK) information indicates a time to maximum serum 
concentration  (Tmax) of 2 hours (range, 2-6 hours), a maximum serum concentration (Cmax) of 
107.8 ± 29.8 ng/mL, and a distribution half-life  (t1/2) of 12.1 ± 2.2 hours (Sridhar et al., 2008). 
 
In vitro studies suggested that CYP enzymes were not significantly involved in the production of 
the principle human metabolites of cediranib, therefore co-administration of known inhibitors or 
inducers of hepatic CYP enzymes would not be expected to have significant effects on the 
clearance of cediranib.  However, since potent inhibitors or inducers of CYP enzymes can also 
affect drug disposition by interaction with transporter proteins and phase II metabolism, 
2 clinical studies were conducted to investigate the PK of cediranib when co-administered with a 
potent inhibitor (ketoconazole,) and a potent inducer (rifampicin) of CYP enzymes.  Co-
administration of ketoconazole 400 mg modestly increased the AUCss and Css,max of cediranib 
20 mg.  Co-administration of rifampicin 600 mg resulted in a decrease in the AUCss and Css,max 
of cediranib 45 mg.  In both studies, due to the relatively small magnitude of change in AUCss 
and Css,max and the known PK variability of cediranib, the effect was not considered to be 
clinically significant (Investigator’s Brochure, 2009).  
 
Preliminary information on blood biomarkers in glioblastoma patients indicates that plasma 
VEGF, placental growth factor (PIGF), and stromal cell-derived factor-1 (SDF1) were 
increased after treatment, and plasma PIGF and VEGF decreased upon cediranib discontinuation.  
Plasma basic fibroblast growth factor (bFGF) and SDF1 and viable circulating endothelial cells 
(CECs) increased when tumors escaped treatment with cediranib (Batchelor et al., 2008). 
 
Additional information on the relationship between clinical outcome and biomarkers has been 
reported for a DCTD-sponsored trial (Sorensen et al., 2009).  Changes in vascular 
permeability/flow as measured by magnetic resonance imaging (MRI) methods (Ktrans), 
microvessel volume, and circulating collagen IV levels were determined.  Of the 30 patients in 
the trial, all three parameters were reliably measured in 28.  A greater reduction in Ktrans after one 

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dose of cediranib was seen in patients with increased progression-free survival (PFS) (P=0.0015) 
and overall survival (OS) (P=0.0039).  A greater increase in the calculated blood volume (CBV) 
of tumor microvessels after one dose of cediranib was seen in glioblastoma patients with 
extended OS (P=0.0056).  A greater increase in collagen IV levels in plasma was detected in 
patients with extended PFS (P=0.0010).  Peripheral blood was evaluated serially for VEGF 
concentration and CECs in another trial (Ramalingam et al., 2008).  A stark increase in CECs 
was noted at progression in several patients 
 
Adverse Events and Efficacy 
Hypertension is an expected pharmacologic effect of agents that inhibit VEGF, and is one of the 
most common adverse events (AEs) reported in trials of cediranib.  Dose-related increases in 
thyroid stimulating hormone (TSH) and decreases in total thyroxine have been observed at doses 
of 30 mg and above, and are most marked at 60 mg.  The most frequently reported AEs on 
company-sponsored trials were fatigue, diarrhea, nausea, vomiting, hoarseness, hand-foot 
syndrome, and hypertension (Investigator’s Brochure, 2009).  The recommended dose for 
monotherapy is 30 mg/day; the recommended dose in combination with chemotherapy agents is 
20 mg/day, although exceptions to these doses may be appropriate in other studies, depending on 
age, patient population, tumor type, or agent(s) given in combination with cediranib. 
 
Complete responses (CRs) and partial responses (PRs) have been reported in clinical trials of 
cediranib in solid tumors such as non-small cell lung cancer (NSCLC) (Gadgeel et al., 2009), 
renal cell carcinoma (RCC) (Sridhar et al., 2008), prostate (Karakunnel et al., 2009), 
mesothelioma (Garland et al., 2009), and gynecologic tumors (Hirte et al., 2008; Matulonis et 
al., 2009). 
 
Clinical Experience 
AstraZeneca has sponsored a total of 15 phase 1 studies of cediranib (single-agent or in 
combination with gefitinib, either FOLFOX, irinotecan [±cetuximab], pemetrexed or docetaxel, 
etoposide/cisplatin, or lomustine), 8 phase 2 studies (single-agent, or in combination with 
fulvestran, FOLFOX, or paclitaxel/carboplatin), one phase 2/3 study (cediranib plus 
bevacizumab), and two phase 3 studies (cediranib plus FOLFOX or XELOX and cediranib plus 
lomustine).  Details of the studies, responses, and safety assessments are summarized in the 
Investigator’s Brochure (2009). 
 
Cediranib has been administered to patients in 23 DCTD, NCI-sponsored clinical trials. 
 
The MTD for cediranib in combination with temozolomide and radiation was established at 
30 mg/day.  Cediranib was then administered at 45 mg/day in a post-radiation setting, and in 
addition to the expected AEs of hypertension, fatigue, and palmar/plantar erythema, one patient 
discontinued due to grade 3 transaminase elevation and one patient required dose reduction to 
15 mg/day due to proteinuria (Chi et al., 2009) 
 
Among 31 patients in a phase 2 trial of cediranib in recurrent glioblastoma, radiographic PRs 
were reported in 16 (Batchelor et al., 2008).  Progression-free survival (PFS) was 117 days, and 
overall survival (OS) was 221 days.  Additionally, cediranib alleviated brain edema, a major 

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cause of morbidity in glioblastoma patients.  Dose-limiting toxicities (DLTs) were observed in 9 
of the 16 patients with hypertension; fatigue and diarrhea were seen most often. 
 
An interim analysis of 19 of 28 patients accrued to a study of cediranib in hepatocellular 
carcinoma (HCC) reported that 16 of the 19 developed grade 3 AEs (Alberts et al., 2007).  
Fatigue, hypertension, and anorexia accounted for the majority of the AEs. 
 
Response information for 45 of 46 patients on a trial of cediranib in malignant pleural 
mesothelioma reported tumor response by RECIST in 4/45 patients; 2 patients with bulky 
disease had 56% and 91% tumor shrinkage, respectively; 15/45 had stable disease (SD); 21/45 
had progressive disease (PD); and one patient suffered early death (Garland et al., 2009).  For 46 
patients, median PFS was estimated at 3 months, median OS at 10 months.  Overall disease 
control rate (complete response [CR]/partial response [PR]/stable disease [SD]) was 42% by 
RECIST.  Eight grade 4 events were reported:  cognitive disturbance, colitis, confusion, ileal 
perforation, hypertension, hyponatremia, hypotension, and renal failure. 
 
Among 47 evaluable patients receiving cediranib in a trial in ovarian, primary peritoneal serous, 
or fallopian tube cancer, the clinical benefit rate was 30%; eight patients had a PR and six had 
SD; there were no CRs (Matulonis et al., 2009).  Median PFS was 5.2 months, and median OS 
had not been reached after a median follow-up time of 10.7 months.  Grade 4 AEs included CNS 
hemorrhage, lipase, and hypertriglyceridemia/hypercholesterolemia/elevated lipase, and 
dehydration/elevated creatinine.  Grade 3 AEs include hypertension, fatigue, and diarrhea.  
Hypertension occurred in 87% of the patients by the end of the study; in 43%, it was grade ≥3 
(Robinson et al., 2010).  Grade 2 hypothyroidism occurred in 43% of patients.  
 
Preliminary information from 60 patients in a phase 2 trial of cediranib in persistent ovarian, 
peritoneal, or fallopian tube cancer has been reported (Hirte et al., 2008).  Patients were divided 
into those whose disease was found to be platinum-resistant and those whose disease was 
platinum-sensitive in a prior therapy regimen.  Response and prolonged SD rate was 41% for 
platinum-sensitive and 29% for platinum-resistant patients, respectively.  In the platinum-
sensitive group, there were two confirmed PRs and one unconfirmed PR, while one unconfirmed 
PR was observed in the platinum-resistant arm.  Median time to progression (TTP) and median 
survival for all patients was 4.1 months and 11.9 months, respectively, with no significant 
differences between the platinum-sensitive and -resistant groups.  The most frequent AEs were 
fatigue, diarrhea, hypertension, and anorexia, while hypertension and fatigue were the most 
frequent grade 3 or higher AEs.  Sixteen patients required dose reduction to 30 mg and 20 mg. 
 
Information on 34 patients in a trial of cediranib in metastatic androgen-independent prostate 
cancer has been reported (Karakunnel et al., 2009).  There have been 13 of 23 evaluable patients 
with tumor shrinkage (4 have met the criteria for PR).  Decreases in lymph node metastases as 
well as in lung, liver, and bone lesions have occurred.  Grade 3 AEs included vomiting, 
prolonged QTc interval, muscle weakness, weight loss, dehydration, fatigue, hypoxia, renal 
failure, transaminitis, and anorexia. 
 
Thirty-two of 43 patients enrolled in a trial of cediranib in renal cell carcinoma (RCC) are 
evaluable for response (Sridhar et al., 2008).  PRs were observed in 12 patients, SD in 15, and 

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PD in 5.  Median PFS was 8.7 months and the 6-month progression-free proportion was 63%.  
Treatment-related grade 3 or higher AEs included hypertension, fatigue, joint pain, abdominal 
pain, and dyspnea. 
 
Cediranib was administered in a phase 2 trial in small cell lung cancer (SCLC), in which one 
unconfirmed PR and eight SD were noted (Ramalingam et al., 2008).  Salient AEs were fatigue 
(four grade 3, two grade 4), and grade 3 diarrhea, skin rash, proteinuria, transaminitis, muscle 
weakness, and hypertension.  However, the original 45 mg/day dose was not tolerable in the 
patient population, and the modest activity seen at 30 mg/day did not support the use of cediranib 
as monotherapy for SCLC. 
 
A combination trial of cediranib plus docetaxel, doxorubicin, and cyclophosphamide in advanced 
breast cancer accrued only two patients, and was closed due to systolic dysfunction that occurred 
with concurrent cediranib and doxorubicin (Denduluri et al., 2007). 
 
Another combination trial of cediranib plus pemetrexed in NSCLC divided patients into two 
arms—those who had not received bevacizumab in prior chemotherapy regimens (Cohort A), 
and those who had (Cohort B) (Gadgeel et al., 2009).  The confirmed response rate was 16% 
(10% Cohort A, 25% Cohort B), and the disease control rate (CR/PR/SD) was 71% (74% Cohort 
A, 67% Cohort B).  Grade 3/4 AEs included neutropenia, febrile neutropenia, fatigue, diarrhea, 
hypertension, anorexia, cardiac ischemia, bronchopleural fistula, and esophagitis.  Of the 17 
patients who received cediranib for 4 cycles, 71% required dose reduction from 30 mg/day, and 
of the 18 patients who received pemetrexed for 4 cycles, 22% required dose reduction.   
Additional information on clinical trials conducted with cediranib is summarized in Lindsay et 
al. (2009). 
 
Results from Phase III trials with cediranib were presented in 2010: 
Horizon III summary (Schmoll et al., 2010): Together with the HORIZON II data showing a 
significant improvement in PFS (HR=0.84) with a comparable hazard ratio to the NO16966 
FOLFOX bevacizumab trial (HR=0.83), HORIZON III data suggest that the oral VEGFR 
inhibitor cediranib has clinical activity in mCRC with no significant difference in efficacy 
outcomes compared to bevacizumab.  However, the toxicity burden is greater than bevacizumab, 
and this would limit its use in routine clinical practice. 
 
Horizon II summary (Hoff et al., 2010): Cediranib is the first small molecule to show clinical 
activity against colorectal cancer. Cediranib met the co-primary endpoint of PFS (HR=0.84; 
P=0.0121); however, no OS benefit was observed (HR=0.94).  There was no significant 
difference in RR, DoR, or rate of liver resection.  The AEs associated with cediranib were 
consistent with previous studies and generally consistent across chemotherapy regimens.  The 
incidence of grade ≥3 AEs was higher in the cediranib arm.  Grade ≥3 diarrhea, hypertension, 
neutropenia and thrombocytopenia were experienced by >5% more patients in the cediranib arm.  
The AEs associated with cediranib were manageable, but resulted in reduced chemotherapy 
delivery. 
 
REGAL summary (Batchelor et al., 2010): Cediranib showed evidence of clinical activity in 
recurrent glioblastoma.  However, the study did not meet the primary endpoint on PFS for either 

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cediranib alone or in combination with lomustine and showed no benefit on OS versus lomustine 
alone.  Effects were observed in some secondary endpoints: Early effects seen (as demonstrated 
by change in contrast enhancing area and response rate) that were not maintained; Statistically 
significant difference between cediranib 30 mg monotherapy and lomustine in change in steroid 
usage; significant difference in favor of the combination arm versus lomustine alone on TDNS 
and change in steroid use.  The adverse event profile was broadly consistent with previous trials.  
Cediranib dose intensity was well maintained in both arms; however, there were more lomustine 
dose reductions in the combination arm compared with lomustine alone. 
 
Table 1: Summary of Pertinent Clinical Trials With Cediranib (Lindsay et al., 2009) 
Study  
Clinical 
phase  
Cancer 
type  
Dose(s) used  
Significant toxicities  
Efficacy  
Drevs et al. 
(2007)  
Phase I 
Solid 
tumors 
RP2D = 45 mg 
once-daily 
21/83 DLTs including 
hypertension (most commonly), 
fatigue and nausea 
2/83 partial responses 
22/83 stable disease 
Laurie et al. 
(2008)  
Phase I 
Lung 
RP2D = 30 mg 
(with carboplatin 
+ paclitaxel) 
Grade III–IV: hypertension (35%), 
fatigue (60%), anorexia (35%), 
diarrhea (30%), mucositis (20%) 
9/20 partial responses 
11/20 stable disease 
Goss et al. 
(2009)  
Phase I 
Lung 
RP2D = 30 mg 
(with cisplatin  
and gemcitabine) 
8 /12 patients had grade III 
toxicities (hypertension, fatigue, 
diarrhea, voice changes); 2 had 
grade IV toxicities (1 reversible 
CNS ischemia, 1 fatigue) 
5/9 partial responses 
4/9 stable disease 
Mayer et al. 
(2007)  
Phase II Breast 
45 mg once-daily Grade III–IV: hypertension (42%), 
diarrhea (19%), fatigue (19%), 
mucositis (12%) 
2/20 partial responses 
10/20 stable disease 
Ryan et al. 
(2007)  
Phase I 
Prostate 
RP2D = 20 mg 
once-daily 
3/4 patients with DLTs of 
hypertension and proximal muscle 
weakness at 30 mg once-daily 
Post-therapy PSA 
decline persisted for 
>17 months in two 
patients.  One 
radiological response 
post-therapy 
Karakunnel et 
al. (2008) 
 
Phase II Prostate 
20 mg once-daily 4/18 grade III toxicities: vomiting, 
myalgia, prolonged QTc 
complexes 
2/18 partial responses 
Sridhar et al. 
(2008) 
Phase II Renal 
45 mg once-daily 36 grade III–IV toxicities 
including hypertension, fatigue and 
arthralgia 
12/32 partial responses 
15/32 stable disease 
Matulonis et 
al. (2008)  
Phase II Ovarian 
45 mg → 30 mg 
once-daily 
13/28 grade III toxicities including 
hypertension, fatigue and diarrhea.  
One grade IV CNS hemorrhage 
5/28 partial responses 
3/28 stable diseases 
Hirte et al. 
(2008) 
Phase II Ovarian 
45 mg → 30 mg 
once-daily 
Most frequent grade III–IV 
toxicities were hypertension 
(20/60) and fatigue (12/60) 
Response and 
prolonged stable 
disease rate was 41% 
and 29% for platinum-
sensitive and 
platinum-resistant 
patients, respectively 

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Study  
Clinical 
phase  
Cancer 
type  
Dose(s) used  
Significant toxicities  
Efficacy  
Cunningham 
et al. (2008)  
Phase II Colorectal 20 mg or 30 mg 
once-daily (with 
FOLFOX) 
↑ hypertension, asthenia and 
thrombocytopenia compared with 
bevacizumab + FOLFOX 
Progression-free 
survival slightly 
longer in bevacizumab 
arm 
 
Starting Dose 
Although 45 mg was the initial recommended Phase II dose based on results from Study 
2171IL/0001, subsequent studies have indicated that many patients require a dose reduction 
(Lindsay et al., 2009).  For example, the starting dose was reduced to 30 mg in two monotherapy 
Phase II trials in ovarian cancer due to toxicities observed at the 45-mg dose level (Hirte et al., 
2008; Matulonis et al., 2008).  In one of these trials, 28 patients received cediranib, and Grade ≥3 
AEs included hypertension, fatigue, diarrhea, vomiting, hyponatremia, oral cavity pain, nausea, 
constipation, abdominal pain, headache, and hypothyroidism; Grade 4 toxicities included CNS 
hemorrhage, lipase, and hypertriglyceridemia (Matulonis et al., 2008).  In the other trial, 
hypertension and fatigue were the most frequent Grade ≥3 AEs (Hirte et al., 2008).  Similarly, in 
a Phase II study of cediranib in recurrent small cell lung cancer, 7 of the first 12 patients enrolled 
were unable to complete the first cycle at 45 mg due to AEs, and the starting dose was 
subsequently reduced to 30 mg).  Salient Grade 3 toxicities were fatigue, proteinuria, diarrhea, 
skin rash, transaminitis, muscle weakness, and hypertension.  Two patients had Grade 4 fatigue. 
 
In summary, a higher incidence of toxicities has been observed in several studies at 45 mg, and 
subsequently 30 mg has been widely used as a single-agent Phase II dose.  In a randomized study 
evaluating both the 30 and 45 mg doses of cediranib with or without antihypertension 
prophylaxis in patients with advanced solid tumors, the overall response rate was similar across 
treatment groups with evidence of antitumor activity at both the 30-mg and 40-mg dose levels 
(N=125; Investigator’s Brochure, 2009).  Cediranib doses as low as 20 mg daily in patients with 
advanced prostate cancer resulted in plasma concentrations above the concentration required to 
inhibit endothelial cell growth (Ryan et al., 2007).   
 
Clinical Efficacy of Cediranib in ASPS 
The clinical efficacy data which form the basis for studying cediranib in ASPS are primarily 
from Phase I and II trials sponsored by Astra Zeneca at the Royal Marsden Hospital, London, 
UK and the Christie Hospital, Manchester, UK.  Efficacy and tolerability data were collected for 
7 patients with ASPS (ages 26–49 years) treated with cediranib; one patient was treated in a 
Phase II randomized trial of cediranib with or without prophylactic antihypertensive therapy, and 
6 patients were treated in a Phase II study in patients with imatinib-refractory gastrointestinal 
stromal tumours (GIST) or other soft tissue sarcoma (Gardner et al., 2009).  Cediranib was 
administered orally once daily at an initial dose of 45 mg/day.  Four patients had confirmed 
partial responses that lasted for 241, 247, 365, and 633 days, respectively.  Two other patients 
had disease stabilization lasting 57 and 449 days, respectively.  The most frequently reported 
adverse events in patients with ASPS were similar to those reported in the other studies (Drevs et 
al., 2007; Langenberg et al., 2009): fatigue, diarrhea, stomatitis, headache, and hypertension 
(Gardner et al., 2009).  These data demonstrated an exciting activity profile for cediranib that 
supported further investigation in patients with ASPS (Figure 2).  
 

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Figure 2: Pre- and post-treatment CT scans from a young woman with ASPS in the axilla 
and lungs treated with cediranib from August 2006 to June 2008. 
 
 
Phase II Single-Center Study of Cediranib at the NCI 
The NCI opened a single-arm Phase II trial to determine the response rate (PR + CR) of 
cediranib in patients with advanced ASPS (09-C-0192) in 2009.  The trial is designed to rule out 
5% clinical response rate (PR+CR; p0 = 0.05) in favor of a modestly high response rate of 25% 
(p1= 0.25).  Patients are treated with 30 mg cediranib by mouth for 28 days in 28-day cycles.  
The target accrual was initially 24 patients but has since been expanded to a total of 54 patients.  
We have accrued 36 patients as of January 2011; 28 of these patients are evaluable for response 
(i.e., have completed at least 2 cycles of therapy).  We have observed 12 PR and 4 MR (defined 
as > 20% reduction in the sum of the longest dimensions of the target lesions).  Adverse events 
have been manageable; CTCAE v. 3.0 Grade 2 and 3, related to study medication: hypertension, 
elevated transaminases, hyperbilirubinemia, neutropenia, anorexia, tumor pain, hypothyroidism, 
weight loss, mucositis, confusion, diarrhea, fatigue, vomiting, and proteinuria.   
 

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Safety Profile 
As of January 2011, 895 patients on DCTD, NCI-sponsored clinical trials of cediranib had been 
evaluated for AEs.  The most common grade 3/4 AEs were hypertension, fatigue, anorexia, 
diarrhea, and metabolic (ASL/SGPT and AST/SGOT).  Please refer to Section 7.1.1 for a 
comprehensive list of potential AEs associated with cediranib. 
 
Hypothyroidism was observed in 14/21 pediatric patients with CNS tumors administered 
cediranib, including one with a prolonged elevated thyroid-stimulating hormone (TSH) and 
thyroxine (T4) that went untreated.  Proteinuria has been seen in seven patients, including two 
grade 3 events in Cycle 1 and Cycle 2, respectively.  Hypertension has been observed in 18/21 
patients who received more than a few days of therapy.  Of the 18 cases, 10 experienced grade 2 
hypertension as the highest reported grade and 8 reported grade 3 hypertension.  Reversible 
posterior leukoencephalopathy syndrome (RPLS) shortly after initiation of Cycle 2 of therapy 
was seen in one patient who had been appropriately managed for grade 3 hypertension  
 
In a phase 2 trial of cediranib in 46 patients with epithelial ovarian, fallopian tube, or peritoneal 
cancer, 31 patients (67%) developed hypertension by Day 3 of treatment, and 87% had 
developed hypertension by the end of the study (Robinson et al., 2010).  Fourteen women 
developed proteinuria, 7 within the first 2 weeks of treatment.  Only 7 of the 20 women who 
developed grade 3 hypertension developed proteinuria. 
 
In a phase 2 study of cediranib in patients with solid tumors, patients (n=126) were assigned to 
cediranib dose groups of either 45 or 30 mg/day with or without antihypertensive prophylaxis 
(Langenberg et al., 2009).  Severe hypertension occurred in one patient receiving prophylaxis 
versus 18 in the nonprophylaxis groups.  Antihypertensive prophylaxis did not result in fewer 
dose reductions or interruptions.  Increases in blood pressure, including moderate and severe 
readings of hypertension, were seen in all groups and successfully managed. 
 
Hypertension and kidney toxicity (i.e., proteinuria) are commonly observed AEs seen in the class 
of angiogenesis inhibitor agents (Izzedine et al., 2007; Launay-Vacher and Deray, 2009).  
Indeed, many of the AEs observed in human clinical trials of cediarnib have been described in 
studies of other angiogenesis inhibitors (Herbst, 2006; Kappers et al., 2009).  A number of 
mechanisms have been described that account for AEs such as impaired wound healing, 
gastrointestinal perforation, hemorrhage and thrombosis, cardiac impairment, endocrine 
dysfunction, and RPLS (Kamba et al., 2007). 
 
As described above (Starting Dose), the 30 mg cediranib dose has generally been better tolerated 
than the 45 mg dose. 
2.3 
Sunitinib Malate 
Sunitinib malate (sunitinib; SU11248; SU011248; Sutent®) is an oral, 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) -α and -β, stem cell factor receptor (KIT), the 
tyrosine kinase (TK) receptor encoded by the ret proto-oncogene (RET; rearranged during 

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transfection), fms-like tyrosine kinase 3 (Flt3), basic fibroblast growth factor (bFGF) and colony-
stimulating factor (CSF)-1R (O'Farrell et al., 2003a; Chow and Eckhardt, 2007; Faivre et al., 
2007; Gan et al., 2009; Mashkani et al., 2010).  Sunitinib selectively and potently inhibits the 
class III and class V split-domain RTKs (Mendel et al., 2003). 
 
Sunitinib shows significant antitumor and anti-angiogenic 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 (Gan et al., 2009; Mena et al., 2010).  As of June 2008, a total of 8932 
subjects with solid malignant tumors have received sunitinib, including patients with renal cell 
carcinoma (RCC) and those with gastrointestinal stromal tumors (GIST) (Investigator’s 
Brochure, 2009).  In phase 2 studies in cytokine-refractory metastatic RCC, sunitinib produced 
objective responses in 40% of patients with a median time-to-tumor-progression (TTP) of 8.7 
months (Motzer et al., 2006).  In phase 3 studies of patients with imatinib-resistant GIST, 
sunitinib was highly superior to placebo (p<0.0001) with respect to median TTP (27.3 weeks vs. 
6.4 weeks), progression-free survival (PFS), and overall survival (OS) (Demetri et al., 2006). 
Sunitinib was granted regular approval on January 26, 2006 by Food and Drug Administration 
(FDA) for the treatment of gastrointestinal stromal tumor (GIST) after disease progression on or 
intolerant to imatinib mesylate and accelerated approval for advanced renal cell carcinoma 
(RCC) (Goodman et al., 2007; Izzedine et al., 2007; Rock et al., 2007), which was changed to 
regular approval on February 2, 2007.   
 
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 anti-angiogenic 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 (Chow and Eckhardt, 2007; 
Gan et al., 2009).  Sunitinib also exerts direct antitumor activity on cells that express target 

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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 antitumor effect. 
 
Clinical Experience 
As of June 2008, 9204 subjects had received at least one dose of sunitinib in 77 completed or 
ongoing clinical studies, with 8986 subjects having received multiple doses of the agent 
(Investigator’s Brochure, 2009).  In phase 1 studies, sunitinib demonstrated single-agent activity 
in patients with RCC, GIST, non-GIST sarcomas, non-small cell lung cancer (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).  Pivotal trials of sunitinib in imatinib-resistant GIST (a placebo-controlled phase 3 trial), 
and metastatic RCC (MRCC) (single-arm, non-randomized, multicenter, open-label trial) and 
supporting trials in each disease were completed and submitted in support of the New Drug 
Application (NDA).  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 350 mg as well as after multiple doses of 25-
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) (Rosen et al., 2003).  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. 
 
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 (Faivre et 
al., 2006).  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: 3 in RCC, 1 in NET, 1 in GIST, and 1 in adenocarcinoma of 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 (O’Farrell et al., 2003b) and the second 
designed as a conventional dose-escalation study (Fiedler et al., 2005).  O’Farrell and colleagues 

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studied FLT3 phosphorylation in 29 AML patients who received a single dose of sunitinib at 
doses ranging from 50-350 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 (Fiedler et al., 2005).  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. 
 
Preliminary results from phase 1 studies exploring the combination of sunitinib with 
chemotherapeutic agents like capecitabine (Sweeney et al., 2007; Chiorean et al., 2008; Royce et 
al., 2008), pemetrexed (Chow et al., 2008), docetaxel (Traynor et al., 2008), gemcitabine (Brell 
et al., 2008; Michaelson et al., 2008), FOLFOX (Leong et al., 2007), FOLFIRI (Starling et al., 
2008), carboplatin/paclitaxel (Heath et al., 2008), and metronomic 
cyclophosphamide/methotrexate (Rugo et al., 2008) in patients with various solid tumors have 
been presented.  The MTD of sunitinib on the 4/2 schedule with docetaxel (60 mg/m2) was 
25 mg daily; with capecitabine (1000 mg/m2), it was 37.5 mg daily.  The MTD of sunitinib on 
the 2/1 schedule with docetaxel (75 mg/m2) was 37.5 mg daily and with capecitabine (1000 
mg/m2) was 50 mg daily.  The MTD for sunitinib as continuous daily dosing (CDD) with 
capecitabine (1000 mg/m2) was 37.5 mg daily and for pemetrexed (500 mg/m2) was 37.5 mg 
daily.  Reported DLTs included febrile neutropenia, fatigue, hand-foot syndrome, gastrointestinal 
hemorrhage, cerebral hemorrhage, and ischemic optic neuropathy.  Phase I trials evaluating the 
combination of sunitinib with other targeted agents like temsirolimus (Patel et al., 2009; Fischer 
et al., 2008), bevacizumab (Feldman et al., 2008; Cooney et al., 2008) and IFN- α (Motzer et al., 
2009a) have shown problems with increased toxicity in patients with RCC (Feldman et al., 2008, 
Fischer et al., 2008; Motzer et al., 2009a).  However, the combination of bevacizumab with 
sunitinib in patients with miscellaneous solid tumors was well tolerated (Cooney et al., 2008). 
 
Phase 2 and 3 Experience 
Updated results have recently been published on 750 patients with MRCC treated on a phase 3 
study of sunitinib at a daily dose of 50 mg on the 4/2 schedule compared to interferon (IFN)-α 9 
MU subcutaneously thrice weekly (Motzer et al., 2009b).  Median overall survival (OS) was 
greater in the sunitinib group than in the IFN-α group (26.4 vs. 21.8 months, respectively).  
Sunitinib treatment was associated with a higher objective response rate (RR) than IFN-α (47% 
vs. 12%, respectively).  Eleven patients in the sunitinib group and four patients in the IFN-α 
group achieved a complete response per investigator assessment.  Median progression-free 
survival (PFS) was 11 months for sunitinib compared with 5 months for IFN-α.  The most 
commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), 

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fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%).  An exploratory analysis, which 
censored 25 patients from the IFN-α group who had crossed over to receive sunitinib on study, 
showed a median OS time of 26.4 months for sunitinib compared with 20 months for the IFN-α 
group.  Results from a phase 1/2 dose-finding trial of sunitinib plus gefitinib, enrolling 
42 patients, have been published (Motzer et al., 2010).  In phase 1, patients received sunitinib 
37.5 or 50 mg on the 4/2 schedule plus gefitinib 250 mg, both once daily.  The MTD was 
determined to be 37.5 mg.  Two DLTs were observed with the 50 mg dose: grade 2 left 
ventricular ejection fraction decline and grade 3 fatigue.  In phase 2, patients received sunitinib 
at the MTD plus gefitinib.  Thirteen patients treated at the MTD achieved a partial response and 
12 had stable disease.  Median PFS was 11 months.  The most commonly reported grade 3/4 
adverse event was diarrhea.   
 
The promising results in phase 1 trials and the involvement of KIT and PDGFR-α, 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 
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 PFS) (Desai et al., 2004).  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 (Demetri et al., 2004).  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 
(Dileo et al., 2005).  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.  
 
Data from a pivotal multinational, randomized (2:1), double-blind, placebo-controlled phase 3 
trial in over 300 patients with imatinib-resistant GIST has shown significant clinical effect with 
sunitinib compared with placebo (Demetri et al., 2006).  Patients on the active treatment arm 
received sunitinib at a dose of 50 mg daily on the 4/2 schedule.  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<0.0001).  Therapy was reasonably well tolerated; the most common adverse events were 
fatigue, diarrhea, skin discoloration and nausea. 
 
In addition to patients with RCC and GIST, sunitinib has been evaluated in breast cancer 
(Burstein et al., 2008), NSCLC (Socinski et al., 2008), transitional cell carcinoma (TCC) 
(Gallagher et al., 2008), NET (Kulke et al., 2008), thyroid carcinoma (Cohen et al., 2008), 
certain subtypes of sarcoma (Keohan et al., 2008; Vigil et al., 2008), gastro-eosophageal cancer 
(Moehler et al., 2009), high-grade glioma (Chaskis et al., 2008), squamous cell carcinoma of the 
head and neck (SCCHN) (Choong et al., 2008), hepatocellular carcinoma (HCC) (Zhu et al., 
2008), colorectal carcinoma (CRC) (Saltz et al. 2007; Starling et al., 2008; Pfeiffer et al., 2009) 

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and uveal melanoma (Chan et al., 2008).  Results from these trials have been summarized in Gan 
et al., 2009. 
 
Clinical Efficacy of Sunitinib in ASPS 
Preliminary results from a Phase II trial of sunitinib malate in ASPS have been published, with 
an update presented at ASCO 2010.  Ten patients with advanced ASPS were administered 
sunitinib at 37.5 mg po qday; 5 patients had PR, and 1 had SD.   Responses were >9 months in 
all cases, with one patient still responsive after 28 months (Stacchiotti et al., 2009; Palassini et 
al., 2010).    
 
A recent case report also describes a patient with aggressive ASPS with lung and bone 
metastases who had failed multiple chemotherapy regimens prior to treatment with sunitinib.  
This patient had complete regression of the primary tumor, with stabilization of his bone 
metastases (Ghose et al. 2010).  
  
Safety Profile 
Sunitinib is reasonably well tolerated, with asthenia, hypertension, dermatitis, and mild 
myelosuppression as the most common AEs (Stadler, 2006).  Additionally, the inhibition of TK 
receptors by agents such as sunitinib can result in cutaneous AEs such as acral erythema, 
subungal splinter hemorrhages, modification of hair and skin pigmentation, mucositis, and 
(occasionally) periocular edema (Robert et al., 2005; Suwattee, 2008).  Hand-foot skin reaction, 
a group of signs and symptoms that can affect, usually bilaterally, the hands and/or feet of 
patients, has occurred in patients receiving sunitinib (Porta et al., 2007; Suwattee, 2008).  A 
recent analysis of dermatological AEs in patients receiving sunitinib therapy has reported that 
all-grade hand-foot skin reactions occurred in 19% of patients (5% grades 3-4), skin 
discoloration in 28% (no grades 3-4), dry skin in 16% (1% grades 3-4), skin rash in 13% (1% 
grades 3-4), dermatitis in 8% (2% grades 3-4), hair color changes in 10% (no grades 3-4), 
alopecia in 6% (no grades 3-4), and phototoxicity in <0.1% (no grades 3-4) (Rosenbaum et al., 
2008). 
 
Cardiotoxicity, including congestive heart failure (3%-8%) and left ventricular dysfunction 
(12%-14%), has been reported in patients undergoing treatment with sunitinib (Chu et al., 2007; 
Khakoo et al., 2008; Schmidinger et al., 2008; Telli et al., 2008).  More subjects treated with 
sunitinib experienced decline in left ventricular ejection fraction (LVEF) than subjects receiving 
either placebo or IFN-α (Investigator’s Brochure, 2009).  In a phase 3 GIST study in subjects 
with imatinib-resistant or -intolerant GIST, 22 of 209 (11%) subjects on sunitinib and 3 of 102 
(3%) subjects on placebo had treatment-emergent LVEF values below the lower limit of normal 
(LLN).  In a phase 3 study treatment-naive RCC patients, 27% and 15% of subjects on sunitinib 
and IFN-α, respectively, had an LVEF value below the LLN.  Among 461 patients enrolled in 
CDUS-monitored trials with sunitinib alone, 2% of patients experienced left ventricular systolic 
dysfunction (CDUS data).  It is unknown whether patients with concurrent cardiac conditions 
may be at a higher risk for developing drug-related LVEF.  Baseline and periodic evaluations of 
LVEF should be considered while these patients are on sunitinib treatment.  In patients without 
cardiac risk factors, a baseline evaluation of LVEF should be considered. 
 

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Sunitinib has been shown to prolong the QT interval in a dose-dependent manner, which may 
lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes.  This 
condition has been reported in <0.1% of sunitinib-exposed patients.  The DCTD, NCI, issued an 
IND AE Action Letter to all investigators using sunitinib describing the occurrence of QTc 
prolongation and Torsade de pointes (ventricular tachycardia) in patients on clinical trials 
utilizing sunitinib.  As a result of this Action Letter, DCTD, NCI-sponsored sunitinib protocols 
were amended to include the requirement for a baseline EKG prior to study treatment, exclude 
patients with histories of serious ventricular arrhythmias or prolonged QTc, and exclude patients 
with certain cardiac conditions. 
 
Among 8054 solid tumor subjects treated with single-agent sunitinib, Grade 3 hypertension was 
reported in 6.1% of patients and was one of the most commonly reported Grade 3 AEs.  Of 
subjects receiving sunitinib for treatment-naive MRCC, 34% receiving sunitinib experienced 
hypertension, compared with 4% on IFN-α.  Grade 3 hypertension was reported in 13% of 
treatment-naive metastatic RCC subjects on sunitinib compared to <1% on IFN-α.  Severe 
hypertension occurred in 4% GIST subjects on sunitinib, 1% GIST subjects on placebo, 9% RCC 
subjects on sunitinib and 1% RCC subjects on IFN-α (Investigator’s Brochure, 2009).  Among 
461 patients enrolled in CDUS-monitored trials with sunitinib alone, 28% experienced 
hypertension (CDUS data). 
 
In subjects receiving sunitinib for treatment-naive MRCC, 37% had bleeding events compared 
with 8% receiving IFN-α (Investigator’s Brochure, 2009).  Bleeding events occurred in 18% of 
patients receiving sunitinib in the double-blind treatment phase of the GIST phase 3 study, 
compared with 17% receiving placebo.  Among 461 patients enrolled in CDUS-monitored trials 
with sunitinib alone or in combination with other agents, there were 103 reported bleeding events 
(CDUS data).  Epistaxis was the most common hemorrhagic AE reported.  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. 
 
Hypothyroidism has been reported in 71% patients with RCC (Rini et al., 2007) and in 36% of 
those with GIST (Desai et al., 2006) treated with sunitinib.  Among subjects treated with single-
agent sunitinib, hyperthyroidism was reported in 0.6% and thyroiditis in 0.1% (Investigator’s 
Brochure, 2009).  Baseline measurement of thyroid function is recommended, and patients with 
thyroid dysfunction should be treated appropriately prior to starting sunitinib therapy. 
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 336 subjects to specifically identify any change in adrenal gland structure or the presence 
of adrenal gland hemorrhage (Investigator’s Brochure, 2009).  Neither event was observed.  
Adrenocorticotropic hormone (ACTH) stimulation testing was done in 400 patients across 
multiple sunitinib trials.  One subject developed consistently abnormal test results during 
treatment that were unexplained and may be related to sunitinib treatment.  Eleven additional 
subjects had abnormalities in the final test, with low peak cortisol levels.  None of these patients 
had clinical evidence of adrenal insufficiency.  However, based on the nonclinical findings, 
patients receiving sunitinib should be clinically followed for signs and symptoms of adrenal 
insufficiency, especially in (1) patients with comorbidities associated with adrenal dysfunction, 
(2) patients with preexisting adrenal insufficiency (primary or secondary), and (3) patients with 

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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. 
Diarrhea, nausea, abdominal pain, vomiting, constipation and dyspepsia are some of the most 
frequent AEs reported with sunitinib (Investigator’s Brochure, 2009).  Serum chemistries 
including phosphate should be performed at the beginning of each treatment cycle.  Supportive 
care may include anti-emetic premedication, supportive oral care products, and analgesics.  
Serious complications due to degeneration or shrinkage of tumors, including gastrointestinal 
perforation and tracheoesophageal fistula, have occurred rarely in patients with abdominal, head 
and neck, thyroid, and other malignancies treated with sunitinib, believed to be the result of the 
antitumor effect of sunitinib.  Other serious effects include thromboembolic events, rare 
reversible posterior leukoencephalopathy syndrome (RPLS), proteinuria with rare nephrotic 
syndrome, and rare microangiopathic hemolytic anemia. 
  
Clinical Pharmacokinetics 
Orally-administered sunitinib is well absorbed in humans, with linear pharmacokinetics (PK) at 
doses of 50-150 mg/day (Sakamoto, 2004).  Sunitinib is highly protein-bound and metabolized 
through N-de-ethylation by cytochrome P450 (CYP) 3A4 to SU12662 (Investigator’s Brochure, 
2009).  SU12662 has a similar inhibitory profile to sunitinib in vitro and similar protein binding 
properties.  SU12662 is further metabolized by CYP3A4 to a minor inactive metabolite 
(Investigator’s Brochure, 2009). 
 
The PK of sunitinib was studied in a variety of company-sponsored studies in both healthy 
volunteers (n=135) and in patients with solid tumors (n=266), including GIST and metastatic 
RCC; the PK was similar in the volunteers and in those with solid tumors.  Terminal half-lives 
(t1/2) of sunitinib and SU12662 are 40-60 hours and 80-110 hours, respectively, with a time to 
maximum concentration (Tmax) of 6-12 hours for sunitinib and its primary active metabolite, 
followed by a biexponential decline in concentrations.  The PK of sunitinib and SU12662 were 
measured in a phase 1 dose-escalation study in patients with advanced solid malignancies (Faivre 
et al., 2006).  Twenty-eight patients received doses ranging from 15 mg/m2 to 59 mg/m2 (ranging 
from 50 mg every other day to 150 mg/day), on a 4 weeks on, 2 weeks off (4/2) schedule.  
Concentration-versus-time data were analyzed using a noncompartmental analytic technique.  
Overall, sunitinib displayed a long half-life and a large volume of distribution with moderate 
interpatient variability.  Trough plasma concentrations of sunitinib and SU12662 increased with 
increasing doses.  However, area under the concentration-time curve (AUC) values increased 
less than proportionally with dose.  Accumulation ratios of sunitinib were >1, with detectable 
trough drug levels, suggesting drug accumulation over time.  At the recommended dose, 
maximum plasma concentration (Cmax) occurred approximately 5 hours after administration and 
t1/2 ranged from 41-86 hours.  Doses of 50 mg daily led to plasma concentrations ranging from 
50-100 ng/mL.  Most patients with DLTs had combined (sunitinib plus SU12662) trough plasma 
concentrations ≥100 ng/mL (Faivre et al., 2006). 
 
PK values determined from body surface area (BSA)-based doses were adjusted to reflect fixed 
doses of 50, 75-100, and 100-150 mg doses to determine if there was a need for BSA-based 
dosing to be employed.  AUC sum values obtained using BSA-normalized and fixed dosing were 
found to be comparable, suggesting that normalizing the dose based on BSA would not improve 

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variability.  Therefore, fixed dosing on a milligram basis was considered appropriate for phase 2 
studies (Faivre et al., 2006). 
 
To determine the effect of food on the PK of sunitinib and its active metabolite SU12662, 16 
healthy subjects received a single dose of sunitinib 50 mg under fasting conditions and 14 
subjects received a single dose of sunitinib 50 mg under fed conditions (Bello et al., 2006).  
Subjects were randomized to one of two treatment sequences each comprising two treatment 
periods (fasted and fed).  In Sequence 1, the fasted treatment period was followed by the fed 
treatment period, and for Sequence 2, the fasted period followed the fed period.  For the fasted 
period, a single oral (PO) dose of sunitinib 50 mg was administered after a 10-hour fast.  For the 
fed period, a single PO dose of sunitinib 50 mg was administered within 30 minutes of a high-
fat, high-calorie meal.  A washout period of at least 4 weeks separated sunitinib dosing between 
the two treatment periods.  Two subjects in Sequence 1 discontinued prematurely due to grade 1 
and 2 rash, but PK information was collected and included in the analysis.  Only a negligible 
difference in Tmax of sunitinib was observed between fed and fasted treatment periods; SU12662 
Tmax was prolonged by 2 hours (median difference) in the fed compared with the fasted state.  
The 90% confidence intervals (CIs) for Cmax and AUC were within the 80-125% bioequivalence 
range, indicating the absence of food effect.  Sunitinib exposure increased slightly in the fed 
compared with the fasted state (ratios of fed/fasted geometric least square means: Cmax 104%, 
AUC0-last and AUC0-∞ both 112%).  There was a delay in the formation/absorption of the active 
metabolite SU12662 in the fed state (mean Cmax decreased 23%), but exposure remained 
unaffected (90% CIs for AUC 0-last and AUC0-∞ were within 80-125%).  Sunitinib and SU12662 
half-lives, and oral clearance of sunitinib, were not affected by food (Bello et al., 2006). 
A study of sunitinib PK in patients with AML indicated that a plasma concentration of 50-100 
ng/mL of combined sunitinib and SU12662 could be achieved on the first cycle of a 50 mg/day 
4/2 regimen, similar to that achieved in studies with patients having other tumor types (Fiedler et 
al., 2005). 
 
In a phase 1 trial of sunitinib given on the 4/2 schedule in pediatric patients with relapsed or 
refractory solid tumors, the median day 21 steady-state trough sunitinib plasma concentration 
was 24.6 ng/mL (range, 6.0-37.7 ng/mL) at the 15 mg/m2 dose and 37.4 (range, 24.2-62.9 
ng/mL) at the 20 mg/m2 dose (DuBois et al., 2008). 
 
Population PK methods indicated that the covariates of weight, gender, race, ethnicity, ECOG 
score, and tumor type had no clinically significant effects on drug exposure, and that adjustments 
of starting doses based on these covariates were not required (Investigator’s Brochure, 2009). 
Concurrent administration of a single dose of sunitinib with ketoconazole (a CYP3A4 inhibitor) 
in healthy volunteers resulted in 49% and 51% increases in the combined (sunitinib + SU12662) 
Cmax and AUC0-∞ values, respectively, compared with sunitinib alone (Washington et al., 2003).  
Concurrent administration of sunitinib and rifampin (a potent CYP3A4 inducer) in healthy 
subjects resulted in 23% and 46% reduction in combined Cmax and AUC0-∞, respectively, 
compared with sunitinib alone (Bello et al., 2005).  Thus, dose adjustments for sunitinib should 
be considered when co-administered with CYP3A4 inhibitors and inducers. 
 

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Proposed Dose and Schedule for Phase II 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.  Alternate regimens of sunitinib are being explored; 50 mg of sunitinib daily for 2 
weeks followed by a 1-week off-treatment period (sunitinib 2/1) (Britten et al., 2008), while 
another schedule is sunitinib 37.5 mg as a CDD (George et al., 2008).  Both schedules were 
well-tolerated, achieved therapeutic plasma concentrations, and showed no significant 
accumulation of the drug.  
2.4 
Rationale  
There is no effective systemic treatment for patients with metastatic ASPS, but both sunitinib 
and cediranib are showing preliminary evidence of activity, supporting further clinical 
investigation (Gardner et al., 2008; Gardner et al., 2009).  Given this promising activity, we 
propose to conduct a randomized trial of cediranib or sunitinib in patients with metastatic ASPS 
that is not considered to be curable.  We plan to enroll 2 sets of patients into separate cohorts for 
analysis: a) patients with non-newly diagnosed ASPS and b) patients with newly diagnosed 
ASPS.  In each cohort, the ORR and 6-month PFS will be determined separately for patients who 
receive cediranib and patients who receive sunitinib.  At the time of disease progression, patients 
who received cediranib will be crossed over to receive sunitinib and patients who received 
sunitinib will be crossed over to receive cediranib, respectively, as long as the treatment arm to 
which they would cross over remains open.  After cross-over, the ORR and rate of disease 
stabilization will be determined for each agent at 24 weeks; this will provide information about 
the efficacy of each agent as a second VEGFR inhibitor (although not necessarily as second-line 
therapy metastatic disease) and possibly suggest the appropriate sequencing of these agents in 
the future.  
2.5 
Correlative Studies Background 
Current knowledge of potential therapeutic targets and their expression pattern in ASPS is 
limited.  Only a few studies of small sample size, using archival pre-treatment tissue, have 
demonstrated some potentially targetable angiogenic factors (Lazar et al., 2007; Stockwin et al., 
2009) through identification of up-regulated angiogenesis genes such as angiogenin, HIF1α, 
TGFβ1, JAG1, midkine, c-MET, and VEGF.  Paired pre- and post-treatment tumor biopsies 
would be of significant benefit in the quest for new target identification.  In addition, early data 
from Phase II studies with single-agent cediranib and sunitinib in patients with ASPS, as well as 
our own data, merit further understanding of the mechanism of action of these therapeutic agents.   
 
A major limitation to the study of therapeutic targets in ASPS is the rarity of this tumor, making 
access to human specimens difficult.  This study provides the rare opportunity to acquire tissue.  
Paired pre- and post-treatment tumor biopsies would be of significant benefit in providing insight 
into the mechanisms of action of cediranib and sunitinib by allowing detection of gene 

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alterations after treatment and by comparing findings with clinical outcome.  Only patients 
enrolled at the Clinical Center, NCI will be asked to give biopsies; tumor biopsies are optional. 
With Amendment H (version dated 11/20/2013), biopsies will no longer be performed on this 
study.  Language referencing biopsy collection has been left in the protocol for historical 
reference purposes. 
 
 
3 PATIENT SELECTION 
3.1 
Eligibility Criteria 
Status Update: Patients enrolled after Amendment G (version dated 08/16/2013), will be 
evaluated and compared to the first 13 patients by the study statistician and the 
Principal Investigator.   
 
• 
Patients must have histologically confirmed metastatic alveolar soft part sarcoma that is not 
curable by surgery.  Diagnosis of malignancy must be confirmed by the department of 
pathology at the institution where the patient is enrolled prior to patient enrollment.  
• 
Patients must show evidence of objective disease progression per RECIST 1 on scans 
within the 6 month period immediately preceding enrollment.  Both scans used to 
determine disease progression should have been obtained within this 6-month period.       
• 
Patients with newly diagnosed, unresectable, metastatic, and measurable ASPS who show 
clinical evidence of disease progression (including history and increasing physical 
symptoms) will also be eligible.  On-study documentation will include a physician’s 
rationale that supports evidence of clinical disease progression (i.e., increasing tumor pain).   
• 
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 11 for the 
evaluation of measurable disease. 
• 
Any prior therapy must have been completed ≥ 4 weeks prior to enrollment on protocol and 
the participant must have recovered to eligibility levels from prior toxicity.  Patients should 
be at least 6 weeks out from nitrosoureas and mitomycin C.  Prior radiation should have 
been completed ≥ 4 weeks prior to study enrollment and all associated toxicities resolved to 
eligibility levels.  Patients who have had prior monoclonal antibody therapy must have 
completed that therapy at least 3 half-lives of the antibody or 6 weeks ago.  Patients who 
have received more than a cumulative dose of 350 mg/m2 of doxorubicin may be enrolled 
at the discretion of the Coordinating Center PI after consultation with a cardiologist and if 
screening echocardiogram is normal. 
• 
Patients must be ≥ 2 weeks since any investigational agent administered as part of a Phase 
0 study (also referred to as an “early Phase I study” or “pre-Phase I study” where a sub-
therapeutic dose of drug is administered) at the Coordinating Center PI’s discretion, and 
should have recovered to eligibility levels from any toxicities. 
• 
Patients with no prior therapy are eligible, provided they have metastatic disease that is not 
curable by surgery.   

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• 
Age ≥ 16 years.  Patients age 16-17 years are eligible only if they have a BSA ≥1.7 m2 or 
weigh ≥60 kg. 
• 
ECOG performance status ≤ 2 (Appendix A). 
• 
Life expectancy of greater than 3 months. 
• 
Patients must have normal organ and marrow function as defined below: 
 
o leukocytes  
 
        >3,000/mcL 
o absolute neutrophil count         >1,500/mcL 
o platelets 
                                >100,000/mcL 
o hemoglobin 
                    >9 g/dL 
o total serum bilirubin 
         within normal institutional limits 
o AST(SGOT)/ALT(SGPT)        2.5 X institutional upper limit of 
                                                                     normal 
creatinine  
                     within normal institutional limits 
OR 
o creatinine clearance 
          >60 mL/min for patients with 
                                                                creatinine levels above institutional 
                                                                normal 
 
• 
QTc <480 msec (with Bazett’s correction) in screening electrocardiogram. 
• 
The following groups of patients are eligible after consultation with a cardiologist and at 
the Coordinating Center PI’s discretion, provided they have New York Heart Association 
Class II (NYHA; see Appendix B) cardiac function on baseline ECHO: 
o those with a history of Class II heart failure who are asymptomatic on treatment 
o those with prior anthracycline exposure greater than a cumulative dose of 
350 mg/m2 
o those who have received central thoracic radiation that included the heart in the 
radiotherapy port. 
• 
Patients must have blood pressure (BP) no greater than 140 mmHg (systolic) and 90 mmHg 
(diastolic) for eligibility.  Initiation or adjustment of BP medication is permitted prior to 
study entry provided that the BP reading prior to enrollment is no greater than 140/90 
mmHg.   
• 
Left ventricular ejection fraction (LVEF) ≥ institutional lower limit of normal. 
• 
Because sunitinib is metabolized primarily by the CYP3A4 liver enzyme, strong CYP3A4 
inhibitors are not permitted within 7 days before and during the study, and strong CYP3A4 
inducers are not permitted within 12 days before and during the study.  A list of drugs that 
may interact with the cytochrome P450 system is included in Appendix C.  Every effort 
should be made to switch patients taking such agents or substances to other medications 1 
week prior to starting therapy, particularly patients with brain metastases who are taking 
enzyme-inducing anticonvulsant agents (Appendix D).  Patients who require potent 
CYP3A4 inducers or inhibitors and cannot switch medications must have their case 
reviewed by the Coordinating Center PI and may be enrolled only after discussion with and 
agreement from the Coordinating Center PI.  Current clinical studies with cediranib have 

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not found clinically significant effects on cediranib PK with co-administration of 
CYP3A4 inducers or inhibitors.  Eligibility of patients receiving any medications or 
substances known to affect or with the potential to affect the activity or pharmacokinetics 
(PK) of cediranib will be determined following review of their case by the Coordinating 
Center PI. 
• 
Both study agents have been shown to terminate fetal development in the rat, as expected 
for a process dependent on VEGF signaling.  For this reason, women of childbearing 
potential must have a negative pregnancy test prior to study entry.  Women of child-bearing 
potential and men must agree to use two reliable forms of contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry, for the duration of study 
participation, and for 2 months following study drug discontinuation.  Should a woman 
become pregnant or suspect she is pregnant while participating in this study, she should 
inform her treating physician immediately. 
• 
Patients who are nursing infants:  because there is an unknown but potential risk for AEs in 
nursing infants secondary to treatment of the mother with study agents, breastfeeding 
should be discontinued if the mother is treated with the study agents. 
• 
Ability to understand and the willingness to sign a written informed consent document. 
• 
Patients must be able to swallow whole tablets and capsules.  
3.2 
Exclusion Criteria 
• 
Patients must not have received prior treatment with any VEGF receptor tyrosine kinase 
inhibitor (e.g., cediranib, sunitinib, pazopanib, sorafenib); however, prior treatment with 
bevacizumab is allowed.   
• 
Patients may not be receiving any other investigational agents. 
• 
Major surgery within 4 weeks prior to entry into the study, or a surgical incision that is not 
fully healed. 
• 
History of familial long QT syndrome, or use of medications that may cause QTc interval 
prolongation (Appendix E). 
• 
Patients with a pre-existing thyroid abnormality who are unable to maintain thyroid 
function in the normal range with medication are ineligible. 
• 
Warfarin and its derivatives are not allowed.  Patient can be receiving low molecular 
weight heparin if clinically indicated.  
• 
Uncontrolled intercurrent illness including, but not limited to hypertension, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements. 
• 
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, 
retain, and/or absorb the drug are excluded. 
• 
Patients with any of the following conditions are excluded: serious or non-healing wound, 
ulcer; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess 
within 28 days of treatment; coronary/peripheral artery bypass graft or stenting within the 

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past 12 months; or cerebrovascular accident (CVA) or transient ischemic attack within the 
past 12 months. 
• 
Greater than 2+ proteinuria on two consecutive dipsticks taken no less than 1 week apart or 
24-hour urine protein of > 1 g.  Patients with < 2+ proteinuria are eligible following initial 
determination by urinalysis within 1 week prior to enrollment and do not need the 
urinalysis repeated. 
• 
HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for PK interactions with cediranib or sunitinib.  Appropriate studies will be 
undertaken in patients receiving combination antiretroviral therapy when indicated. 
3.3 
Research Eligibility Evaluation 
3.3.1 Clinical Evaluations 
• 
A complete history and physical examination will be completed within 8 days prior to 
subject enrollment.  This will include determination of performance status. 
• 
EKG will be done for determination of QTc within 8 days prior to subject enrollment. 
• 
Echocardiogram scan for determination of LVEF within 28 days prior to subject 
enrollment. 
• 
Diagnostic imaging studies must be performed within 28 days prior to enrolling on study.  
This will include appropriate imaging studies for tumor measurement.   
3.3.2 Laboratory Evaluations 
Laboratory tests to establish eligibility should be performed within 8 days prior to subject 
enrollment unless stated otherwise. 
• 
Hematological profile: CBC with differential and platelet count 
• 
Biochemical profile: albumin, alkaline phosphatase, total bilirubin, BUN, calcium, 
creatinine, glucose, magnesium, phosphorus, potassium, total protein, SGOT[AST], 
SGPT[ALT], sodium, TSH 
• 
Troponin T or I 
• 
Urinalysis 
• 
Urine pregnancy test in women of childbearing potential 
3.3.3 Pathology Review 
A block or 6 unstained slides of primary tissue will be required from each study subject to 
confirm diagnosis.  Tissue blocks from a known recurrence will be accepted if the original tumor 
samples are unavailable.  Diagnosis of malignancy must be confirmed by the department of 
pathology at the institution where the patient is enrolled.   
3.4 
Inclusion of Women and Minorities 
This study will be open to all individuals regardless of gender, ethnicity, or race provided that the 
aforementioned inclusion and exclusion criteria are met.  For safety reasons, pregnant women 
and children age <16 years are excluded from this study.  Efforts will be made to extend accrual 
to each representative population.  If differences in outcome that correlate to ethnic identity are 

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noted, a follow-up study may be written to investigate those differences more fully.  This study 
will be open to all individuals regardless of gender, ethnicity, or race provided that the 
aforementioned inclusion and exclusion criteria are met.  Accrual targets are listed below. 

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35 
 
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
 
  6 
+ 
 
  6 
= 
 
12 
Not Hispanic or Latino 
 
21 
+ 
 
14 
= 
 
35 
Ethnic Category: Total of all subjects 
 
27 (A1) 
+ 
 
20 (B1) 
= 
 
47 (C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
 
0 
Asian 
2 
+ 
2 
= 
 
4 
Black or African American 
3 
+ 
3 
= 
 
6 
Native Hawaiian or other Pacific Islander 
0 
+ 
0 
= 
 
0 
White 
22 
+ 
15 
= 
 
37 
Racial Category: Total of all subjects 
        27 (A2) 
+ 
        20 (B2) 
= 
 
47 (C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
Accrual 
Rate: 
1 
pts/month 
Total Expected Accrual: 
44 
Min 
47 
Max 
 
4 REGISTRATION PROCEDURES 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations require IND sponsors to select qualified 
investigators.  NCI policy requires all persons participating in any NCI-sponsored clinical trial to 
register and renew their registration annually.  To register, all individuals must obtain a CTEP 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN or RAVE or acting as 
a primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation 
requirements per registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 

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Documentation Required 
IVR 
NPIVR AP 
A 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
Additional information can be found on the CTEP website at < 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact the 
RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
4.2 
Patient Registration 
Eligible participants will be entered on study by a member of the Coordinating Center study 
team.   
4.2.1 Coordinating Site Registration Process 
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates, found here: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825 
 
Cohorts: 
Cohort 1, Non-newly Diagnosed 
Cohort 2, Newly Diagnosed 
 
Arms: 
Arm 1, Part I 
Arm 2, Part II 
 
Arm Assignment: 
Subjects in cohorts 1 and 2 will be assigned to arm 1, and may cross over to arm 2 when 
they come off arm 1. 
 

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4.2.2 Participating Site Registration 
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates, found here: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825 
 
To register a patient after they have signed the consent, complete Appendix F (Eligibility/Pre-
Registration Worksheet) and fax (or email) it, along with all supporting records to the 
Coordinating Center’s Research Nurse, Ashley Bruns, Phone: (240) 858-3162, 
ashley.bruns@nih.gov.  The Coordinating Center will notify you either by e-mail or fax that the 
protocol registration form has been received.  The Coordinating Center will register the patient 
and provide the participating site with the patient’s unique patient ID number.  This unique ID 
number is to be used on all research samples and data entry for this patient.  Questions about 
eligibility should be directed to the Coordinating Center’s Research Nurse, Ashley Bruns, Phone: 
(240) 858-3162, ashley.bruns@nih.gov.   
 
4.2.3 Randomization Procedure 
The subject will be randomized by the Coordinating Center using a predetermined, balanced list.  
During randomization, the unique subject identifier (subject number / subject ID) will be 
submitted to the randomization node; the randomization node will select the next available 
treatment assignment, record the subject number in the list, and return the treatment arm 
associated with the selected randomization record.  Once a randomization number has been 
assigned, it will not be reused. 
4.2.4 Off Protocol Therapy and Off-Study Procedure 
Status updates (e.g., when a participant is taken off protocol therapy and when a participant is 
taken off-study) will take place per CCR SOP ADCR-2, CCR Participant Registration & Status 
Updates, found here: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825 
 
Participating sites: When a patient is taken off protocol therapy and when a patient is taken off-
study, the Participant Status Updates Form included in Appendix F must be completed and faxed 
or emailed to the Coordinating Center’s Research Nurse, Ashley Bruns, Phone: (240) 858-3162, 
ashley.bruns@nih.gov. 
 
 
5 TREATMENT PLAN 
Patients enrolled after Amendment G (version dated 08/16/2013), will be evaluated and 
compared to the first 13 patients by the study statistician and the Principal Investigator.  
PFS at 24 weeks will be calculated for all the study participants and for the initial 13 
patients and the rest of the patients separately to assess for any differences. Patients with 
newly diagnosed ASPS and clinical evidence of disease progression will also be assessed 
separately.  

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This is a randomized, open-label Phase II trial of cediranib and sunitinib in patients with ASPS.  
Patients will be randomized at study entry (Part I) to receive cediranib (30 mg) or sunitinib 
(37.5 mg) orally, once a day, in 28-day cycles.  As of Amendment Y (dated May 6, 2019), we 
have closed the cediranib arm of the newly diagnosed ASPS cohort due to inadequate activity; 
all newly diagnosed ASPS patients will be assigned to the sunitinib malate treatment arm. 
 
At the time of disease progression (documented by RECIST 1), patients will cross over to the 
other treatment arm (Part II) after a 2-week wash-out period.  However, if the other treatment 
arm has been closed due to inadequate activity (as defined in Section 13) or unacceptable 
toxicity, patients will not be eligible to cross over to that arm and will receive no further 
treatment on study.  During Part II, patients will receive the other agent, cediranib (30 mg) or 
sunitinib (37.5 mg), orally, once a day, in 28-day cycles.  Both arms will be analyzed 
independently for the primary and secondary endpoints.  As of Amendment Y (date May 6, 2019), 
we have closed the cediranib arm of the newly diagnosed ASPS cohort due to inadequate 
activity; patients in this cohort are not eligible to cross over to the cediranib arm. 
 
If the patient has disease progression that would require palliative radiation therapy (i.e., bone or 
brain) then crossover to the other arm can be delayed until the palliative radiation therapy is 
completed.  There will be a minimum wash out period of 2 weeks after completion of radiation 
therapy.  Crossover to Part II of the protocol can be delayed up to 6 weeks to allow the patient to 
recover from the side effects of treatment.  Patients will be required to meet all eligibility criteria 
prior to crossover.  No data or adverse events that result from radiation therapy will be captured.   
 
Appropriate anatomic imaging studies will be performed at baseline (within 28 days prior to start 
of protocol therapy), and imaging studies from the eligibility screening may be used if they are 
within this time period.  Repeat imaging scans will be performed every 2 cycles.  Responses will 
be confirmed according to the RECIST 1.0 (Section 11), with restaging scans at least 4 weeks 
apart.  Independent radiology review will be arranged of patient scans (including eligibility scans 
demonstrating disease progression prior to enrolling).  Copies of anatomic imaging scans will be 
maintained by the research teams to facilitate radiology review.  
 
Patients will be provided with a Study Diary (Appendix G), instructed in its use, and asked to 
bring it with them, along with any unused drug, to each appointment.  A new copy of the Study 
Diary will be given to patients who cross over to the other treatment arm (Part II) and to patients 
whose dose is reduced due to adverse events. 
 
Blood pressure will be monitored every 2 weeks by any health care provider during the first 
cycle of Part I and Part II, then at least at the start of every cycle for the duration of treatment 
(unless patients have experienced elevated blood pressure requiring drug therapy, at which point 
the frequency of BP monitoring by a health care provider will be determined by the local PI).  
Patients who have been on study for more than two years will have blood pressure monitored at 
the start of every third cycle.  Additionally, all patients will be required to monitor their BP at 
home at least once a day while on study and record the readings in the Study Diary (Appendix 
G).  (See Section 6 for hypertension management and dose reduction.) 
 

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Patient evaluations will be performed throughout the study as described below.  Baseline history, 
physical examination, laboratory evaluations, and EKG must be conducted within 8 days prior to 
start of protocol therapy.  If protocol therapy is started within 8 days of the eligibility screening 
evaluations (see Section 3.3.1 and Section 3.3.2), the results from these screening evaluations 
may be used as baseline measurements.  If >8 days have passed since the screening evaluations, 
the medical history, physical examination, laboratory evaluations, and EKG must be repeated 
prior to starting protocol therapy. 
 
Labs (CBC with differential, serum chemistries) will be performed every 2 weeks for the first 
2 cycles of Part I and Part II, and then at the start of every cycle for the duration of treatment.  
Patients who have been on study for more than two years will have labs performed at the start of 
every third cycle.   
 
EKGs and ECHOs will be performed at baseline (within 8 and 28 days prior to start of protocol 
therapy, respectively), and prior to patients starting on Part II, and as clinically indicated; EKGs 
will be performed at the start of every cycle (every three cycles for patients on study longer than 
2 years).  Routine monitoring for cardiac function (ECHO) will be performed every other cycle 
of treatment in the following groups of patients:  (1) those entering the trial with NYHA Class II 
cardiac dysfunction (see Appendix B), (2) those with a history of Class II heart failure who are 
asymptomatic on treatment, and (3) in those previously exposed to anthracyclines or thoracic 
irradiation if the heart was included in the radiotherapy port.   
 
Patients with bulky solid tumors should be monitored closely for pneumothorax, intestinal 
fistulae, or intestinal perforation in the event of rapid tumor destruction. 
 
At the end of the study, blocks or stained slides of primary soft tissue will undergo central 
pathology review by a pathologist with expertise in evaluation of soft tissue sarcomas.  Six 
sections of archival tissue should be sent to the Coordinating Center’s Research Nurse using the 
shipping manifest in Appendix N.   
 
Sparse PK evaluation for cediranib has been added to the study.  (See Appendix O: PK 
Evaluation for Cediranib)    
 
5.1 
Drug Administration 
At a given time, a patient will be receiving cediranib OR sunitinib orally, once a day, in 28-day 
cycles.  (Start of next cycle may be changed by 1 day or delayed for up to 1 week to 
accommodate scheduling conflicts.)  Treatment will be administered on an outpatient basis.  
After cycle 2, a cycle will be considered completed if 90% of the prescribed doses are 
administered.  Reported adverse events and potential risks are described in Section 7.  
Appropriate dose modifications are described in Section 6.  No other investigational or 
commercial agents may be administered with the intent to treat the patient’s malignancy.  Tablets 
and capsules must be swallowed whole.  Should the patient vomit within 15 minutes of taking 
the study drug, the dose should be repeated.  If patient vomits more than 15 minutes after taking 
the study drug, then no additional medication should be taken.  A missed dose can be taken 

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within 3 hours of the usual dosing time; if more than 3 hours have passed, the missed dose 
should not be made up.  If a patient misses a dose, he or she should be instructed to resume 
dosing with the next scheduled dose. 
5.1.1 Cediranib Administration  
• 
Patients will take 30 mg cediranib orally, once daily on an empty stomach (at least 1 hour 
before or 2 hours after meals).  The drug should be taken at approximately the same time 
each day.   
5.1.2 Sunitinib Administration  
• 
Patients will take 37.5 mg sunitinib orally, once daily in the morning, with or without food, 
as desired.  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. 
 
• 
Although adrenal gland insufficiency is rarely seen with sunitinib treatment, patients 
should be clinically followed for the signs and symptoms of this complication, 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. 
5.2 
General Concomitant Medication and Supportive Care Guidelines  
5.2.1 CYP3A4 Inhibitors and Inducers 
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.) 
 
Efforts should be made to switch patients who are taking enzyme-inducing anticonvulsant agents 
(Appendix D) to other medications at least 1 week before the study, and these medications 
should be avoided as much as possible during treatment. 
 
Eligibility of patients receiving any medications or substances known to affect or with the 
potential to affect the activity or pharmacokinetics (PK) of cediranib will be determined 
following review of their case by the Coordinating Center PI.  Current clinical studies with 
cediranib have not found clinically significant effects on cediranib PK with co-administration of 
CYP3A4 inducers or inhibitors. 
 
Co-administration of potent inhibitors or inducers of CYP3A4 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, the following agents should be avoided up to 

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12 days before and during the study for patients enrolled on either arm of the study.  Patients 
who require such medication and cannot be switched must have their case reviewed by the 
Coordinating Center PI, and may be administered only after discussion with and agreement from 
the Coordinating Center PI. 
 
Inhibitors – prohibited 1 week before and during the study 
azole antifungals 
(ketoconazole, itraconazole) 
verapamil 
clarithromycin 
HIV protease inhibitors (indinavir, 
saquinavir, ritonavir, atazanavir, nelfinavir) 
erythromycin 
delavirdine 
diltiazem 
 
 
Inducers – prohibited 12 days before and during the study 
rifampin  
phenytoin 
rifabutin 
St. John’s wort 
carbamazepine 
 
phenobarbital 
 
 
Aprepitant, fluconazole, and voriconazole are clinically relevant moderate CYP3A4 inhibitors 
that should be avoided, if possible, or used with great caution. 
 
Systemic 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.  Topical and intranasal steroids are allowed.  Corticosteroid 
therapy is permissible only for treatment of increased intracranial pressure or for hormonal 
replacement and should not be used as a prophylactic antiemetic. 
 
In addition, patients and their caregivers should be provided the patient information sheet 
(Appendix L) describing potential interactions of sunitinib with other drugs, remedies, and 
medications. 
5.2.2 Anti-epileptic Drugs 
Anti-epileptic drugs may be used, if indicated.  Efforts should be made to switch patients who 
are taking enzyme-inducing anticonvulsant agents (Appendix D) to other medications at least 1 
week prior to administration of cediranib and during administration, and these medications 
should be avoided as much as possible during treatment.  Patients requiring a change in 
anticonvulsants once on therapy should be switched to an anticonvulsant with a similar effect on 
hepatic enzymes. 
5.2.3 Febrile Neutropenia 
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 (Smith et al., 2006).  Packed red blood cell and platelet transfusion should be 

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administered as clinically indicated.  Erythropoietic agents may be used at the discretion of the 
treating physician.  Measures include laboratory testing, blood and urine cultures, and institution 
of broad-spectrum antibiotics. 
5.2.4 Growth Factors 
Routine use of growth factors (i.e., Filgrastim, Sargramostim, Erythropoietin) is not permitted.  
However, therapeutic use of filgrastim or sargramostim may be considered at the investigator’s 
discretion and administered according to accepted American Society of Clinical Oncology 
(ASCO) guidelines.     
5.2.5 Anti-emetics 
Patients with treatment-related nausea should be treated initially with a phenothiazine 
(prochlorperazine – 10 mg every 6 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). 
5.2.6 Anti-diarrheals 
If diarrhea develops and does not have an identifiable cause other than study drug administration, 
anti-diarrheals such as Lomotil (diphenoxylate HCl 2.5 mg plus atropine sulfate 0.025 mg/tablet) 
dosed according to package insert or loperamide 4 mg po after the first unformed stool with 2 mg 
po every 2 hours as long as unformed stools continue (4 mg every 4 hours while asleep).  No 
more than 16 mg of loperamide should be taken in during a 24-hour period.  This regimen can be 
repeated for each diarrheal episode.  Diarrhea will be considered refractory if it does not resolve 
within 24 hours ≤ to Grade 2 with the above regimen (16 mg, or less if there is resolution of the 
symptoms, of loperamide in a 24-hour period).  
5.2.7 Agents With Proarrhythmic Potential 
Use of agents with pro-arrhythmic potential (Appendix E) is not permitted during the study.  A 
comprehensive list of agents with proarrhythmic potential can be found at 
http://www.azcert.org/index.cfm.  
5.2.8 Hand-Foot Syndrome 
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.  Avoid exposure to heat, hot water, pressure, or friction.  Use of soft, well-fitting 
shoes may help, as may use of acetaminophen if needed for analgesia. 
5.2.9 Abnormal Thyroid Function 
Cediranib therapy has been associated with increases in TSH.  In the majority of patients, this 
has not resulted in reductions in either total thyroxine or free T4 to below the lower limit of the 
normal range, but clinical hypothyroidism has been reported in a small number of patients.  
Patients have responded to replacement therapy without the need for stopping or reducing the 
dose of cediranib.  Replacement levothyroxine will be given when clinically indicated to 

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normalize the thyroxine level to within the normal range, and before the patient becomes 
clinically symptomatic.  Replacement levothyroxine therapy may also be considered in patients 
with TSH increases (and thyroxine levels within the normal range), together with adverse events 
and symptoms suggestive of incipient hypothyroidism.  Thyroid function will be monitored 
frequently and the dose of levothyroxine titrated as required. 
5.2.10 Anticoagulants 
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. 
5.2.11 Supportive Care Guidelines 
• Frequent blood pressure (BP) monitoring is important in patients receiving cediranib.  
Experience to date suggests that increases in blood pressure may occur following dosing with 
cediranib for a number of weeks and that these increases may occur over a relatively short 
time frame.  It is imperative that the investigator institute appropriate measures to control BP.  
This may necessitate changes to existing antihypertensive medication, addition of new 
medication(s), and/or interruption/withdrawal of cediranib.  Section 6 includes specific 
guidelines on the management and, if appropriate, dose modifications for treatment-emergent 
hypertension.  Recommendations for hypertension monitoring and management are presented 
in Appendix I. 
• Renal function (creatinine and urinary protein) should be frequently monitored as suggested 
by the pathologic changes noted in animal studies and evidence from studies of other anti-
angiogenic agents.  Specific guidelines for management of proteinuria are presented in 
Section 6.  
• Patient levels of troponin T or troponin I should be monitored because of the potential for 
myocardial injury with cediranib as clinically indicated. 
5.3 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), subjects may continue on the study as 
long as they are tolerating the drugs and responding to treatment, or until one of the following 
criteria are met:   
• 
Disease progression during Part II of the study, 
• 
Intercurrent illness that prevents further administration, 
• 
More than 2 dose reductions required for toxicity in Part II of the study (patients taken off 
treatment during Part I have the option to cross over to Part II of the study), 
• 
Patient completed Part I of the study (due to toxicity or disease progression) and the other 
treatment arm has been closed due to inadequate activity (as defined in Section 13) or 
unacceptable toxicity, 
• 
Pregnancy, 
• 
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 opinion of the principal investigator. 

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44 
 
5.4 
Duration of Follow-up 
Patients will be followed for 30 days after the last dose is administered or until one of the 
following occurs: patient enrolls on another protocol, patient receives standard of care, or death, 
whichever comes first.  The follow-up will consist of a phone call between Days 27-30 after the 
last dose to evaluate adverse events that were ongoing and any new events that might be deemed 
related to the therapy.  Unacceptable toxicities (i.e., AEs related to the intervention) that have not 
resolved by Day 30 post-treatment will be followed via biweekly phone calls until stabilization 
or resolution. 
5.5 
Criteria for Removal From Study 
Patients will be removed from study for one of the following reasons: completed 30-day follow-
up period, toxicities are unresolved but stabilized, patient enrolls on another protocol, or patient 
receives standard of care.  The reason for study removal and the date the patient was removed 
must be documented in the Case Report Form and communicated to Central Registration per 
Section 4.4. 
 
 
6 DOSING DELAYS/MODIFICATIONS 
6.1 
Dose Modifications  
Doses will be held or modified only for adverse events that are felt to be at least possibly related 
to study drug.  Exacerbation of tumor pain can occur with administration of study drugs; dose 
reduction of study drugs will not be required for grade 3 or 4 tumor pain. 
 
Dose will be held and/or modified (as defined below) for grade 3 or greater non-hematologic 
toxicity (except electrolyte abnormalities unless these are not correctable within 48 hours and 
tumor pain unless refractory to supportive measures) and/or grade 4 hematologic toxicity (except 
lymphopenia, anemia).  Treatment once held, will not be re-initiated until toxicities resolve to 
grade 2 or less.  Up to 14 days will be allowed for resolution of toxicity, otherwise patients will 
be taken off treatment.  
 
Please note:  Sunitinib should NOT be re-administered if subjects develop ≥ grade 3 hepatic 
failure per CTCAE v5.0 definition.  (Please see the company’s prescribing information regarding 
hepatotoxicity at www. sutent.com.) 
 
If administration of study drug is interrupted for any reason, counting of the cycle days continues 
(i.e., if a patient stops drug on Day 15 and resumes 2 days later, they will be considered on 
Day 17). 
 
During Part I and Part II, patients will be started on the initial dose of 30 mg cediranib OR  
37.5 mg sunitinib orally, once per day for 28 days, in 28-day cycles.  Up to 2 dose reductions 
will be permitted before a patient is taken off treatment.  Patients taken off treatment for toxicity 
during Part I have the option to cross over to Part II of the study (after a 2-week wash-out 

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period), as long as the other arm has not been closed due to inadequate activity (as defined in 
Section 13) or unacceptable toxicity. 
 
Dose Modification Table: 
 
Dose Level 
Cediranib Dose 
(mg/day) 
Sunitinib Dose (mg/day) 
1 
30 
37.5 
-1 
20 
25 
-2 
15 
25 mg/day, 3 weeks on, 
one week off 
 
6.2 
Cediranib 
6.2.1 General Management of Adverse Events 
Note:  General Management guidelines refer to all AEs except those mentioned otherwise.  See 
Appendix I for hypertension management.  For management of reversible posterior 
leukoencephalopathy Syndrome (RPLS) or similar leukoencephalopathy syndrome, and cardiac 
toxicity, please refer to Section 6.4.  Toxicities will be managed according to standard medical 
practice. 
 
Observation 
Action 
AE resolves promptly with supportive care 
Maintain dose level 
1. 
Grade 3 or higher (non-hematologic or grade 4 
(hematologic) AE related to cediranib and lasting 
>5 days that does not resolve to grade 2 or below 
despite maximum supportive care for < 48 hours. 
2. 
Lower grade but related AEs (e.g., proteinuria) 
 
 
Reduce one dose level* 
AE does not resolve to grade 2 or below after treating 
patient at the lowest (i.e., 15 mg qd) reduced dose level. 
In general, remove patient from 
study 
* 
Alternatively and if medically appropriate, investigators may choose to hold dose for up 
to 14 days or withdraw patient from study. 
 
6.2.2 Management of Hypertension 
Increases in 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 cediranib treatment has been seen in 
animal studies as well as clinical trials.  Specific guidance for management of this AE is 
provided in Appendix I; additional suggestions for BP collection/recording can be found in 
Appendix H. 
Notes: 
• While patients are receiving treatment with cediranib, the early initiation of 
antihypertensive treatment for grade 2 hypertension to minimize more severe or 

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persistent hypertension is not considered a grade 3 AE.  
• Decisions to hold or decrease the cediranib dose during treatment must be based 
on BP readings taken in the clinic by a medical professional. 
6.2.3 Management of Proteinuria 
CTCAE v5.0 will be used for grading of proteinuria.  Although patients with > 2+ proteinuria at 
entry are ineligible, increases in proteinuria may occur during treatment and should be managed 
as follows: 
 
• During treatment if a patient has two consecutive two plus (++) urine protein 
dipstick measurements, or one three plus (+++) or greater measurement, a 24-hour 
urine specimen or urine protein/creatinine ratio sample should be collected.  A 
urine protein/creatinine ratio of 0.15 (urine protein and urine creatinine expressed 
in mg/dL) approximates a 24-hour urine protein of 150 mg/24 hours or 
0.15g/24 hours, which is the upper limit of normal (Rodby et al., 1995; Schwab et 
al., 1987; Wingo and Clapp, 2000). 
• If 24-hour proteinuria or urine protein creatinine ratio is classified as CTCAE 
grade 3, please follow the general guidance in Section 6.2.1 which has general 
guidance on CTCAE Grade 3 toxicities.  If nephrotic syndrome occurs, cediranib 
should be permanently discontinued. 
6.3 
Sunitinib 
6.3.1 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 I.  In addition, guidance on the collection and recording of BP information is provided 
in Appendix H.   

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6.3.2 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* and severe grade 2, 
at investigator discretion 
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 
Fever or flu-like 
symptoms 
Grades 1-4 
Maintain dose 
Fatigue (lethargy, 
malaise, asthenia) 
Grades 1 and 2 
Maintain dose 
Grade 3* and severe grade 2, 
at investigator discretion 
Hold sunitinib until < grade 2, then reduce 1 dose 
level and resume treatment 
 
 
 
 
 
 
 
QTc prolongation 
Do not use CTCAE 
v5 grades 
>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: 
If there is a plausible explanation for AE other than 
sunitinib treatment, resume sunitinib at current 
dose level. 
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, then increase one dose level and continue 
sunitinib. 
If QTc remains <500 msec after another 14 days, 
then the original dose of sunitinib may be resumed. 
Hand-foot syndrome 
Grades 1 and 2 
Maintain dose 
Grade 3* 
Hold sunitinib until < grade 1, then resume 
treatment at same dose or reduce 1 dose level 
AST and/or ALT 
elevation 
(SGOT, SGPT) 
 
Grades 1 and 2 
Maintain dose 
Grades 3 and 4 
Sunitinib should be dose delayed if elevation of 
ALT is >5 × ULN, AST is >5 × ULN, and/or 
bilirubin is >3 × ULN.  Sunitinib may be re-
administered when levels of ALT and AST are ≤5 
× ULN and bilirubin is ≤3 × ULN.  Sunitinib 
should NOT be re-administered if subjects develop 
≥ grade 3 hepatic failure (CTCAEv5 definition).  
 
Patients must have LFTs checked at baseline and 
during each treatment cycle.  LFTs should be 
obtained at any time when they are clinically 
indicated. 
 
      *Recurrent grade 3 events require dose reduction. 

Clinical Center # 11-C-0200 
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6.3.3 Management of Other Clinically Significant AEs (not specifically addressed above) 
Sunitinib should NOT be re-administered if subjects develop ≥ grade 3 hepatic failure per 
CTCAE v5.0 definition.  Please see the company’s prescribing information regarding 
hepatotoxicity at www.sutent.com.    
 
Note:  General Management guidelines refer to all AEs except those mentioned otherwise.  For 
management of reversible posterior leukoencephalopathy Syndrome (RPLS) or similar 
leukoencephalopathy syndrome, and cardiac toxicity, please refer to Section 6.4.  Toxicities will 
be managed according to standard medical practice. 
 
General Management Guidelines 
Observation 
Action 
AE resolves promptly with supportive care 
Maintain dose level 
1. Grade 3 or higher (non-hematologic or grade 4 
(hematologic) AE related to sunitinib and lasting 
 >5 days that does not resolve to grade 2 or below despite 
maximum supportive care for < 48 hours. 
 
2. Lower grade but related AEs (e.g., creatinine) 
 
 
 
Reduce one dose level 
AE does not resolve to grade 2 or below after treating patient 
at the lowest (i.e., 25 mg/day, 3 weeks on, one week off) 
reduced dose level. 
In general, remove patient 
from study 
6.4 
Dose Reduction 
6.4.1 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or similar 
leukoencephalopathy syndrome 
Cediranib or sunitinib should be held in patients with symptoms/signs suggestive of RPLS, 
pending work-up and management, including control of blood pressure.  Cediranib or sunitinib 
should be discontinued upon diagnosis of RPLS.  After consultation with the Coordinating 
Center PI and CTEP, NCI, consideration of restarting the study agent may be evaluated in light 
of any clinical benefit.   
 
RPLS or clinical syndromes related to vasogenic edema of the white matter have been rarely 
reported in association with cediranib therapy (<3%) as well as other VEGFR agents.  Clinical 
presentations are variable and may include altered mental status, seizure, and cortical visual 
deficit.  Hypertension is a common risk factor and was present in most (though not all) patients 
on cediranib who developed RPLS.  MRI scans are key to diagnosis and typically demonstrate 
vasogenic edema (hyperintensity in T2 and FLAIR images and hypointensity in T1 images) 
predominantly in the white matter of the posterior parietal and occipital lobes; less frequently, 
the anterior distributions and the gray matter may also be involved.  RPLS should be in the 

Clinical Center # 11-C-0200 
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49 
 
differential diagnosis in patients presenting with unexplained mental status changes, visual 
disturbance, seizure or other CNS findings.  RPLS is potentially reversible, but timely correction 
of the underlying causes, including control of blood pressure and interruption of the offending 
drug, is important in order to prevent progression to irreversible tissue damage.   
6.4.2 Cardiac Toxicity 
For patients who develop compromised LVEF: 
1. Discontinue cediranib or sunitinib in patients who develop symptomatic heart failure; 
2. Modify the cediranib or sunitinib dose using the table presented in Appendix J. 
 
 
7 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
7.1 
Comprehensive Adverse Events and Potential Risks Lists 
7.1.1 CAEPR for Cediranib (AZD2171, NSC 732208) 
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 1608 patients. Below is the CAEPR for 
Cediranib (AZD2171).  
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 2.15, November 7, 20181   
 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Hemolytic uremic 
syndrome 
  
 
 
Thrombotic 
thrombocytopenic purpura 
  
CARDIAC DISORDERS 
  
 
 
Heart failure 
  

Clinical Center # 11-C-0200 
CTEP # 8875 
 
50 
 
 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
 
Left ventricular systolic 
dysfunction 
  
ENDOCRINE DISORDERS 
  
 
Hyperthyroidism 
 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3)   
 
Anal mucositis 
 
 Anal mucositis (Gr 2) 
 
Constipation 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dysphagia 
 
 Dysphagia (Gr 2) 
 
 
 Gastrointestinal fistula2 
  
 
 
 Gastrointestinal 
perforation3 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
 
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 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
 Infection4 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase 
increased 
 
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Lymphocyte count 
decreased 
 
  
 
Neutrophil count decreased  
  

Clinical Center # 11-C-0200 
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51 
 
 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
Platelet count decreased 
 
  
 
Thyroid stimulating 
hormone increased 
 
 Thyroid stimulating hormone 
increased (Gr 2) 
 
Weight loss 
 
 Weight loss (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Generalized muscle 
weakness 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
Lethargy 
 
  
 
 
Leukoencephalopathy 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
 
Nephrotic syndrome 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Laryngeal mucositis 
 
 Laryngeal mucositis (Gr 2) 
 
Pharyngeal mucositis 
 
 Pharyngeal mucositis (Gr 2) 
 
Tracheal mucositis 
 
 Tracheal mucositis (Gr 2) 
Voice alteration 
 
 
 Voice alteration (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Palmar-plantar 
erythrodysesthesia syndrome 
 
 Palmar-plantar 
erythrodysesthesia syndrome 
(Gr 2) 
VASCULAR DISORDERS 
  
 
 
Arterial 
thromboembolism 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event 
 
 Thromboembolic event (Gr 4) 
 
Vascular disorders - Other 
(hemorrhage)5 
 
  

Clinical Center # 11-C-0200 
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52 
 
 
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 fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Enterovesical 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. 
 
3Gastrointestinal 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. 
 
4Infections includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
5Hemorrhage is a known consequence of VEGF/VEGFR signaling inhibition. The majority of 
hemorrhage events reported were mild; however, serious events, defined as symptomatic bleeding in a 
critical area or organ system (e.g., eye, gastrointestinal tract, genitourinary [GU] tract, respiratory tract, 
and nervous system) have been reported. 
 
 
 
Adverse events reported on cediranib (AZD2171) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that cediranib (AZD2171) caused the adverse 
event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system 
disorders - Other (polycythemia); Bone marrow hypocellular; Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Cardiac disorders - Other 
(premature ventricular complexes); Cardiac disorders - Other (valvular heart disease); Chest pain - 
cardiac; Mobitz (type) II atrioventricular block; Myocardial infarction; Palpitations; Pericardial effusion; 
Pericarditis; Restrictive cardiomyopathy; Sinus bradycardia; Sinus tachycardia; Supraventricular 
tachycardia 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (ears feel full/plugged); 
Ear and labyrinth disorders - Other (viral labyrinthitis); Tinnitus; Vertigo 
EYE DISORDERS - Blurred vision; Eye disorders - Other (blindness); Eye disorders - Other (visual 
disturbance); Papilledema; Photophobia; Retinal vascular disorder 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal pain; Ascites; Bloating; Colitis; 
Colonic obstruction; Duodenal ulcer; Dyspepsia; Enterocolitis; Esophageal necrosis; Esophageal ulcer; 
Esophagitis; Flatulence; Gastric necrosis; Gastric ulcer; Gastroesophageal reflux disease; Gastrointestinal 
disorders - Other (diverticulitis); Gastrointestinal disorders - Other (hydrops); Gastrointestinal disorders - 
Other (tongue sensitivity); Ileus; Oral pain; Periodontal disease; Peritoneal necrosis; Rectal pain; Small 
intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; 
Edema limbs; Fever; Gait disturbance; Hypothermia; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder obstruction; Hepatic pain; Hepatobiliary 
disorders - Other (bile duct obstruction); Hepatobiliary disorders - Other (jaundice cholestatic) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Immune system disorders - Other 

Clinical Center # 11-C-0200 
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53 
 
(systemic inflammatory response syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Dermatitis radiation; 
Fracture; Injury, poisoning and procedural complications - Other (tracheostomy malfunction); Intestinal 
stoma leak; Venous injury; Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; 
Blood lactate dehydrogenase increased; CPK increased; Cardiac troponin I increased; Cardiac troponin T 
increased; Cholesterol high; Creatinine increased; Ejection fraction decreased; Electrocardiogram QT 
corrected interval prolonged; GGT increased; Hemoglobin increased; INR increased; Investigations - 
Other (elevated ammonia level); Investigations - Other (increased blood erythropoietin); Lipase 
increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypertriglyceridemia; Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; 
Hypomagnesemia; Hyponatremia; Metabolism and nutrition disorders - Other (failure to thrive) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Avascular 
necrosis; Back pain; Bone pain; Chest wall pain; Muscle cramp; Muscle weakness lower limb; Muscle 
weakness upper limb; Myalgia; Myositis; Neck pain; Pain in extremity; Rotator cuff injury 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Central nervous system necrosis; Cognitive disturbance; 
Depressed level of consciousness; Dysarthria; Dysgeusia; Dysphasia; Encephalopathy; Hydrocephalus; 
Ischemia cerebrovascular; Memory impairment; Muscle weakness left-sided; Nervous system disorders - 
Other (coma); Nervous system disorders - Other (right hemiparesis); Olfactory nerve disorder; Peripheral 
motor neuropathy; Peripheral sensory neuropathy; Seizure; Somnolence; Spinal cord compression; 
Stroke; Syncope; Transient ischemic attacks; Tremor 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Depression; Hallucinations; Insomnia; Suicide 
attempt 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Cystitis 
noninfective; Hematuria; Urinary retention; Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; Menorrhagia; 
Vaginal fistula 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Aspiration; Hypoxia; 
Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Pneumothorax; Pulmonary edema; Pulmonary 
fistula; Pulmonary hypertension; Sinus pain 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail loss; 
Pruritus; Purpura; Rash acneiform; Rash maculo-papular; Skin and subcutaneous tissue disorders - Other 
(petechiae); Skin and subcutaneous tissue disorders - Other (plantar warts); Skin ulceration; Urticaria 
VASCULAR DISORDERS - Capillary leak syndrome; Flushing; Hypotension; Vasculitis 
 
Note: Cediranib (AZD2171) 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. 
 
 
7.1.2 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 

Clinical Center # 11-C-0200 
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54 
 
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 2.14, February 15, 20191 
 
 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 5.0 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) 
 
 Papilledema 
  
 Papilledema (Gr 2) 
 
 
 Vision decreased 
 Vision decreased (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) 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
55 
 
 
 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 5.0 Term) 
[n= 7115] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<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)  
 
Flu like symptoms 
 
  
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Cholecystitis 
  
 
 
Hepatic failure 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction3 
  
INFECTIONS AND INFESTATIONS 
  
 
 
Infections 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 
 
  
 
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) 
 
Hypocalcemia 
 
  
 
 
Hypoglycemia 
  

Clinical Center # 11-C-0200 
CTEP # 8875 
 
56 
 
 
 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 5.0 Term) 
[n= 7115] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
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 (fistula formation) 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
 
 
Osteonecrosis of jaw 
  
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
 
 
Rhabdomyolysis 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
  
 
 
Leukemia secondary to 
oncology chemotherapy 
  
 
 
Myelodysplastic syndrome 
  
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 
  
 
 
Nephrotic syndrome 
  
 
 
Proteinuria 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
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 
  
 
 Hair color changes 
 
 Hair color changes (Gr 2) 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
57 
 
 
 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 5.0 Term) 
[n= 7115] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
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 (pyoderma 
gangrenosum) 
  
 
Skin hypopigmentation 
 
 Skin hypopigmentation (Gr 2) 
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
 
Thromboembolic event 
  
 
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 
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; Hypokalemia; 
Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain 
NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Peripheral sensory neuropathy; Seizure; Spinal cord 
compression; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion 
RENAL AND URINARY DISORDERS - Hematuria; Urinary retention 

Clinical Center # 11-C-0200 
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REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Hematosalpinx 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Pharyngolaryngeal pain; Pleural effusion; 
Pneumothorax 
VASCULAR DISORDERS - Flushing; Hypotension 
 
 
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 
CTEP Reporting Requirements 
7.2.1 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 4.0 will be 
utilized until March 31, 2018 for AE reporting.  CTCAE version 5.0 will be utilized for AE 
reporting beginning April 1, 2018.  All appropriate treatment areas should have access to a copy 
of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) for expedited 
reporting purposes only.  ‘Expected’ AEs (the ASAEL) 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. 
7.2.2 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. 
 
7.2.3 Expedited Adverse Event Reporting 
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 7.2.3). 
 
A 24-hour notification is to be made to CTEP by telephone at 301-897-7497 only when internet 
connectivity is disrupted.  Once internet connectivity is restored, an AE report submitted by 
phone must be entered electronically into CTEP-AERS by the original submitter at the site. 

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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.  
7.2.4 Expedited Reporting Guidelines 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be provided. 
 
IMPORTANT:  Deaths clearly due to progressive disease should NOT be reported via 
CTEP-AERS but rather should be reported via routine reporting methods (e.g., CDUS 
and/or CTMS). 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
electronic submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
60 
 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.2.5 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
Lymphopenia (any grade), alopecia (any grade), anemia (grade 2), electrolytes (grade 2: 
sodium, potassium, phosphorous, and magnesium), albumin (grade 2), hyperuricemia 
(grade 3), INR (grade 2), and PTT (grade 2) will NOT be reported through CTEP-AERS 
but will be reported in the routine data submissions.   
7.2.6 Multicenter Guidelines for Expedited Adverse Event Reporting  
Adverse Event Reporting via CTEP-AERS: 
Follow sponsor expedited AE reporting requirements in Section 7.2.4.  Copy Ashley Bruns 
(ashley.bruns@nih.gov) and Alice Chen, MD (chenali@mail.nih.gov) on all CTEP-AERS 
reports. 
 
Adverse Event Reporting to NIH IRB: 
The site PI must immediately report to the Coordinating Center PI any serious adverse event, 
whether or not considered drug related, including those listed in the protocol or investigator 
brochure and must include an assessment of whether there is a reasonable possibility that the 
drug caused the event within 24 hours of PI awareness of the event.  The site PI must also report 
any protocol deviations or violations to the Coordinating Center PI within 7 days of PI 
awareness.  Participating centers must also submit the report to their IRB in accordance with 
their institutional policies. 
 
Follow NIH IRB expedited AE reporting requirements in Section 7.3.  Complete the NIH IRB 
Expedited AE form supplied by the Coordinating Center.  Send the completed form to Ashley 
Bruns, RN, either by e-mail to ashley.bruns@nih.gov or by fax to (301) 451-5625. 
 

Clinical Center # 11-C-0200 
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61 
 
7.2.7 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS.  Three options are available to describe the event:  
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
7.2.8 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified.    
 
7.3 
NIH IRB Reporting Requirements  
7.3.1 Definitions 
 
Please refer to definitions provided in Policy 801: Reporting Research Events 
(https://irbo.nih.gov/confluence/display/IRBO/Policies+and+SOPs). 
 
7.3.2 OHSRP Office of Compliance and Training / IRB Reporting  
 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at 
https://irbo.nih.gov/confluence/display/IRBO/Policies+and+SOPs 
 
Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to 
be reported per these policies. 
 
 
7.3.3 IRB Requirements for PI Reporting at Continuing Review 
 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at 
https://irbo.nih.gov/confluence/display/IRBO/Policies+and+SOPs  

Clinical Center # 11-C-0200 
CTEP # 8875 
 
62 
 
 
 
7.3.4 NCI Clinical Director Reporting  
 
Problems expeditiously reported to the OHSRP/IRB in iRIS will also be reported to the NCI 
Clinical Director.  A separate submission is not necessary as reports in iRIS will be available to 
the Clinical Director. 
 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
 
To report these deaths, please send an email describing the circumstances of the death to the 
Clinical Director/designee at NCICCRQA@mail.nih.gov within one business day of learning of 
the death. 
 
 
8 PHARMACEUTICAL INFORMATION   
8.1 
Cediranib (NSC 732208) 
Chemical Name: 4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin-1-
ylpropoxy) quinazoline maleate 
 
Other Names: AZD2171, AZD2171 maleate, Recentin™ 
 
Molecular Formula: C25H27FN4O3 · C4H4O4 
 
Molecular Weight: 566.59 as maleate salt (450.52 as free base) 
 
Approximate Solubility: The aqueous solubility of cediranib has been measured as 
0.0006 mg/mL for the free base (distilled water, pH 8.1 at 25°C) and 1.9 mg/mL for the maleate 
salt (distilled water, pH 4.4 at 25°C). 
 
Mode of Action: Cediranib is a highly potent inhibitor of vascular endothelial growth factor 
receptor (VEGFR) tyrosine kinase activity, which may inhibit vascular endothelial growth 
factor-A (VEGF) driven angiogenesis and, as a consequence, constrain solid tumor growth. 
 
Astra-Zeneca supplies and CTEP, NCI, DCTD distributes cediranib.  The agent is available as 
beige film-coated tablets containing 15 mg and 20 mg of cediranib free base.  The 15 mg and 20 
mg tablets are 7 mm and 8 mm in diameter, respectively.  Each bottle contains 35 tablets. 
 
In addition to the active ingredient, the tablets contain mannitol, dibasic calcium phosphate 
anhydrous, sodium starch glycollate, microcrystalline cellulose, and magnesium stearate with a 

Clinical Center # 11-C-0200 
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63 
 
film coat coating hypromellose 2910 polyethylene glycol 400, red iron oxide, yellow iron oxide, 
black iron oxide, and titanium dioxide.  
 
Storage: The intact bottles should be stored at controlled room temperature (68-77°F) and 
protected from light. 
 
Stability: Stability studies are ongoing.   
 
Route of Administration: Oral.  Cediranib tablets should be taken either 1 hour before or 2 hours 
after meals.   
 
Potential Drug Interactions: Cediranib (AZD2171) clearance is primarily mediated by flavin-
containing monooxygenase enzymes (FMO1 and FMO3) and UGT1A4. It is not a substrate of 
CYP450 enzymes. In vitro studies suggest that cediranib (AZD2171) is a substrate for P-
glycoprotein (Pgp), but not breast cancer resistance protein (BCRP). Since clinically relevant 
induction or inhibition of FMO enzymes is uncommon, use caution in patients taking concomitant 
medications that are strong inhibitors (e.g. ketoconazole) or strong inducers (e.g. rifampicin, 
carbamazepine, phenobarbital, phenytoin and St. John’s Wort) of UGT1A4 or Pgp in particular. 
If chronic concomitant administration of strong inducers or inhibitors is unavoidable, consult the 
protocol document and/or the principal investigator before making any dose adjustments. 
 
In vitro studies using hepatic cultures show that cediranib (AZD2171) did not inhibit CYP 1A2, 
2A6, 2C8, 2C9, 2C19 and 2E1 and showed no induction of CYP 1A2, 2B6 and 3A4/5. It did 
weakly inhibit CYP 2D6 and 3A4/5, but this inhibition not expected to cause any clinically 
relevant drug interactions.  The possibility that cediranib (AZD2171) may induce gastrointestinal 
CYP3A and UGT enzymes cannot be excluded; therefore the efficacy of hormonal 
contraceptives may be reduced. Advise women study participants to use an additional non-
hormonal contraceptive method. 
 
In vitro studies show that cediranib (AZD2171) is a weak inhibitor of BCRP, Pgp, OATP1B1, 
OATP1B3, OCT2 and MATE1. Use caution in patients who are taking concomitant medications 
that are sensitive substrates of these transporters since there is a low potential for drug-drug 
interactions. In vivo studies show that cediranib (AZD2171) could increase exposure of drugs 
like metformin by inhibiting renal tubular transporter MATE2-K, but this is thought to be 
infrequent and mild in severity. Cediranib is not an inhibitor of OAT1 or OAT3.  
 
Cediranib (AZD2171) is approximately 95% bound to human plasma proteins, with human 
serum albumin and α1-acid glycoprotein accounting for most of this binding. Use caution in 
patients taking concomitant medications with narrow therapeutic ranges that are also highly 
protein-bound. 
 
Oral anticoagulants are not absolutely contraindicated during treatment with AZD2171 
(cediranib); however, use cediranib (AZD2171) with caution and increase monitoring in patients 
while on study. Patients who receive VEGF inhibitors are at increased risk of bleeding and 
hemorrhage. 
 

Clinical Center # 11-C-0200 
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64 
 
Patient Care Implications: Agents that inhibit VEGF signaling have the potential to affect 
wound healing. For patients already enrolled onto the protocol, the manufacturer recommends 
holding cediranib (AZD2171) for 2 weeks prior to elective surgery and restarting when the 
surgical wound is healed. Protocol exclusion criteria should include patients who have had major 
thoracic or abdominal surgery within 2 weeks prior to start of study or patients with any surgical 
incision that is not fully healed.  
 
Advise women study participants of reproductive potential to use effective contraception while 
receiving study treatment and for at least 6 weeks after the last dose of cediranib (AZD2171). 
Refer to the protocol document for specific guidance. 
AZD2171 is provided to the NCI under a Clinical Trials Agreement (CTA) between AstraZeneca 
International (the Pharmaceutical Collaborator) and the DCTD, NCI (see Section 12.4). 
 
Availability: Cediranib is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI.  
 
8.2 
Sunitinib Malate (NSC 736511) 
Chemical Name: N-[2-(Diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3- 
ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, compound with (S)-
2- hydroxybutanedioic acid 
 
Other Names: SU011248 L-malate, Sutent 
 
Classification: Multi-kinase inhibitor 
 
Molecular Formula:   C22H27FN4O2•C4H6O5 
 
Molecular Weight: 532.57 Daltons 
Mode of Action: Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases 
(RTKs), some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic 
progression of cancer. Sunitinib is an inhibitor of platelet-derived growth factor receptors 
(PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and 
VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony 
stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor 
receptor (RET). 
 
Description: Sunitinib malate is the L-malate salt of SU011248 free base. 
 
How Supplied: Sunitinib malate capsules are supplied by Pfizer, Inc. and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI. Capsules are packaged in 28-count 
bottles with mannitol, croscarmellose sodium, povidone (K-25) and magnesium stearate as 
inactive ingredients in the following strengths: 
• 12.5 mg hard gelatin capsule (size 4) with orange cap and orange body, printed 
with white ink "Pfizer" on the cap and "STN 12.5 mg" on the body. 

Clinical Center # 11-C-0200 
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65 
 
• 25 mg hard gelatin capsule (size 3) with caramel cap and orange body, printed with 
white ink "Pfizer" on the cap and "STN 25 mg" on the body. 
Orange gelatin capsule shells contain titanium dioxide, and red iron oxide.  Caramel 
gelatin capsule shells contain titanium dioxide, red iron oxide, yellow iron oxide, and black 
iron oxide.  White printing ink contains shellac, propylene glycol, sodium hydroxide, 
povidone, and titanium dioxide. 
 
Storage: Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). 
 
Stability: Refer to the package label for expiration. 
 
Route of Administration: Oral administration, take with or without food. 
 
Potential Drug Interactions: Sunitinib is metabolized primarily by CYP3A4.  Avoid 
co-administration of strong CYP3A4 inducers/inhibitors. 
 
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 12.4) 
8.3 
Agent Ordering and Agent Accountability 
Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution.  The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents.  The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead participating investigator at that institution. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, a “current” password, and active 
person registration status.  For questions about drug orders, transfers, returns, or accountability, 
call or email PMB any time.  Refer to the PMB’s website for specific policies and guidelines 
related to agent management.   
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final disposition of all 
agents received from the PMB using the appropriate NCI Investigational Agent (Drug) 
Accountability Record (DARF) available on the CTEP forms page.  Store and maintain separate 
NCI Investigational Agent Accountability Records for each agent, strength, formulation and 

Clinical Center # 11-C-0200 
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66 
 
ordering investigator on this protocol. 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application.  Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, a “current” password and 
active person registration status.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET). 
 
9 CORRELATIVE STUDIES 
With Amendment H (version dated 11/20/2013), biopsies will no longer be performed as part 
of this study.  Language referencing biopsy collection has been left in the protocol for 
historical reference purposes.  
 
Optional tumor biopsies will be collected from patients enrolled at the Clinical Center, NCI only 
for use in gene expression profiling studies, and for future analyses once more information is 
available from ongoing studies regarding the underlying mechanism of action of these agents in 
ASPS.  When appropriate analyses are identified, the proposed correlative studies for the flash-
frozen tumor samples will be submitted to the IRB for approval. 
9.1 
Laboratory Contact 
At least 24 hours prior to taking the biopsies, the research nurse will contact the NCI Phase I/II 
PK/PD Support Group in NIH Building 10: E-mail (preferred): NCIPK-
PDsupportgroup@mail.nih.gov; Pager (preferred): 102-12798; Phone: (240) 858-3963; Fax: 
(301) 480-5871.  Tubes pre-labeled with the participant ID, biopsy date, protocol #, and site of 
tissue biopsy will be provided for tumor biopsy collection.   

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9.2 
Timing of Biopsies 
Biopsies will be performed at the following times from patients enrolled at the Clinical Center, 
NCI only:  
• Before starting treatment on study (baseline) 
• Between day 3 and day 5 of cycle 1 (Part I only) 
 
The time point for the second biopsy has been selected to maximize the possibility that any 
transcriptional changes seen are due to a direct drug mechanism of action versus any 
inflammatory infiltrate- or other endpoint-related findings.  The timing of the post-treatment 
biopsy may be adjusted depending on initial gene expression profile results, but the total number 
of biopsies per patient will not change. 
9.3 
Biopsy Procedure  
Serial tumor biopsies will be obtained through Interventional Radiology by a percutaneous 
approach.  For tumor biopsy site other than lung, 2 to 3 cores 18-gauge in diameter and at least 
1 cm in length will be obtained at each time point.  One core will be preserved in RNAlater for 
gene expression profiling; any additional cores will be flash frozen and kept for future analysis.  
For lung as site of tumor biopsy, only a fine needle aspiration (FNA) sample will be acquired and 
preserved in RNAlater for gene expression profiling. 
 
It is estimated that there will be between 2-5 million cells from each biopsy.  If a site is deemed 
appropriate for biopsy with minimal risk to the participant by agreement between the 
investigators and Interventional Radiology, an attempt at biopsy will be made.  Determination of 
a disease site amenable to biopsy will be determined on an individual case basis after discussion 
with an interventional radiologist.  The biopsy procedure to be used in this protocol is described 
below; local anesthesia will be administered.  Such biopsies can be safely performed as 
evidenced by literature reports (Dowlati et al., 2001) as well as our experience at the Clinical 
Center.  Risks of the procedure include, but are not limited to, bleeding, infection, pain, and 
scarring.  We will follow Clinical Center Interventional Radiology SOPs for coagulant panel and 
platelets. 
 
• All biopsies will be by percutaneous approach  
• No biopsy by an invasive (endoscopic, laparoscopic, or surgical) procedure will be 
performed. 
• Only cutaneous, subcutaneous, or easily accessible parenchymal lesion core biopsies will 
be performed. 
• However, there will be no core biopsies of lung lesions.  Only FNA of a lung lesion may be 
performed at the discretion of the PI after discussion with an interventional radiologist. 
 
The use of imaging to facilitate biopsies will be decided by members of the Interventional 
Radiology team and may include ultrasound, CT scan, or MRI.  Should CT scan be needed for 
biopsy, the number of scans for each procedure will be limited to the minimum number needed 
to safely obtain a biopsy.  All cases will be carefully reviewed with the interventional 

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radiologists at NIH who have extensive experience in performing such procedures.  Only if the 
procedure is considered to be low risk will we proceed with tumor biopsy in a given participant.   
 
Tumor biopsies are optional.  Baseline biopsies will be performed following patient enrolling on 
study.  If an initial attempt at percutaneous biopsy is unsuccessful, the patient will be given an 
option to proceed with a repeated attempt at percutaneous biopsy.  A separate consent form must 
be signed for each biopsy procedure, so patients may choose not to undergo subsequent biopsies.  
If the baseline biopsy is unsuccessful or the patient chooses not to undergo subsequent biopsies, 
no further biopsies will be performed but the patient will remain on study and receive study 
medication.   
9.4 
Processing of Patient Tumor Samples For RNA Analysis 
9.4.1 Biopsy Sample Collection and Storage 
• 
Biopsy samples will be collected in 2.0 mL eppendorf tubes (RNAse and DNAse free, 
sterile) filled with  RNAlater RNA Stabilization Reagent (# 76106 Qiagen)  and sealed 
with parafilm.  (Before use, check for RNAlater precipitate in tubes: in the unlikely event 
it is present, heat tubes at 37oC and agitate until completely dissolved). 
• 
Maintain tubes upright. 
• 
Samples collected in the RNAlater can be held/stored at 4ºC OR room temperature until 
being shipped (within 48 h). 
 
Ship via courier to: 
 
 
Curtis Hose/Anne Monks 
 
Functional Genomics Lab 
 
DTP, National Cancer Institute at Frederick 
 
Bldg. 432, Room 232 
 
Frederick, Maryland 21702 
 
Tel: (301)-846-1033 or 5528 
 
Fax: (301)-846-6081  
 
Confirm time of courier pick-up to: hosec@mail.nih.gov and monksa@mail.nih.gov.  
9.4.2 Sample Analysis 
Samples will be disrupted by FastPrep in RNA lysis buffer provided from Qiagen 
(RNeasy mini kit, #74106), and RNA will be extracted according to manufacturer’s 
procedure. 
 
100 ng of high quality RNA (Agilent RIN > 7) will be utilized for transcription profiling 
on Affymetrix U133 plus2 arrays, according to their protocols.  The .cel files will be 
analyzed by Partek and Gene Sifter, for evaluation of individual drug-modulated genes 
and impact on pathways. 

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9.5 
Processing of Frozen Tumor Samples 
Biopsy samples will be transferred into a 1.5-mL pre-chilled cryovial prelabeled with a Unique 
Identifier Code for the specimen per NCTVL SOP340507, and the vial with the specimen will 
be immediately dropped into liquid nitrogen.  Frozen specimens will be transported on dry ice 
by Clinical Service Program courier to the PADIS lab at FNLCR, where they will be logged into 
the record keeping system and stored in Dr. Robert Kinders’ laboratory for future analysis. 
 
Robert J. Kinders, PhD 
Principal Scientist 
PADIS, LHTP 
Applied/Developmental Research Directorate 
Leidos Biomed/FNLCR 
Bldg 431, Rm 129 
Frederick, MD 21702-1201 
Tel: 301-846-6410 
9.6 
Sample Collection and Processing  
Biospecimens will be collected and processed using validated SOPs that will ensure both 
specimen quality and patient confidentiality pursuant to informed consent provisions.  
 
Using a computerized inventory system and a backup hardcopy process, all specimen collection 
and processing steps will be documented and the specific location of each specimen will be 
tracked.  Each new specimen collected will be assigned a unique barcode identifier that can be 
linked to the original specimen collected and other relevant information within the inventory 
system.  To ensure patient confidentiality, only containers used for the initial specimen 
collections will be labeled with patient identifiers.  Only the barcode identifier will be applied to 
all subsequent specimen containers.  When specimens are processed and aliquoted, no patient 
information will be included on the new containers.  Original specimen containers will be 
discarded.  Only barcode-labeled specimens without patient identifiers will be sent for analysis 
and/or storage.  Specimen labels will indicate: protocol number, order in which the patient 
enrolled on the trial, type of sample, collection time, and total volume collected, as appropriate.   
 
The inventory process contains other security provisions sufficient to safeguard patient privacy 
and confidentiality.  Access to the inventory system and associated documents will be restricted 
to appropriate individuals.  Requests to use specimens stored in the repository must be approved.  
The only patient information available in the inventory system will be the patient sex, diagnosis, 
and level of informed consent given.  SOPs ensure that any changes in informed consent made 
by a patient and relayed to the PI will be reflected in the inventory system to ensure that 
specimens are destroyed as appropriate.  All laboratory personnel will be trained to adhere to 
SOPs and will be monitored for high-quality performance. 
 
Following completion of this study, samples will remain in storage as detailed above.  Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.  
 

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70 
 
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request.  Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), and reported as such to the 
IRB.  Any samples lost (in transit or by a researcher) or destroyed due to unknown sample 
integrity (i.e., broken freezer allows for extensive sample thawing, etc.) will be reported as such 
to the IRB. 
 
Any new use of these samples will require prospective IRB review and approval; any loss or 
destruction of samples and the planned disposition of samples after the protocol is terminated 
will be reported to the IRB. 
 
10 STUDY CALENDAR 
Eligibility screening evaluations are to be conducted within 8 days prior to enrollment, with the 
exception of informed consent, echocardiogram and diagnostic imaging, which must be done 
within 28 days prior to enrollment.  Baseline history, physical examination, laboratory 
evaluations, and EKG are to be conducted within 8 days prior to the start of protocol therapy.  If 
protocol therapy is started within 8 days of the eligibility screening evaluations, values from the 
screening evaluations may be used as baseline measurements; if > 8 days have passed since the 
screening evaluations, the medical history, physical examination, laboratory evaluations, and 
EKG must be repeated prior to starting protocol therapy.  Baseline imaging scans and 
echocardiogram scans must be done within 28 days prior to the start of protocol therapy.  Start of 
next cycle may be changed by 1 day or delayed for up to 1 week to accommodate scheduling 
conflicts.  The calendar restarts at Cycle 1 when patients start treatment on Part II.  The research 
team may perform additional safety/monitoring tests as clinically indicated. 
 
 

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71 
 
   
Pre-Study 
Eligibility 
Screening 
C1 
C2 
C3 
on Washout
/Pre-  
Part IIa 
Off Tx 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
 4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
 
Cediranib OR sunitiniba 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
 
X----------------------------------------------------------X 
 
 
Physical exam/vital 
signs/weight/ 
performance statusb 
X 
Xl 
 
X 
 
X 
 
 
 
X 
X 
X 
EKGc 
X 
Xl 
 
 
 
X 
 
 
 
X 
X 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistryd 
 
X 
 
Xl 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
CBC w/diff, pltsd 
 
X 
 
Xl 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
B-HCGe 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Tumor measurementsf 
X 
Xl  
Tumor measurements are repeated every 2 cycles* 
X 
Urine dipstick or 
urinalysis for proteing 
X 
Xl 
 
 
 
X 
 
 
 
X 
X 
X 
 
Echoh 
 
X 
 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Adverse event 
evaluation 
 
 
X --------------------------------------------------------X 
 
X 
TSH, T3, and T4i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X i 
X 
 
X 
Troponin T or Ij 
X 
 
 
 
 
 
 
 
 
 
 
 
PK Evaluationk 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
a: Cediranib (30 mg) OR sunitinib malate (37.5 mg) orally, once a day in 28-day cycles.  At the time of 
disease progression, patients will cross over to the other treatment arm after a 2-week wash-out 
period, provided the other arm has not been closed due to inadequate activity (as defined in Section 
13) or unacceptable toxicity.  Eligibility tests will be repeated within 1 week prior to patients starting 
on Part II.  The calendar restarts at Cycle 1 when patients start treatment on Part II.   
b: BP monitoring by a health care provider should be performed every 2 weeks during cycle 1 of Part I 
and Part II and then at the beginning of subsequent cycles (every 3 cycles for patients on study for 2 
years or longer).  Patients should measure and record their blood pressure at home at least once per 
day for the duration of the study.  History and physical exam will be done at the start of each cycle 
(every 3 cycles for patients on study for 2 years or longer) (up to 3 days before start of new cycle)  

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c: For eligibility screening and at baseline (within 8 days prior to enrolling or starting study drug, 
respectively), prior to patients starting on Part II, at the start of every cycle (every 3 cycles for 
patients on study for 2 years or longer), and as clinically indicated. 
d: CBC (WBC, Hgb, Hct, platelets, ANC, % neutrophils, bands, lymphocytes) and serum chemistry 
(albumin, alkaline phosphatase, total bilirubin, BUN, calcium, creatinine, glucose, magnesium, 
phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT], sodium) every 2 weeks for the first 2 
cycles of Part I and Part II, and then at the start of each cycle (every 3 cycles for patients on study for 
2 years or longer) (up to 3 days before start of new cycle). 
e: Urine pregnancy test (women of childbearing potential) for eligibility screening and prior to starting 
on Part II. 
f: Appropriate anatomic imaging studies will be done for eligibility screening and at baseline (within 28 
days prior to enrollment or starting study drug, respectively), and repeat imaging scans will be 
performed every 2 cycles (*every 3 cycles for patients on study for 2 years or longer).  
Documentation (radiologic) must be provided at time of crossover and during Part II if a patient is 
removed from study for progressive disease.   
g:   Evaluation of urine protein should occur for eligibility screening and at baseline (within 8 days prior 
to enrolling or starting study drug, respectively), and at the start of every cycle (every 3 cycles for 
patients on study for 2 years or longer) (up to 3 days before start of new cycle) if not previously 
abnormal (defined as ≥ 1+).  If patient has significant proteinuria (>1+), obtain a 24 hour urine for 
protein and creatinine clearance. 
h:  ECHO will be obtained for eligibility screening and at baseline (within 28 days prior to enrolling or 
starting study drug, respectively) and prior to patients starting on Part II; if abnormal it will be 
repeated every 2 cycles.  ECHO will be performed every other cycle of treatment in the following 
groups of patients:  (1) those entering the trial with NYHA Class II cardiac dysfunction (see 
Appendix B), (2) those with a history of Class II heart failure who are asymptomatic on treatment, 
and (3) in those previously exposed to anthracyclines or thoracic irradiation if the heart was included 
in the radiotherapy port. 
i: 
TSH every 2 cycles.  T3, T4 as clinically indicated 
j: 
Troponin T or troponin I will be measured for eligibility and as clinically indicated for patients 
receiving cediranib. 
k:  Blood samples for PK analyses of Cediranib will be collected in 4 cc EDTA (purple top) tubes pre-
dose , and at the following time points prior to drug administration on that day: cycle 1 day 15, 
C2D1, C3D1, and C4D1.  One 4 cc EDTA (purple top) tube will be obtained for each time point. 
l: 
Eligibility screening results may be used for these baseline measurements if conducted within 8 days 
(for medical history, physical exam, EKG, serum chemistry, CBC, and urinalysis) or 28 days (for 
echo and tumor measurements) prior to the start of protocol therapy. 
 
11 MEASUREMENT OF EFFECT 
11.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response every 2 cycles 
(8 weeks) or every 3 cycles for patients on study for 2 years or longer.  Response and 
progression will be evaluated in this study using the original international criteria proposed by 
the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1) 
[Therasse et al. 2000].  Changes in the largest diameter (unidimensional measurement) of the 

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73 
 
tumor lesions are used in RECIST 1.  All radiographic studies will undergo an independent 
review to confirm the presence of objective responses.     
11.1.1 Definitions 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with cediranib or sunitinib. 
 
Evaluable for objective response.   Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one dose 
of either drug, will be considered evaluable for non-target disease.  The response assessment is 
based on the presence, absence, or unequivocal progression of the lesions.  
11.1.2 Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by 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). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. 
 
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/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above.  However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 5 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 

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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.  A previously irradiated lesion 
can be considered a target lesion if it shows clear evidence of disease progression.  
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 10 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
11.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  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.  
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. 
  
Ultrasound  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.  
 
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.   
 
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 

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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.  
 
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. 
11.1.4 Response Criteria 
11.1.4.1 
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 of the LD. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of the target lesions, 
taking as reference the smallest sum on study of the 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 of the LD since the treatment started. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.   
 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.     
 

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Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
11.1.4.3  Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
        
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once >4 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
11.1.5 Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  

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11.1.6 Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression or death, whichever occurs first. 
 
 
12 DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7. 
12.1 
Data Reporting 
12.1.1 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). 
 
Note:   All adverse events that have occurred on the study, including those reported through 
CTEP-AERS, must be reported via the monitoring method identified above. 
12.1.2 Responsibility for Submission  
Study participants are responsible for submitting CDUS data and/or data forms to the 
Coordinating Center quarterly to allow time for Coordinating Center compilation, Principal 
Investigator review, and timely submission to CTEP (see Section 12.1.1).  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.   
12.2 
Data Safety and Monitoring Plan 
The investigators at each participating center will be responsible for the collection, maintenance, 
and quality control of the study data.  Adverse events observed in patients enrolled on the trial 
will be monitored in real time by the Principal and Associate Investigators, and attribution of 
these events to the research will be determined at the end of each treatment cycle in each subject.  
The clinical research team (PI, adjunct PI, research nurses, data managers) will meet weekly 
when patients are being actively treated on the trial to discuss each patient in detail and ensure 
that all events are graded appropriately, and that the attribution to study drug is correct.  The 
Coordinating Center is responsible for establishing conference calls between participating sites 
to discuss the observed toxicities and protocol issues at least on a monthly basis.  
 
All SAEs will be reported through CTEP-AERS to CTEP, to the Coordinating Center PI at NCI, 
and forwarded to the IRB per Section 7.  In all cases where the dose of the study treatment has 
been reduced/modified or the patient withdrawn due to unusual or unusually severe toxicity 
considered related to the study treatment, the investigator must contact and inform the 
Coordinating Center PI.  All sites will be monitored by the CTEP drug monitor who will receive 
data from all participating sites. 

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78 
 
 
Data will be monitored regularly by the PI to identify significant toxicity trends.  Any new 
significant finding that may affect the patient’s willingness to continue in the study will be 
shared with patients.   
 
Confidentiality will be maintained as much as possible, consistent with applicable regulations.  
Names of participants or identifying material will not be released without patient permission, 
except when such release is required by law.  No patient’s name or identifying information will 
be released in any publication or presentation.  Records are maintained according to current legal 
requirements, and are made available for review according to the requirements of the FDA or 
other authorized user, only under guidelines established by the Federal Privacy Act.  
 
Safety Monitoring Committee: 
Because this is a multi-institutional protocol for which the NCI CCR is the coordinating center, it 
will be monitored by the NCI Safety Monitoring Committee (SMC).  
12.3 
Multicenter Guidelines  
This protocol will open initially at the NCI.  The NIH IRB will be notified once the participating 
centers’ IRBs have approved the studies to open.  This protocol will follow the CCR’s Clinical 
Research Operations’ SOPs for multicenter trials.  
12.3.1 IRB Approvals  
As the Coordinating Center for a trial, it is the PI’s responsibility to ascertain that no patients are 
entered on the trial at a participating institution without full IRB approval.  Thus, the NIH IRB 
must approve the addition of each participating institution to the protocol and will require a copy 
of the local IRB approval from each participating institution before NIH IRB approval will be 
granted. 
  
The PI will provide the NIH IRB with a copy of the participating institution’s approved yearly 
continuing review.  Registration will be halted at any participating institution in which a current 
continuing approval is not on file at the NIH IRB.  
12.3.2 Amendments and Consents  
The NCI PI will provide the NIH IRB with copies of all amendments, consent forms, and 
approvals from each participating institution. 
12.3.3 Data Collection 
The investigators will be responsible for the collection, maintenance, and quality control of the 
study data.  All data collected for each study subject will be entered into the Cancer Central 
Clinical Database (C3D), an NCI electronic case report form/database, every 2 weeks.  The 
participating sites will be able to enter the data remotely into the web-based C3D system.  Each 
site investigator is also responsible for maintaining all source documentation related to the study, 
including any films, tracings, computer discs or tapes.  NCI will be responsible for data 
management, data analysis, and reporting.  Data collection forms will be provided to the 

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participating institutions.  Required data include, not exclusively: prior disease-related therapies 
with dates, disease type, stage, disease sites, with measurements, and concurrent medications.  
12.3.4 Data and Center Audits 
Audits will be conducted yearly to ensure data integrity and provide quality control.  These 
audits will be conducted by the NCI research team.  Selected patient charts should be audited as 
well as the participating institution’s Standard Operating Procedures (SOP) at the time of the 
visit.  Data from participating institutions should be available when the protocol is audited at the 
NCI.  
12.3.5 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 K. 
 
• 
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). 
12.4 
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 (CTA) between the Pharmaceutical Company [hereinafter 
referred to as “Collaborator”] and the NCI Division of Cancer Treatment and Diagnosis.  
Therefore, the following obligations/guidelines, in addition to the provisions in the “Intellectual 
Property Option to Collaborator” 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. 
 

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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.”): 
 
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 to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
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 Principal Investigator 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 

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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: E-mail: ncicteppubs@mail.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. 
12.5 
Publication Policy 
Recognizing the need to make clinical trial outcomes rapidly available to the cancer clinical trials 
community (Doroshow, 2008), publication of the results from this study will be a priority 
following completion of accrual, follow up, and data analyses.   
 
Authorship of this group-wide study will include the Coordinating Center PI, the study 
statistician, and one representative from each participating institution listed on the cover page of 
the protocol that contributed more than 10% of the eligible, evaluable cases.  The first author, 
last author, corresponding author(s), and study statistician, will all be NCI investigators.  The 
CTEP medical monitor will also be listed as an author.  Lead investigators from laboratories 
involved in conducting correlative studies will be listed as authors if data from their laboratories 
are included in the clinical results manuscript.  
 
If several investigators were responsible for a participating institution’s accrual, the designated 
representative from that institution ordinarily will be the PI.  When an individual other than the 
PI is largely responsible for a participating institution’s accrual, the PI is expected to substitute 
that individual as an author in place of himself/herself.  The intent is to offer recognition to the 
individuals who have been most directly involved in the study.  Because the Coordinating Center 
PI will often be unaware of the relative contributions of investigators at each institution, the PIs 
at participating institutions accruing more than 10% of cases will be solicited routinely to 
determine whether another individual should be substituted for them in authorship.  There will be 
only one author from each of the participating institutions listed on the cover page of the 
protocol.  If the PI is already an author, based on scientific contribution to the study, a second 
person from that PI’s institution will not automatically be accepted for authorship based on 
institutional accrual.   
 
This protocol includes several correlative studies that may be published with the group-wide 
clinical results paper or as separate, stand-alone scientific papers.  The decision to publish 
correlative study papers separately will be made by the Coordinating Center PI and relevant 
correlative study investigators, and will be subject to the Collaborative Agreement for study 
publications described in Section 12.4.  Authorship of the correlative results paper will include 
the Coordinating Center PI, the correlative study lead investigators, and researchers from the 

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correlative studies laboratories nominated by the correlative study lead investigators.  Correlative 
study lead investigators may also nominate authors who have contributed to the feasibility of the 
study and/or the development of assays and procedures that supported evaluation of study 
samples.  The final decision on the authorship of any manuscripts related to this trial will be 
made by the Coordinating Center PI. 
 
 
13 STATISTICAL CONSIDERATIONS 
Patients enrolled after Amendment G (version dated 08/16/2013), will be evaluated and 
compared to the first 13 patients by the study statistician and the Principal 
Investigator.  PFS at 24 weeks will be calculated for all the study participants and for the 
initial 13 patients and rest of the patients separately to assess for any differences. Patients 
with newly diagnosed ASPS and clinical evidence of disease progression will also be 
assessed separately.  
 
The primary objective of this study is to determine whether either sunitinib or cediranib can be 
associated with a modest rate of clinical response in patients with ASPS.  In addition, it will be 
of interest to obtain estimates of the PFS for each agent separately, as well as estimates of the 
response rate and the PFS for each agent when administered after patients progress on their 
initial agent.  
 
For patients who are not newly diagnosed: 
 
In each of the two arms, which are randomized against one another to prevent bias in patient 
selection only, the study will be conducted as an optimal two-stage phase II trial (Simon, 1989) 
to rule out an unacceptably low 15% clinical response rate (PR+CR; p0=0.15) in favor of a 
modestly high response rate of 40% (p1=0.40).  With alpha=0.10 (probability of accepting a poor 
treatment=0.10) and beta = 0.10 (probability of rejecting a good treatment=0.10), the study will 
initially enroll 10 evaluable patients in each arm.  If 0 or 1 of the 10 patients has a clinical 
response, then no further patients will be accrued.  That treatment arm will be closed to the 
accrual of new patients, and there will be no crossover of patients who progressed on the other 
agent to the closed arm.  If 2 or more of the first 10 patients have a response, then accrual would 
continue until a total of 22 patients have enrolled in that arm.  As it may take several weeks to 
determine whether a patient has experienced a clinical response, a temporary pause in the accrual 
to the trial may be necessary to ensure that enrollment to the second stage is warranted.  If there 
are 2-5 responses in 22 patients, this would be an uninterestingly low response rate in that arm, 
while if there were 6 or more responses in 22 patients, then this would be sufficiently interesting 
to warrant further study in later trials.  Under the null hypothesis (15% response rate), the 
probability of early termination is 54% for each arm. 
 
There will be no formal comparison of the response rates obtained on the two arms as this is not 
the purpose of the study and the trial does not have sufficient power to detect any reasonable 
difference between the arms.  Treatment in this trial is open label, and there will be no 
comparisons to placebo.  The response rates and 90% and 95% confidence intervals will be 
presented.  If accrual ends to one arm because of lack of adequate responses in the first stage, the 

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other arm will remain open to accrue all necessary patients.  The PFS will be estimated based on 
the 22 evaluable patients randomized to each treatment.  The 4- and 6-month estimates will be 
formed, and reported with 90% and 95% confidence intervals, as well as presenting the Kaplan-
Meier curve for PFS.  In addition, once patients progress on their initially assigned therapy, the 
response rate for the second therapy will be determined as well as the corresponding 90% and 
95% confidence intervals.  The PFS will also be determined from the date of progression for 
patients upon crossing over to the other agent.  At the end of the study we will also analyze for 
the best response in two stages, and the time to final disease progression following treatment 
with both agents for the two arms, at 24 weeks.  
 
Following Amendment K (8/26/14), patients with newly diagnosed ASPS will be accrued 
and assessed separately using their own individual two-stage designs as follows: 
 
In each of the two arms of the newly diagnosed ASPS cohort, which are randomized against one 
another to prevent bias in patient selection only, the study will be conducted as a Minimax two-
stage phase II trial (Simon, 1989) to rule out an unacceptably low 15% clinical response rate 
(PR+CR; p0=0.15) in favor of a modestly high response rate of 45% (p1=0.45).  With 
alpha=0.10 (probability of accepting a poor treatment=0.10) and beta = 0.20 (probability of 
rejecting a good treatment=0.20), the study will initially enroll 8 evaluable newly diagnosed 
patients in each arm.  If 0 or 1 of the 8 patients has a clinical response, then no further newly 
diagnosed patients will be accrued to that arm.  That treatment arm will be closed to the accrual 
of new patients, and there will be no crossover of patients who progressed on the other agent to 
the closed arm.  If 2 or more of the first 8 patients have a response, then accrual would continue 
until a total of 11 patients have enrolled in that arm.  As it may take several weeks to determine 
whether a patient has experienced a clinical response, a temporary pause in the accrual to the 
trial may be necessary to ensure that enrollment to the second stage is warranted.  If there are 2-3 
responses in 11 patients, this would be an uninterestingly low response rate in that arm, while if 
there were 4 or more responses in 11 patients, then this would be sufficiently interesting to 
warrant further study in later trials.  Under the null hypothesis (15% response rate), the 
probability of early termination is 66% for each arm. 
 
If a treatment arm is closed due to inadequate activity, as defined above, or unacceptable 
toxicity, patients will not be eligible to cross over to that arm.  As of Amendment Y (dated May 
6, 2019), we have closed the cediranib arm of the newly diagnosed ASPS cohort due to 
inadequate activity (1 PR out of 8 evaluable patients).  All newly diagnosed ASPS patients will 
be assigned to the sunitinib malate treatment arm; they will not cross over to the cediranib 
treatment arm. 
13.1 
Sample Size/Accrual Rate 
With an anticipated accrual of 14-16 patients per year, it is expected that 4-5 years will be 
required to enroll 44 evaluable non-newly diagnosed and 22 newly diagnosed patients.  To allow 
for a small number of inevaluable patients, the accrual ceiling will be set at 70. 
 

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14 HUMAN SUBJECTS PROTECTION 
14.1 
Rationale for Subject Selection 
This study will be open to all individuals regardless of gender, ethnicity, or race provided that the 
aforementioned inclusion and exclusion criteria are met.  For safety reasons, pregnant women 
and children age <16 years are excluded from this study.  The NCI is the coordinating center for 
this multi-institutional study.  This study will be recruited through internal referral, our physician 
referral base, and through various cancer information hotlines (i.e., Clinical Studies Support 
Center, 1-800-4Cancer.)  Participants should realize that there is no guarantee of benefit to them 
from participation in this trial.  The results of this trial may benefit future cancer patients.  To 
date, there is no information that suggests that differences in drug metabolism or effect on tumor 
would be expected in one ethnic group compared to another.  Efforts will be made to extend 
accrual to each representative population, but a balance must be struck between participant safety 
considerations and limitations on the number of individuals exposed to potentially ineffective 
treatments on the one hand and the need to explore racial/ethnic aspects of clinical research on 
the other hand.  If differences in outcome that correlate to ethnic identity are noted, a follow-up 
study may be written to investigate those differences more fully. 
 
Inclusion of Women and Minorities:  
This study will be open to all individuals regardless of gender, ethnicity, or race provided that the 
aforementioned inclusion and exclusion criteria are met.  The table below includes accrual 
estimates for the duration of the study. 
14.2 
Justification for Exclusions 
Pregnant women are excluded from this study because sunitinib and cediranib are VEGF 
inhibitors with known abortifacient effects.  Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with these agents, 
breastfeeding should be discontinued.  Participants with unstable or serious medical conditions 
such as uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, 
unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements are excluded due to the possibility that the underlying condition may obscure the 
attribution of effect and adverse events and may limit study compliance. HIV-positive patients 
on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic 
interactions with cediranib.  Appropriate studies will be undertaken in patients receiving 
combination antiretroviral therapy when indicated. 
14.3 
Participation of Children   
This study includes patients 16 years of age and older.  Because insufficient dosing or adverse 
event data are currently available on the use of cediranib in patients <16 years of age, children 
are excluded from this study, but may be eligible for future pediatric trials.  Studies will be 
performed in patients <16 years of age when it is appropriate to do so.  

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14.4 
Evaluation of Benefits and Risks/Discomforts 
There may or may not be any clinical benefit to a patient from participation in this trial.  Their 
participation will benefit future cancer patients.  Potential risks include the possible occurrence 
of any of a range of side effects that are listed in the consent document.  The procedure for 
protecting against or minimizing risks will be to medically evaluate patients as described in 
Section 5.  Although no compensation is available, any injury will be fully evaluated and treated 
in keeping with the benefits or care to which participants are entitled under applicable 
regulations.  
14.5 
Consent and Assent Process and Documentation 
An associate or principal investigator on the trial will inform patients (and the parents of patients 
aged 16 or 17) of the purpose, alternatives, drug administration plan, research objectives, and 
follow-up of this trial.  The patient (and the parents of patients aged 16 or 17) will be provided an 
IRB-approved consent for review and his/her questions will be answered.  After a decision is 
made to enroll into the study, a signature will be obtained from the patient (or, in the case of 
patients aged 16 or 17, written assent from the patient and written consent from the patient’s 
parent will both be documented).  The original signed consent goes to Medical Records; a copy 
will be placed in the research record. Patients will not be consented by telephone. 
 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on study. 
 
The investigators are requesting a waiver from the IRB to allow only one parent to sign the 
informed consent to enter a child on the protocol. Because many patients must travel to the NIH 
from long distances at substantial expense, requiring both parents to be present for the consent 
process could be a financial hardship for many families. When guardianship status of the child is 
uncertain, documentation of custody status must be obtained. In situations where there is joint 
custody of a child, both parents must sign consent. If only one parent can be present at NIH, the 
other parent’s consent can be obtained by telephone. 
14.5.1 Consent for minors when they reach the age of majority  
When a pediatric subject reaches age 18, continued participation (including ongoing 
interactions with the subject or continued analysis of identifiable data) will require re-
consenting of the now adult with the standard protocol consent document to ensure 
legally effective informed consent has been obtained. Given the length of time that has 
transpired for some of the subjects since their last visit for this study, we request waiver 
of informed consent for those individuals who have completed their participation in the 
research study or who become lost to follow up during their participation in the research 
study. 
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d): 
(1) The research involves no more than minimal risk to the subjects. 
a. Analysis of samples and data from this study involves no additional 
risks to subjects. 

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(2) The waiver or alteration will not adversely affect the rights and welfare of the 
subjects. 
a. Retention of these samples or data does not affect the welfare of 
subjects.  
(3) The research could not practicably be carried out without the waiver or 
alteration. 
a. Considering the length of time between the minor’s last contact with 
the research team and their age of majority, it will likely be very 
difficult to locate them again.  A significant reduction in the number of 
samples analyzed is likely to impact the quality of the research.  
(4) Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation. 
a. We only plan to request a waiver of reconsent for those subjects who 
have been lost to follow-up or who, prior to the approval of 
Amendment T, have been taken off study before reaching the age of 
majority. 
 
 
14.5.2 Participation of Subjects Unable to Give Consent 
Adults unable to give consent are excluded from enrolling in the protocol.  However re-
consent may be necessary and there is a possibility, though unlikely, that subjects could 
become decisionally impaired. For this reason and because there is a prospect of direct 
benefit from research participation (i.e., long-term stabilization and/or improvement in 
the pain and physical impairment caused by ASPS; Section 14.4), all subjects ≥ age 18 
will be offered the opportunity to fill in their wishes for research and care, and assign a 
substitute decision maker on the “NIH Advance Directive for Health Care and Medical 
Research Participation” form so that another person can make decisions about their 
medical care in the event that they become incapacitated or cognitively impaired during 
the course of the study. Note: The PI or AI will contact the NIH Ability to Consent 
Assessment Team for evaluation.  For those subjects that become incapacitated and do 
not have pre-determined substitute decision maker, the procedures described in NIH 
OHSRP Policy 403 for appointing a surrogate decision maker for adult subjects who are 
(a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 
 
14.6 
Procedure for Protecting Against or Minimizing Any Potential Risks 
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity.  This study may involve risks to patients, which are currently unforeseeable.  All 
patients will be monitored for side effects from taking study medication.  This research 
represents a greater than minimal risk to participants, but presents the prospect of direct benefit 
to individual subjects. 
 

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For patients enrolled at the Clinical Center, NCI only, the research component of this study 
required to obtain 2 CT tumor biopsies confers radiation exposure at an effective dose of 
0.29 rem.  This dose is below NIH RSC guidelines and represents a slightly greater than minimal 
risk to patients.  With Amendment H (version dated 11/20/2013), research biopsies will no longer 
be performed as part of this study.  
 
14.6.1 Patient Advocate 
The patients’ rights representative is available to patients receiving treatment on this protocol at 
the NIH Clinical Center at (301) 496-2626 in Building 10 of the Clinical Research Center, Room 
1-3521, on the Bethesda NIH campus.  Patients enrolled at other sites will be given information 
regarding their local patient advocate.  Patients will be informed that they can contact the study 
PI or RN at any time with questions about their medical care, and that the patients’ rights 
representative is also available to answer non-medical questions about the study.  
 
 

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Cunningham D, Wong RP, D'haens G, et al. A phase II, double-blind, randomized multicenter study of 
cediranib with FOLFOX versus bevacizumab with FOLFOX in patients with previously treated 
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of 11 cases. World J Surg Oncol 2008;6:71. 
 
Demetri GD, Desai J, Fletcher JA, et al. SU11248, a multi-targeted tyrosine kinase inhibitor, can 
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metastatic gastrointestinal stromal tumor (GIST). J Clin Oncol  2004;22: 3001. 
 
Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with 
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2006;368:1329-38. 

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Denduluri, N., A.W. Berman, U. Vatas, et al.  Cardiotoxicity after doxorubicin and AZD2171, an oral 
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disease.  Blood 2005; 105:986-993. 
 

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with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009b; 27:3584-90. 
 
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metastatic renal cell carcinoma.  Am J Clin Oncol.  2010;33:614-618. 
 
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vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with 
metastatic renal cell carcinoma. J Clin Oncol 2006;24:16-24. 
 
O'Farrell, A.M., T.J. Abrams, H.A. Yuen, et al.  U11248 is a novel FLT3 tyrosine kinase inhibitor with 
potent activity in vitro and in vivo.  Blood 2003a; 101:3597-605 
 
O’Farrell, A.-M., J.M. Foran, W. Fiedler, et al.  An innovative phase I clinical study demonstrates 
inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients.  Clin Cancer Res 
2003b; 9:5465-5476. 
 
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patients from the Japanese Musculoskeletal Oncology Group. Oncology 2003;65:7-13. 
 
Palassini E, Stacchiotti S, Negri T, et al. Sunitinib malate (SM) in alveolar soft part sarcoma (ASPS). J 
Clin Oncol ;28:A10014. 
 
Patel, P.H., P.L. Senico, R.E. Curiel, R.J. Motzer, et al.  Phase I study combining treatment with 
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Cancer 2009; 7: 24-27. 
 
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Ramalingam SS, Mack PC, Vokes EE, et al. Cediranib (AZD2171) for the treatment of recurrent small 
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26:A8078. 

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Lancet Oncol 2005;6: 491-500. 
 
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solid tumors. J Clin Oncol 2003;22:A765. 
 
Rosenbaum SE, Wu S, Newman MA, West DP, Kuzel T, Lacouture ME. Dermatological reactions to the 
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with capecitabine in patients with advanced solid tumors.  ASCO Breast Cancer Symposium 2008; A169. 
 
Rugo, H.S., J. Lyandres, M. Melisko, et al.  Phase I study of sunitinib (SU) in combination with 
metronomic dosing of cyclophosphamide and methotrexate (CM) in patients with metastatic breast cancer 
(MBC).  ASCO Breast Cancer Symposium 2008; A165. 
 
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cancer after failure of standard therapy. J Clin Oncol 2007;25:4793-9. 
 
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Appendix A: Performance Status Criteria 
 
 
 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on 
all pre-disease performance without restriction. 
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). 
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. 
3 
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead. 
 
 
 
 
 
 
 

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Appendix B: New York Heart Association Classification of Cardiac Disease 
 
 
Class 
Functional Capacity 
Objective 
Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal 
cardiovascular disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
 
 
 

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Appendix C: Potential Cytochrome P450 (CYP) Drug Interactions 
 
Consult a frequently updated drug information reference regarding potential drug interactions. 

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Appendix D: Enzyme-Inducing Anticonvulsant Drugs 
 
 
For drugs not listed, please contact the Study Chair. 
 
Anticonvulsants with little or no enzyme induction 
Generic Name 
Trade Name 
Ethosuximide 
Zarontin 
Gabapentin 
Neurontin 
Lamotrigine 
Lamictal 
Levetiracetam 
Keppra 
Tigabine 
Gabitril 
Topiramate 
Topamax 
Valproic acid, divalproex 
Depakote, Depakene 
Zonisamide 
Zonegran 
Enzyme-inducing anticonvulsant drugs 
Generic Name 
Trade Name 
Carbamazepine 
Tegretol 
Felbamate 
Felbatol 
Phenobarbital 
Phenobarbital 
Phenytoin 
Dilantin 
Primidone 
Mysoline 
Oxcarbazepine 
Trileptal 
 
 
 

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Appendix E: Medications That May Cause QTc Prolongation 
 
The following table presents a list of drugs that prolong, may prolong, or are unlikely to 
prolong the QTc.  Please note that this list is frequently updated.  For the most current list of 
medications, users should be directed to the following Web site: 
http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm. 
 
 
Compound 
Compound Half Life 
Possible 
Washout Period 
– Hours 
Possible 
Washout 
Period - Days 
Alfuzocin 
~10 hours 
 
7 
Amantadine 
17 +/- 4 hours (10-25) 
 
4 
Amiodarone (cordarone) 
58 days (15-142) 
36 days (active metabolite) 
 
180 
Amitriptyline* 
> 24 hours, wide interpatient variability 
 
 
Arsenic trioxide 
Not characterized 
 
 
Azithromycin 
40 hours 
 
 
Bepridil 
42 hr (26-64) 
 
10 
Chloral hydrate 
Readily converted to Trichloroethanol (active 
metabolite T1/2=7-10 hour) 
48 
 
Chloroquine 
Prolonged (days to weeks) 
 
 
Chlorpromazine 
30 +/- 7 hours 
 
7 
Cisapride 
6 – 12 hour, up to 20 hour 
60 
 
Clarithromycin 
Non linear PK3-4 hr (250mg Q12) 
5-7 hr (500mg Q12) 
36 
 
Cloroquine 
6 to 60 days; mean 20 days 
 
 
Desipramine* 
> 24 hours, wide interpatient variability 
 
 
Disopyramide 
6.7 hr (4-10) 
36 
 
Dofetilide 
10 hr 
48 
 
Dolesetron 
8.1 hr 
 
 
Domperidone 
7-8 hr 
48 
 
Doxepin* 
> 24 hours, wide interpatient variability 
 
 
Droperidol 
2.2 hours 
10 
 
Erythromycin 
* Each salt form has different Half life* 
 
 
Felbamate 
20-23 hr 
 
5 
Flecainide 
20 hr (12-27) 
 
5 
Foscarnet  
87.5+/-41.8 hours 
*distribution and release from bone* 
 
20 
Fosphenytoin 
12-29 hr 
 
6 
Gatifloxacin 
7-14 hr 
48 
 
Gemifloxacin 
7 hours 
48 
 
Grepafloxacin 
16 hr 
 
3 
Halofantrine 
6-10 days ( variable among individual) 
 
45 
Haloperidol 
18 +/-5 hr 
 
5 
Ibutilide 
6 hours (2-12) * variable among subject* 
36 
 
Imipramine* 
> 24 hours, wide interpatient variability 
 
 
Indapamide 
14 hours (biphasic elimination) 
 
3 
Isradipine 
8 hours ( multiple metabolites) 
48 
 
Levofloxacin 
6-8 hours 
48 
 
Levomethadyl 
Multiple compartment PK with active metabolite 
2.6 day for LAAM, 2 day for nor-LAAM, 4 day 
for dinor-LAAM 
 
20 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
103 
 
Compound 
Compound Half Life 
Possible 
Washout Period 
– Hours 
Possible 
Washout 
Period - Days 
Lithium 
24 hour (10-50) 
 
7 
Mesoridazine 
24-48 hours ( animal study) 
 
10 
Methadone 
15-30 hours 
 
7 
Moexipril/HCTZ 
2-9 hour (include active metabolite) for moexipril; 
5.6-14.8 hours for HCTZ  
48 
 
Moxifloxacin 
12 +/-1.3 hours 
72 
 
Naratriptan 
6 hours 
36 
 
Nicardipine 
~ 2 hour post IV infusion 
12 
 
Nortriptyline* 
> 24 hours, wide interpatient variability 
 
 
Octreotide 
1.7 hours 
12 
 
Ofloxacin 
5 to 7.5 hours 
 
2 
Ondansetron 
4 hours (IV/IM); 3 hours (PO) 
 
1 to 3 
Pentamidine 
6.4+/-1.3 hours 
36 
 
Pimozide 
55 hours 
 
10 
Procainamide 
3-4 hour for PA and NAPA (active metabolite) 
24 
 
Protiptyline* 
> 24 hours, wide interpatient variability 
 
 
Quetiapine 
6 hours 
36 
 
Quinidine 
6-8 hours in adult; 3-4 hours in children 
36 
 
Quinine 
4-5 hours 
 
 
Risperidone 
3-20 hours (extensive to poor metabolizer) 
9-hydroxyrisperidone (active metabolite) T ½ 
=21-30 hours (extensive to poor metabolizer) 
 
4 
Salmeterol 
5.5 hours (only one datum) 
36 
 
Sotalol 
12 hours 
72 
 
Sparfloxacin 
20 hours (16-30) 
 
4 
Sumatriptan 
2.5 hours 
12 
 
Tacrolimus 
~34 hours in healthy; ~19 hours in Kidney 
transplant 
 
7 
Tamoxifen 
5-7 days (biphasic) 
 
30 
Telithromycin 
2-3 hr 
24 
 
Thioridazine 
20-40 hours (Phenothiazines) 
 
7 
Tizanidine 
2.5 hours 
12 
 
Vardenifil 
4 to 5 hours 
 
 
Venlaflaxine 
5 +/-2 hours for parent comp. 
11+-2 hours for OVD (active metabolite) 
60 
 
Voriconizole 
6 hours; dose dependent 
 
 
Ziprasidone 
7 hr 
36 
 
Zolmitriptan 
2.8-3.7 hours (higher in female) 
18 
 
*Weakly associated with Torsades de Pointes and/or QT prolongation but that are unlikely to be a risk for Torsades 
de Pointes when used in usual recommended dosages and in patients without other risk factors (e.g., concomitant 
QT prolonging drugs, bradycardia, electrolyte disturbances, congenital long QT syndrome, concomitant drugs that 
inhibit metabolism). 
 
References: 
1. Physician’s Desk Reference 2002 
2. Facts and Comparisons (update to June 2005) 
3. The Pharmacological Basis of Therapeutics 9th Edition, 1996 
 
 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
104 
 
 
Appendix F: Eligibility/Pre-Registration Worksheet 
A Phase II Trial in Which Patients With Metastatic Alveolar Soft Part Sarcoma Are 
Randomized to Either Sunitinib or Cediranib Monotherapy, With Cross-Over at Disease 
Progression 
 
 
 
Coordinating Center: NCI 
 
 
Protocol Chair:  
 
 
Bethesda, MD 20892 
 
Alice Chen, MD 
 
 
Contact: Ashley Bruns 
Phone: (240) 858-3162  
Fax: (301) 451-5625  
E-mail: ashley.bruns@nih.gov 
 
 
National Cancer Institute 
Tel: (240) 781-3320 
E-mail: chenali@mail.nih.gov 
 
 
 
 
 
 
Patient’s Name: (FML)  
  
Institution:  
  
Medical Record Number:  
  
Investigator:  
  
Patient’s Birth date:  
  
Signature of  Treating 
Physician 
  
  
Sex: ______male ______female  
  
IRB approval valid until (date):  
  
Date Informed Consent 
was signed:  
  
Race:  
Ethnicity:  
Projected start date of 
treatment:  
  
  
  
  
  
  
  
  
  
  
  
  
  
_____ Black  
___Hispanic  
_____ Caucasian  
___Non-Hispanic  
_____ Asian  
___Other:_____  
_____ American Indian  
  
_____Native Hawaiian/ 
Pacific Islander  
  
_____ Other 
_________________  
  
 
 
 
 
 
 
 

Clinical Center # 11-C-0200 
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105 
 
INCLUSION CRITERIA: All responses must be YES.  A NO response will make the 
subject ineligible.  
 
Histologically documented (confirmed by the department of pathology at the 
institution where the patient is enrolled prior to patient enrollment) alveolar 
soft part sarcoma that is not curable by surgery. 
Block or 6 tumor sections available?   
Yes 
No N/A 
 
 
 
 
 
  
Patients must show evidence of objective disease progression per RECIST 1 
on scans within the 6 month period immediately preceding enrollment.  Both 
scans used to determine disease progression should have been obtained within 
this 6-month period.   
 
 
 
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 11 for the evaluation of measurable disease. 
 
 
 
Any prior therapy must have been completed ≥4 weeks prior to enrollment on 
protocol and the participant must have recovered to eligibility levels from 
prior toxicity.  Patients should be at least 6 weeks out from nitrosoureas and 
mitomycin C.  Prior radiation should have been completed ≥4 weeks prior to 
study enrollment and all associated toxicities resolved to eligibility levels.  
Patients who have had prior monoclonal antibody therapy must have 
completed that therapy at least 3 half-lives of the antibody or 6 weeks ago.  
Patients who have received more than a cumulative dose of 350 mg/m2 of 
doxorubicin may be enrolled at the discretion of the Coordinating Center PI 
after consultation with a cardiologist and if screening echocardiogram is 
normal.  Patients must be ≥2 weeks since any investigational agent 
administered as part of a Phase 0 study (also referred to as an “early Phase I 
study” or “pre-Phase I study” where a sub-therapeutic dose of drug is 
administered) at the Coordinating Center PI’s discretion, and should have 
recovered to eligibility levels from any toxicities. 
 
 
 
Patients with no prior therapy are eligible, provided they have metastatic 
disease that is not curable by surgery.   
 
 
 
Patients with newly diagnosed, unresectable, metastatic, and measurable 
ASPS who show clinical evidence of disease progression (including history 
and increasing physical symptoms) are eligible providing that on-study 
documentation includes a physician’s rationale that supports evidence of 
clinical disease progression (i.e., increasing tumor pain). 
 
 
 
Age ≥ 16 years? 
 
 
 
If 16-17 years old, BSA ≥1.7 m2 OR weight ≥60 kg? 
 
 
 
ECOG performance status ≤2 (please enter status _______), see Appendix A? 
 
 
 
Life expectancy of greater than 3 months? 
 
 
 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
106 
 
Patients must have normal organ and 
marrow function as defined below: 
a. Leukocytes >3,000/mcL 
b. Absolute neutrophil count >1,500/mcL 
c. Platelets >100,000/mcL 
d. Hemoglobin >9 g/dL 
e. Total serum bilirubin within normal 
institutional limits 
f. AST(SGOT)/ALT(SGPT) 2.5 X 
institutional upper limit of normal 
g. Creatinine within normal institutional 
limits OR creatinine clearance 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional 
normal 
Results: 
WBC_________ 
Date____________ 
ANC_________  
Date____________ 
Platelets_______ 
Date____________   
Hgb__________ 
Date____________ 
Total Bilirubin_______ 
ULN______ Date__________ 
AST(SGOT)_________  
ULN______ Date_________  
ALT(SGPT)__________ 
ULN______ Date__________ 
Creatinine_________      
ULN______  Date________ OR  
Creatinine clearance__________ 
Date_________ 
 
 
  
QTc <480 msec (with 
Bazett’s correction)? 
EKG Date__________
 
QTc____________ 
 
 
 
The following groups of patients are eligible after consultation with a 
cardiologist and at the Coordinating Center PI’s discretion, provided they 
have New York Heart Association Class II (NYHA; see Appendix B) cardiac 
function on baseline ECHO: 
o those with a history of Class II heart failure who are asymptomatic on 
treatment 
o those with prior anthracycline exposure greater than a cumulative 
dose of 350 mg/m2 
o those who have received central thoracic radiation that included the 
heart in the radiotherapy port. 
 
 
 
BP ≤ 140 mmHg (systolic) and ≤ 90 mmHg (diastolic).  
Initiation or adjustment of BP medication is permitted 
prior to study entry provided that the BP reading prior 
to enrollment is ≤ 140/90 mmHg. 
BP 
reading__________ 
Date__________ 
 
 
 
Patients who require potent CYP3A4 inducers or inhibitors and cannot switch 
medications must have their case reviewed by the Coordinating Center PI and 
may be enrolled only after discussion with and agreement from the 
Coordinating Center PI.  Eligibility of patients receiving any medications or 
substances known to affect or with the potential to affect the activity or PK of 
cediranib will be determined following review of their case by the 
Coordinating Center PI. 
 
 
 
Agree to use two reliable forms of contraception (hormonal or barrier method 
of birth control; abstinence) prior to study entry, for the duration of study 
participation, and for 2 months following study drug discontinuation. 
 
 
 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
107 
 
Has a signed informed consent/assent been obtained by the patient or 
parent/legal guardian? 
 
 
 
Left ventricular ejection fraction (LVEF) 
≥ institutional lower limit of normal? 
ECHO Date__________ 
LVEF__________ 
 
 
 
Able to swallow whole tablets and capsules? 
 
 
 
EXCLUSION CRITERIA: Responses should be NO 
Uncontrolled intercurrent illness including, but not limited to hypertension, 
ongoing or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
Yes 
No N/A 
 
 
 
Major surgery within 4 weeks prior to entry into the study, or a surgical 
incision that is not fully healed. 
 
 
 
Any of the following conditions: serious or non-healing wound, ulcer; history 
of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess 
within 28 days of treatment; coronary/peripheral artery bypass graft or 
stenting within the past 12 months; or cerebrovascular accident (CVA) or 
transient ischemic attack within the past 12 months. 
 
 
 
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 
the patient’s ability to swallow, retain, and/or absorb the drug? 
 
 
 
Taken potent inhibitors or inducers of CYP3A4 in the past 7 or 12 days, 
respectively?  (Eligibility will be determined following a review of their case 
by the Coordinating Center PI.) 
 
 
 
History of familial long QT syndrome, or use of medications that may cause 
QTc interval prolongation (Appendix E)? 
 
 
 
Pre-existing thyroid abnormality and unable to maintain thyroid function in 
the normal range with medication? 
 
 
 
Greater than 2+ proteinuria on two consecutive dipsticks taken no less than 1 
week apart or 24-hour urine protein of > 1 g? (Patients with < 2+ proteinuria 
are eligible following initial determination by urinalysis within 1 week prior 
to enrollment and do not need the urinalysis repeated.) 
 
 
 
Receiving any other investigational agents? 
 
 
 
Prior treatment with any VEGF receptor tyrosine kinase inhibitor (e.g., 
cediranib, sunitinib, pazopanib, sorafenib)?  (Prior treatment with 
bevacizumab is allowed.) 
 
 
 
Pregnant? 
Pregnancy Test Date: 
 
 
 
Breastfeeding? 
 
 
 
HIV-positive on combination antiretroviral therapy? 
 
 
 
Requires use of warfarin or its derivatives?  (Note: Low molecular weight 
heparin is permitted if clinically indicated.) 
 
 
 

Clinical Center # 11-C-0200 
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108 
 
 
Pre Study Eligibility Screening Evaluations (required within the designated 
number of days prior to patient enrollment): 
Date Done: 
History and Physical Exam (8 days) 
 
Height, Weight, vital signs, EKG, and performance status (8 days) 
 
CBC, Diff, Plts, Blood Chemistries* (8 days)  
* Na+, K+, phosphorus, magnesium, Creatinine, BUN, calcium, glucose, albumin, 
SGPT (ALT), SGOT (AST), Alkaline Phos, Bilirubin, total protein, TSH 
 
Troponin T or I (8 days) 
 
Urinalysis (8 days) 
 
Appropriate anatomic imaging studies (28 days) 
 
EKG (8 days) 
 
Echo (28 days) 
 
Pregnancy Test (8 days if clinically indicated) 
 
 
DESCRIPTIVE FACTORS: 
Primary: ___________________________________               Histology: ____________________ 
Other Chronic Diseases: Y / N (If yes, please explain):  
 
 
 
 
 
 
 
 
 
 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
109 
 
PRIOR THERAPY (Please specify date, procedure, agent, dose, response) 
YES   NO 
 
____    ____         1. Surgery/Biopsy:  
 
____    ____         2. Chemotherapy:  
____    ____         3. Radiotherapy:  
____    ____         4. Hormonal Therapy:  
____    ____         5. Immunotherapy:  
 
 
 
Physician’s Signature: ____________________________        Date: _________________ 
Printed Name of Physician: ________________________ 
To be completed by participating center when registering a patient: 
 
Date Registered with NCI ______/_______/_______ 
Spoke With: ______________________________________ 
Study ID: ________________________________________ 
Eligibility Checklist Completed By: __________________ 
Assigned CRA / Data Manager: _____________________ 
 
A confirmation of registration will be sent to you by the NCI. 
 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
110 
 
Participant Status Updates Form 
Complete form and send via encrypted email to NCI Central Registration Office (HOIS) at 
ncicentralregistration-l@mail.nih.gov AND fax or email to the Coordinating Center Research Nurse 
at (240) 858-3162 ashley.bruns@nih.gov 
Patient Information: 
First name 
_____________________________ 
Last name 
_____________________________ 
Middle initial 
___________ 
ID number:________________________________________ 
Protocol Number (CC# preferred):_____________________ 
Off Treatment Date (mm/dd/yy):_____________________ 
Off Treatment Reason:_____________________________ 
Off Study Date (mm/dd/yy): _________________________ 
 
Choose one of the following off-study reasons: 
 
C: Completed Study 
 
L: Lost to follow-up 
 
R: Refused Further Treatment 
 
T: Toxicity 
 
D: Death 
 
P: Progressive Disease  
 
O: Other 
 
Death Date: (mm/dd/yy): ______________________________ 
 
Choose one or more of the following DOD Sources: 
Social Security Death Index SS#:______________________ 
http://ssdi.rootsweb.com/ 
 Obituaries 
Document:_______________________http://www.legacy.com/washingtonpost/DeathNotices 
Cause of 
Death:_____________________________________________________________________ 
Place of 
Death:______________________________________________________________________ 
Family/staff member name notifying DOD:_________________________________________ 
 
Registrar:  
Name:___________________________________________ 
Work Phone:________________________ Today's Date: ___________________________ 
 
Comments: 
 
 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
111 
 
Appendix G: Study Diary 
Page 1 Cediranib 
 
 
 
Cycle Number _______ 
CTEP-assigned Protocol # _____________ 
 
Local Protocol # ______________________ 
Today’s date ________________________________ 
Patient Name________________________________  Patient Study ID ________________________ 
(initials acceptable) 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle. 
2. 
You will take your dose of cediranib each day at approximately the same time.  Please take the tablet(s) on an 
empty stomach at least 1 hour before or 2 hours after meals.  You will take ____15 mg tablets and ____ 20 mg 
tablets every morning. 
3. 
Record the date, the number of tablets 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 bring your pill bottle and this form to your physician when you go for your next appointment. 
 
Date 
 
Day 
Time of 
daily dose 
# of tablets taken 
Blood Pressure 
Comments 
15 mg 
20 mg 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
Patient’s Signature: _____________________________________________  Date: _____________________________ 
Physician’s Office will complete this section: 
1. 
Date patient started protocol treatment______________ Date patient was removed from study________________ 
2. 
Patient’s planned daily dose_____________________    Total number of pills taken this month ______________ 
Physician/Nurse/Data Manager’s Signature __________________________________________________________ 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
112 
 
Appendix G: Study Diary 
Page 2 Cediranib 
 
 
 
Cycle Number _______ 
CTEP-assigned Protocol # _____________ 
 
Local Protocol # ______________________ 
Today’s date ________________________________ 
Patient Name________________________________  Patient Study ID_____________________________ 
(initials acceptable) 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle. 
2. 
You will take your dose of cediranib each day at approximately the same time.  Please take the tablet(s) on an 
empty stomach at least 1 hour before or 2 hours after meals.  You will take ____15 mg tablets and ____ 20 mg tablets 
every morning. 
3. 
Record the date, the number of tablets 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 bring your pill bottle and this form to your physician when you go for your next appointment. 
 
Date 
 
Day 
Time of 
daily dose 
# of tablets taken 
Blood Pressure 
Comments 
15 mg 
20 mg 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
Patient’s Signature: _____________________________________________  Date: _______________________________ 
Physician’s Office will complete this section: 
1. 
Date patient started protocol treatment_________       Date patient was removed from study _________________ 
2. 
Patient’s planned daily dose_________________    Total number of pills taken this month   _________________ 
Physician/Nurse/Data Manager’s Signature ___________________________________________________________ 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
113 
 
Appendix G: Study Diary 
Page 1 Sunitinib 
 
 
 
Cycle Number _______ 
CTEP-assigned Protocol # _____________ 
 
Local Protocol # ______________________ 
Today’s date ________________________________ 
Patient Name________________________________  Patient Study ID___________________________ 
(initials acceptable) 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle. 
2. 
You will take your dose of sunitinib each day in the morning.  You will take  ___12.5 mg capsules and ___ 25 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 bring your pill bottle and this form to your physician when you go for your next appointment. 
 
Date 
 
Day 
Time of 
daily dose 
# of capsules taken 
Blood Pressure 
Comments 
12.5 mg 
25 mg 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
Patient’s Signature: _____________________________________________  Date: _______________________________ 
Physician’s Office will complete this section: 
1. 
Date patient started protocol treatment_____________   Date patient was removed from study_________________ 
2. 
Patient’s planned daily dose_____________________    Total number of pills taken this month _______________ 
Physician/Nurse/Data Manager’s Signature ____________________________________________________________ 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
114 
 
Appendix G: Study Diary 
Page 2 Sunitinib 
 
 
 
Cycle Number _______ 
CTEP-assigned Protocol # _____________ 
 
Local Protocol # ______________________ 
Today’s date ________________________________ 
Patient Name________________________________  Patient Study ID__________________________ 
(initials acceptable) 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle. 
2. 
You will take your dose of sunitinib each day in the morning.  You will take ____12.5 mg capsules and ___ 25 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 bring your pill bottle and this form to your physician when you go for your next appointment. 
 
Date 
 
Day 
Time of 
daily dose 
# of capsules taken 
Blood Pressure 
Comments 
12.5 mg 
25 mg 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
Patient’s Signature: _____________________________________________  Date: _______________________________ 
Physician’s Office will complete this section: 
1. 
Date patient started protocol treatment_____________   Date patient was removed from study_________________ 
2. 
Patient’s planned daily dose_____________________    Total number of pills taken this month________________ 
Physician/Nurse/Data Manager’s Signature _____________________________________________________________ 
 
 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
115 
 
Appendix G: Study Diary 
Page 1 Sunitinib DL -2 Only 
 
 
 
Cycle Number _______ 
CTEP-assigned Protocol # _____________ 
 
Local Protocol # ______________________ 
Today’s date ________________________________ 
Patient Name________________________________  Patient Study ID___________________________ 
(initials acceptable) 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle. 
2. 
You will take your dose of sunitinib each day in the morning for 3 weeks (Days 1-21).  You will take ____12.5 mg 
capsules and ____ 25 mg capsules.  You may take the capsules with or without food as you wish.   
During week 4 (Days 22-28), you will not take sunitinib.   
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 bring your pill bottle and this form to your physician when you go for your next appointment. 
 
Date 
 
Day 
Time of 
daily dose 
# of capsules taken 
Blood Pressure 
Comments 
12.5 mg 
25 mg 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
Patient’s Signature: _____________________________________________  Date: ______________________________ 
Physician’s Office will complete this section: 
1. 
Date patient started protocol treatment_____________   Date patient was removed from study_________________ 
2. 
Patient’s planned daily dose______________________    Total number of pills taken this month_______________ 
Physician/Nurse/Data Manager’s Signature ____________________________________________________________ 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
116 
 
Appendix G: Study Diary 
Page 2 Sunitinib DL -2 Only 
 
 
 
Cycle Number _______ 
CTEP-assigned Protocol # _____________ 
 
Local Protocol # ______________________ 
Today’s date ________________________________ 
Patient Name________________________________  Patient Study ID___________________________ 
(initials acceptable) 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle. 
2. 
You will take your dose of sunitinib each day in the morning for 3 weeks (Days 1-21).  You will take ____12.5 mg 
capsules and ____ 25 mg capsules.  You may take the capsules with or without food as you wish.   
During week 4 (Days 22-28), you will not take sunitinib.   
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 bring your pill bottle and this form to your physician when you go for your next appointment. 
 
Date 
 
Day 
Time of 
daily dose 
# of capsules taken 
Blood Pressure 
Comments 
12.5 mg 
25 mg 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
NO DRUG 
 
 
 
 
 
23 
NO DRUG 
 
 
 
 
 
24 
NO DRUG 
 
 
 
 
 
25 
NO DRUG 
 
 
 
 
 
26 
NO DRUG 
 
 
 
 
 
27 
NO DRUG 
 
 
 
 
 
28 
NO DRUG 
 
 
 
 
Patient’s Signature: _____________________________________________  Date: _______________________________ 
Physician’s Office will complete this section: 
1. 
Date patient started protocol treatment_____________   Date patient was removed from study__________________ 
2. 
Patient’s planned daily dose______________________    Total number of pills taken this month_______________ 
Physician/Nurse/Data Manager’s Signature _____________________________________________________________ 

Clinical Center # 11-C-0200 
CTEP # 8875 
 
117 
 
Appendix H: Blood Pressure Collection and Recording 
 
General Guidelines 
Frequency of monitoring: Blood pressure will be monitored every 2 weeks by any health care provider 
during the first cycle of Part I and Part II, then at the start of every cycle for the duration of treatment 
(unless patients have experienced elevated blood pressure requiring drug therapy, at which point the 
frequency of BP monitoring by a health care provider will be determined by the local PI).  Patients on 
study for 2 years or longer will have their blood pressure monitored at the start of every third cycle.  
Additionally, all patients will be required to monitor their BP at home at least once a day while on study 
and record the readings in the Study Diary (Appendix G).   
 
Data recording: All required data should be recorded in the appropriate eCRF 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 
 
Risk factors for hypertension (assess and record data in eCRF) 
• 
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) 
 
Baseline data collection (at registration) 
All patients: 
• 
Current BP 
• 
Proteinuria, if present 
 
Patients with preexisting hypertension (i.e., those for whom “hypertension” is entered as a concomitant 
condition at registration, or those who are currently receiving therapy with antihypertensive medication) – 
also record: 
• 
Date of HTN diagnosis (original) 
• 
Type HTN (essential or secondary) 
• 
CTCAE v5.0 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) 
 
Follow up BP data collection (while on study) 
All patients (at each clinic visit): 
• 
Current BP 
• 
Proteinuria, if present 
 
 

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Patients with treatment-emergent hypertension [defined as >140/90] – record at time of hypertension 
diagnosis and at all subsequent visits: 
• 
BP changes from baseline (or from previous assessment) (specify grade changes per Table in 
Appendix I) 
• 
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 
 
 
Patients with preexisting hypertension at study entry – record at each visit: 
• 
BP changes from previous clinic visit (specify grade changes per Table in Appendix I) 
• 
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, angiotensin II receptor antagonists. 

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Appendix I: Management of Hypertension  
 
Recommended Hypertension Monitoring and Management 
(BP in mmHg) 
 
Grade 
(CTCAE v5) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Sunitinib/Cediranib 
Dose Modification 
Persistent Grade 1 
Pre-hypertension 
Systolic 120-139 
Diastolic 80-89  
 
 
Standard       
 
No change 
Persistent Grade 2- 
Moderate 
Systolic 140-159  
Diastolic 90-99  
   
Protocol-specific 
guidance supersedes any 
other management 
guidelines, including 
CTCAE v5  
Step 1)  Initiate LA DHP CCB 
treatment and  if needed, after 
24-48 hr Rx,  increase dose in 
stepwise  fashion every 24-48 
hours  until BP is controlled or 
at max dose of Rx 
 
Step 2) If BP still not 
controlled, add another 
antihypertensive Rx, a BB,  
ACE1, ARB, or ABB; 
increase dose of this drug as 
described in step 1   
 
Step 3) If BP still not 
controlled, add 3rd drug from 
the list of antihypertensives in 
step 2; increase dose of this 
drug as described in step 1 
 
Step 4) If BP still not 
controlled, consider either 1 
dose reduction of 
sunitinib/cediranib or stopping 
sunitinib/cediranib  
 
NOTE: Stopping or reducing 
the dose of sunitinib/cediranib 
is expected to cause a 
decrease in BP The treating 
physician should monitor the 
patient for hypotension and 
adjust the number and dose of 
antihypertensive 
medication(s) accordingly. 
 
BP should be 
monitored as 
recommended by 
the treating 
physician  
No change except as 
described in step 4 

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Persistent Grade 3 
Severe  
Systolic >160 
Diastolic >100  
 
Protocol-specific 
guidance supersedes any 
other management 
guidelines, including  
CTCAE v5 
HOLD sunitinib/cediranib 
until systolic BP <159 and 
diastolic BP <99.  
 
 
BP management is identical to 
that for Grade 2 (see steps 1-4 
above) with 2 major 
exceptions:  
1)  If systolic BP >180 or 
diastolic BP >110 and the 
patient is symptomatic: 
optimal management with 
intensive IV support in ICU; 
STOP sunitinib/cediranib 
and notify hospital staff that 
stopping sunitinib/cediranib 
may result in a decrease in 
BP 
 and  
2) If systolic BP >180 or 
diastolic BP >110 and the 
patient is asymptomatic, 
2 new anti-hypertensives 
must be given together in 
step 1 (and dose escalated 
appropriately as in step 1). 
 
NOTE: Stopping or reducing 
the dose of sunitinib/cediranib 
is expected to cause a 
decrease in BP The treating 
physician should monitor the 
patient for hypotension and 
adjust the number and dose of 
antihypertensive 
medication(s) accordingly 
BP should be 
monitored as 
recommended by 
the treating 
physician unless 
the patient is 
symptomatic with  
systolic BP >180 or 
diastolic BP >110 
in which case, 
monitoring should 
be intensive. 
 
 
HOLD 
sunitinib/cediranib 
until systolic BP <159 
and diastolic BP  
<99. 
 
In most circumstances, 
if   BP cannot be 
controlled after an 
optimal trial of anti-
hypertensive 
medications, consider 
either 1 dose reduction 
of sunitinib/cediranib 
or stopping 
sunitinib/cediranib. 
HOWEVER, 
if the patient requires 
hospitalization for 
management of  
symptomatic systolic 
BP >180 or diastolic 
BP >110,  permanently 
discontinue 
sunitinib/cediranib or 
if BP is controlled, re-
start 
sunitinib/cediranib at 1 
lower dose level after 
consultation with the 
study Principal 
Investigator 
 
 
 
 
 
Grade 4 
Life-threatening 
consequences of 
hypertension 
 
Optimal management with 
intensive IV support in ICU; 
STOP sunitinib/cediranib 
and notify hospital staff that 
stopping sunitinib/cediranib 
may result in a decrease in 
BP 
Intensive 
Permanently 
discontinue 
sunitinib/cediranib or 
if BP is controlled, re-
start 
sunitinib/cediranib at 1 
lower dose level after 
consultation with the 
study Principal 
Investigator 
Abbreviations: dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers (BB), angiotensin 
converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), alpha beta blocker (ABB) 
• If patients require a delay of >2 weeks for management of hypertension, discontinue protocol therapy 
• If patients require >2 dose reductions, discontinue protocol therapy 
• Patients may have up to 2 drugs for management of hypertension prior to any dose reduction in sunitinib/cediranib 
• 24-48 hours should elapse between modifications of anti-hypertensive therapy 
• Hypertension should be graded using CTCAE v5. 

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Oral Antihypertensive Medication List 
 
Agents in bold characters are suggested as optimal choices to avoid or minimize 
potential drug-interactions with cediranib through CYP450. 
 
Agent 
class 
 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine XL 
30 mg daily 
60 mg daily 
90 mg daily 
CYP 3A4 substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
and inhibitor 
Selective 
 Blockers 
(BB) 
metoprolol 
25 mg 
twice daily 
50 mg 
twice daily 
100 mg  
twice daily 
CYP 2D6 substrate 
atenolol 
25 mg daily 
50 mg daily 
100 mg daily 
No 
acebutolol 
100 mg 
twice daily 
200-300 mg 
twice daily 
400 mg  
twice daily 
Yes (CYP450 
unknown) 
bisoprolol 
2.5 mg daily 
5-10 mg daily 
20 mg daily 
Yes (CYP450 
unknown) 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
 
captopril 
12.5 mg 3x daily 
25 mg 3x daily 
50 mg 3x daily 
CYP 2D6 substrate 
enalapril 
5 mg daily 
10-20 mg daily 
40 mg daily 
CYP 3A4 substrate 
ramipril 
2.5 mg daily 
5 mg daily 
10 mg daily 
Yes (CYP450 
unknown) 
lisinopril 
5 mg daily 
10-20 mg daily 
40 mg daily 
No 
fosinopril 
10 mg daily 
20 mg daily 
40 mg daily 
Yes (CYP450 
unknown) 
Rarely used:       
perindopril 
4 mg daily 
none 
8 mg daily 
Yes, but not CYP450 
Rarely used:       
quinapril 
10 mg daily 
20 mg daily 
40 mg daily 
No 
Angiotensin 
II Receptor 
Blockers 
(ARBs) 
losartan 
25 mg daily 
50 mg daily 
100 mg daily 
CYP 3A4 substrate 
candesartan 
4 mg daily 
8-16 mg daily 
32 mg daily 
CYP 2C9 substrate 
irbesartan 
75 mg daily 
150 mg daily 
300 mg daily 
CYP 2C9 substrate 
telmisartan 
40 mg daily 
none 
80 mg daily 
Yes, but not CYP450 
valsartan 
80 mg daily 
none 
160 mg daily 
Yes, but not CYP450 
 and   
Blocker 
labetolol 
100 mg  
twice daily 
200 mg  
twice daily 
400 mg  
twice daily 
CYP 2D6 substrate 
and inhibitor 
 
 

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Appendix J: LVEF Dose Modification Table 
 
Asymptomatic Decrease in LVEF 
 
The decision to continue or hold STUDY DRUG is based on the LVEF as it relates to the 
institutions’s lower limit of normal (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 
LVEF Decrease  
< 10% 
LVEF Decrease   
10-15% 
LVEF Decrease  
≥ 16% 
Normal 
Continue 
Continue 
Continue and repeat 
ECHO within 1-2 
cycles 
1-5% below LLN 
Continue and repeat 
ECHO within 1-2 
cycles 
Continue and repeat 
ECHO within 1-2 
cycles 
HOLD and repeat 
ECHO within 1-2 
cycles 
≥ 6% below LLN 
Continue and repeat 
ECHO within 1-2 
cycles 
HOLD and repeat 
ECHO within 1-2 
cycles 
HOLD and repeat 
ECHO within 1-2 
cycles 
 
Discontinue STUDY DRUG if: 
 
• 
Two consecutive HOLD catagories occur. 
 
• 
Three intermittant HOLD catagories occur (at the discretion of the investigator, STUDY 
DRUG may also be permanently discontinued prior to the occurance of 3 intermittant 
HOLD catagories). 
If LVEF is maintained at a “Continue and repeat ECHO” or improves from a HOLD to a 
“Continue and repeat ECHO” category, additonal echocardiograms prior to the next scheduled 
ECHO will be at the discretion of the investigator. 
 
Symptomatic Cardiac Events 
 
Discontinue STUDY DRUG if: 
• 
A patient has symptoms of congestive heart failure (CHF) and a diagnosis of CHF is 
confirmed. 
• 
A patient has a myocardial infarction. 
 
 
 
 

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Appendix K: 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. 
• 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. 

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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 L:  Information on Possible Interactions with Other Agents for 
Patients and their Caregivers and Non-study Health Care Team 
 
Sunitinib 
The patient _________________ is enrolled on a clinical trial using the experimental agent 
sunitinib.  This clinical trial is sponsored by the National Cancer Institute.  This form is 
addressed to the patient, but includes important information for others who care for this patient.  
 
Sunitinib interacts with many drugs that are processed by your liver.  Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study.  It is 
also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study.  When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the counter 
remedy), or anything that you buy from the health food store or grocery store (herbal 
supplement).  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants, or nurse practitioners) that you are taking part in a clinical trial.  
Bring this paper with you.  These are the things that you and they need to know:  
 
• 
Sunitinib is metabolized (converted in the body) by a liver enzyme called CYP3A4.  
Sunitinib must be used very carefully with other medicines that need this liver enzyme to be 
effective or to be cleared from your system.  
• 
You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
• 
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 
CYP3A4.” 
• 
Your regular prescribers should look at a frequently updated drug information reference to 
see if any medicine they want to prescribe is on a list of drugs to avoid.   
• 
Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s usually 
big and catches your eye.  They also have a generic name—it’s usually small and printed on 
the ingredient list.  Find the generic name (your pharmacist can help) and look at the table 
on the back of this page.  Be careful. 
• 
You should not take St. John’s wort or grapefruit juice with sunitinib.  
• 
You should not receive steroids unless they are absolutely necessary; tell your study doctor 
if you are taking, have a prescription for, or have been given steroids. 
• 
You should not take drugs that affect your heart rhythm.  Tell your study doctor if you are 
taking, have a prescription for, or have been given such heart medications. 
 
Other medicines can be a problem with your study drugs.  
• 
You should check with your doctor or pharmacist whenever you need to use an over-the-
counter medicine or herbal supplement.  

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• 
Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you.  Your study doctor’s name is ___________________ 
and he or she can be contacted at _______________________.  
 
 
 

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Cediranib 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, cediranib (AZD2171). This clinical trial is sponsored by the National 
Cancer Institute (NCI). This form is addressed to the patient, but includes important information 
for others who care for this patient.  
 
These are the things that you as a prescriber need to know:  
Cediranib (AZD2171) interacts with certain specific enzymes in the liver and certain transport 
proteins that help move drugs in and out of cells.  
• 
The enzymes in question are CYP 3A4, 2D6, flavin-containing monooxygenase (FMO) and 
UGT1A4. Cediranib (AZD2171) is metabolized by FMO1, FMO3 and UGT1A4 and may 
be affected by other drugs that strongly inhibit or induce these enzymes. Cediranib 
(AZD2171) weakly inhibits CYP 2D6 and 3A4 and may increase levels of affected 
substrates.  
• 
Cediranib (AZD2171) may induce gastrointestinal CYP3A and UGT enzymes, therefore 
potentially reducing the effectiveness of hormonal contraceptives.  
• 
The transport proteins in question are P-glycoprotein (P-gp) and breast cancer resistance 
protein (BCRP). Cediranib (AZD2171) requires P-gp to move in and out of cells. Cediranib 
(AZD2171) inhibits BCRP, P-gp, OATP1B1, OATP1B3, OCT2, MATE1 and MATE2-K 
and this may affect the clearance of other drugs that are dependent on these transport 
proteins.  
• 
Cediranib (AZD2171) is 95% protein bound (human serum albumin and alpha-1-acid 
glycoprotein) and may displace other highly protein-bound drugs. Use caution in patients 
taking concomitant medications with narrow therapeutic ranges.  
• 
Patients receiving Cediranib (AZD2171) are at increased risk of bleeding and hemorrhage. 
Increase monitoring in patients who also receive anticoagulation therapy.  
June 2016  
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.  
Cediranib (AZD2171) interacts with many drugs which can cause side effects. Because of this, it 
is very important to tell your study doctors about all of your medicines before you enroll on this 
clinical trial. It is also very important to tell them if you stop taking any regular medicines, or if 
you start taking a new medicine while you take part in this study. When you talk about your 
medications with your doctors, include medicine you buy without a prescription (over-the-
counter remedy), or any herbal supplements such as St. John’s Wort. It is helpful to bring your 
medication bottles or an updated medication list with you.  
 
Many health care prescribers can write prescriptions. You must also tell your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
 
 

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These are the things that you and they need to know:  
Cediranib (AZD2171) must be used very carefully with other medicines that need certain liver 
enzymes and transport proteins to be effective or to be cleared from your system. Before you 
enroll onto the clinical trial, your study doctor will work with your regular health care providers 
to review any medicines and herbal supplements that are considered “strong inducers/inhibitors 
of FMO1, FMO3, UGT1A4 and P-gp.” Cediranib (AZD2171) inhibits enzymes “CYP 2D6 and 
3A4, transport proteins BCRP, P-gp, OATP1B1, OATP1B3, OCT2, MATE1 and MATE2-K and 
is highly protein-bound.” These characteristics may change how other medicine works in your 
body.  
• 
Please be very careful! Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug. Speak to your doctor or pharmacist to 
determine if there could be any side effects.  
• 
Cediranib (AZD2171) can increase the risk of bleeding and interferes with wound healing. 
Let your doctor know if you recently had or are planning to have any surgery.  
• 
Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any  
 
medicine. Your study doctor’s name is _______________________________  
 
and he or she can be contacted at ____________________________________. 
June 2016  
 
STUDY DRUG INFORMATION WALLET CARD 
You are enrolled on a clinical trial using the experimental 
drug AZD2171 (cediranib). This clinical trial is sponsored by 
the NCI. Cediranib (AZD2171) interacts with drugs that are 
processed by your liver, or use certain transport proteins in 
your body. Because of this, it is very important to:  
➢ Tell your doctors if you stop taking regular medicines or 
if you start taking any new 
➢ Tell all of your health care providers (doctors, physician 
assistant, nurse practitioners, pharmacists) 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.  
➢ Cediranib (AZD2171) interacts with CYP3A4, 2D6, FMO1, 
FMO3, UGT1A4 and transport proteins, P-gp and BCRP 
and must be used very carefully with other medicines 
that interact with these enzymes and proteins. 
➢ Before you enroll onto the clinical trial, your study doctor 
will work with your regular health care providers to 
review any medicines that are considered ““strong 
inducers/inhibitors of FMO1, FMO3, UGT1A4 and P-gp.” 
Cediranib (AZD2171) inhibits “CYP 2D6 and 3A4 and 
transport proteins BCRP, P-gp, OATP1B1, OATP1B3, 
OCT2, MATE1 and MATE2-K and is highly protein-
bound.” It may change how other medicine works in your 
body.  
➢ Before prescribing new medicines, your regular health 
care providers should go to a frequently-updated 
medical reference for a list of drugs to avoid, or contact 
your study doctor.  
➢ Your study doctor’s name is ___________________  
 
and can be contacted at _____________________.  

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Appendix M: Informed Consent Form Template for Cancer Treatment Trials 
 
Study Title: A Phase II Trial in Which Patients With Metastatic Alveolar Soft Part Sarcoma Are 
Randomized to Either Sunitinib or Cediranib Monotherapy, With Cross-Over at Disease 
Progression 
 
 
Introduction 
We invite you to take part in this research study. 
 
First, we want you to know that: 
Taking part in this research is entirely voluntary. 
 
You may choose not to take part, or you may withdraw from the study at any time.  In either 
case, you will not lose any benefits to which you are otherwise entitled.  Leaving the study 
will not affect your medical care.  You can still get your medical care from our institution. 
 
You may receive no benefit from taking part.  The research may give us knowledge that may 
help people in the future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your doctors or research team before you agree to the 
study. 
 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with family, friends or your personal 
physician or other health professional. 
 
If you are signing for a minor child, “you” refers to “your child” throughout the consent 
document. 
 
Why is this study being done? 
The purpose of this study is to find out what effects, good and/or bad, the drugs cediranib and 
sunitinib have on you and your alveolar soft part sarcoma.  This study will also help to find out 
how cediranib and sunitinib work in patients who have your type of cancer.  The 2 drugs will not 
be given in combination during this study.  You will receive one drug (either cediranib or 
sunitinib) until that drug is no longer working to control your cancer or you have too many side 
effects, and then the other drug will be given.   
 
Cediranib is an experimental drug not yet approved by the Food and Drug Administration.  
Sunitinib has been approved for treating a certain type of kidney cancer and gastrointestinal 
cancer, but is considered experimental in the treatment of alveolar soft part sarcoma.  Cediranib 
and sunitinib work by blocking the creation of new blood vessels.  All solid tumors need new 
blood vessels to grow.  We hope cediranib and sunitinib will stop tumor growth by preventing 
the growth of new blood vessels.  So far, more than 800 patients have taken part in clinical trials 

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of cediranib, including more than 40 patients with alveolar soft part sarcoma.  More than 8,000 
patients have received sunitinib, and at least 10 of these patients had alveolar soft part sarcoma.  
Some patients with alveolar soft part sarcoma treated with cediranib or sunitinib had tumors that 
either decreased in size or remained stable without growth for a prolonged period of time.  Both 
cediranib and sunitinib are considered experimental drugs for your type of cancer.  
 
How many people will take part in the study? 
Up to 70 patients with alveolar soft part sarcoma will take part in this study across several 
centers in the United States. 
 
Description of Research Study 
What will happen if you take part in this research study?   
After you are accepted for this study and you choose to take part, you will be "randomized" into 
one of the treatment groups (called “arms”).  Randomization means that you are put into a group 
by chance.  A computer program will place you in one of the treatment arms.  Neither you nor 
your doctor can choose the treatment arm you will be in.  This study is divided into two parts.  
During Part I, you will begin taking cediranib or sunitinib (depending on which arm you are in) 
by mouth once a day, every day.  The treatment will be given in cycles.  Each cycle is 28 days 
long.  You will continue taking the study drug assigned to you (either cediranib or sunitinib) 
until that drug is no longer working to control your cancer, or you have too many side effects.  
After this happens, you will not get a study drug for 2 weeks before beginning Part II of the 
study.  During Part II, you will receive the other study drug (either cediranib or sunitinib) that 
you did not take during Part I.  However, if too many patients in a treatment arm have serious 
side effects or not enough patients have disease that responds, that treatment arm may be closed 
to new patients.  If the other treatment arm is closed, you would not receive the other drug and 
your participation in the study would end after you complete Part I.  Currently, the cediranib 
treatment arm for patients with newly diagnosed ASPS is closed.  No patients will enroll or cross 
over to this arm to receive cediranib. 
 
Cediranib and sunitinib can be taken while you are an outpatient.  You will take either cediranib 
or sunitinib during Part I and switch to the other drug during Part II.  You are to swallow the 
tablets or capsules whole at about the same time each morning.  Cediranib must be taken on an 
empty stomach, 1 hour before or 2 hours after meals.  Sunitinib can be taken with or without 
food as you wish.  You should write down the number of pills you take and the time you took 
them in the diary that your study team will give you.  If you miss doses, please write this in your 
diary.  If you remember your missed dose within 3 hours of the time you usually take a dose, you 
can take enough pills to make up for the missed dose; if not, do not make up the missed dose.  
The dose will be changed if you have any serious side effects.  This will be determined by your 
study team.   
 
Standard procedures being done because you are in this study; these may be done more 
often because you are in the study: 
 
• Clinic visit to ask how you are feeling and to evaluate you with a physical examination at 
the start of each cycle (every 4 weeks) (every 3 cycles for patients on study for 2 years or 
longer) 

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• Vital signs: You will need to have your vital signs (measurement of your temperature, 
breathing rate, and blood pressure) measured each time you are seen in the outpatient 
clinic.  You will also need to have your blood pressure measured by a health care 
provider every 2 weeks for the first cycle of Part I and Part II.  If you have high blood 
pressure and need medication to control it, the study doctor will tell you how often you 
will need to have your blood pressure checked during the study.  We will also ask you to 
measure your own blood pressure at home each day for the entire study.  If your blood 
pressure is ever more than 150/90, or if the diastolic pressure (the bottom number) 
increases by more than 20, you should call the research team.  You should also call the 
research team if you experience any symptoms of high blood pressure, such as chest pain, 
shortness of breath, headache, blood in the urine, or double vision. 
• Blood tests: Measurement of your white blood cells, red blood cells and platelets, and 
measurements of your blood sugar and electrolytes and of how your liver and kidneys 
work, will be done every 2 weeks for the first 2 cycles of Part I and Part II and then at the 
start of all other cycles (every 3 cycles for patients on study for 2 years or longer).  Doing all 
of these blood tests will require 1-2 tablespoons (20-30 mL) of blood each time.  
• Urine test: You will be asked to give a urine sample for testing at the start of each cycle, 
(every 3 cycles for patients on study for 2 years or longer) or more often if your results have 
been abnormal.  Depending on the results, you may be asked to collect your urine for 24 
hours for further testing. 
• Pregnancy test in women who are able to become pregnant before you start cediranib or 
sunitinib and before you start Part II. 
• EKGs (a recording of the heart’s electrical activity) to check your heart will be done before 
you start cediranib or sunitinib, before you start Part II, and at the start of each cycle (every 
3 cycles for patients on study for 2 years or longer) to check for signs of possible damage to 
your heart. 
• Echocardiogram to check your heart will be done before you start cediranib or sunitinib, 
before you start Part II, and at other times if needed to check for signs of possible damage 
to your heart.  If abnormal, a repeat echocardiogram will be done every 2 cycles. 
• CT scans (a computerized x-ray examination) or other imaging tests such as 
ultrasound (an examination using sound waves) or MRI (an examination using magnetic 
field and radio waves) that detect your tumor will be done every 2 cycles.  PET scans (a 
scan that detects a small amount of radioactive substance that has been injected through a 
vein) will also be done at the start of the study and may be repeated.  This is done so that 
any benefit of the drug can be seen, and so that if your cancer is not responding to the 
drug, the study team can tell you and help you move to a different treatment program 
(discussed further below). 
• Plain x-ray: If you are younger than 18 years old, an x-ray of your lower legs will be 
taken to see if your bones have stopped growing before you start cediranib or sunitinib.  
This test is done because in some growing animals that received drugs similar to 
cediranib or sunitinib, changes in the structure of the bones were seen.  The x-ray will 
only be repeated if your study doctor thinks it is necessary. 
 

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Tests and procedures that are either being tested in this study or being done to see how the 
drug is affecting your body: 
 
• Measurement of cediranib in your blood: We will collect multiple blood samples 
throughout the study to measure the amount of cediranib in your blood and to help us find 
out how the body handles cediranib.  Please see the study chart for more details.  The total 
blood for all these tests will be about 1~2 tablespoons.   
 
When you are finished taking study drugs 
You can take part in this study until either you or your study team decides that the study drugs 
are not helping you.  If the first drug you are taking (either cediranib or sunitinib) is not helping 
you, you can move on to Part II of the study and receive the other drug if that treatment arm is 
open to new patients.  Your taking part is voluntary, so you can stop taking cediranib or sunitinib 
at any time, but we ask that you speak to your study team before stopping the study drug.   
 
Your study team will be watching you and your cancer during the study.  If your cancer is clearly 
getting worse during Part II of the study, then your study team will stop the study treatment.  At 
the end of the study, we will check with you or your local doctor for 30 days after you stop 
taking cediranib or sunitinib to see how you are doing.  No more testing will be required. 
 
Study Chart 
The treatment is given over 28-day periods of time called cycles.  The 28-day treatment cycle 
will be repeated as long as you are not having serious side effects and your cancer is either 
steady or getting better.  If the drug you receive during Part I of the study is no longer working to 
control your cancer or you have too many side effects, you can move on to Part II of the study 
and get the other drug if that treatment arm is open.  Before you start Part II of the study there 
will be 2 weeks during which you get no study drug.  This is called a “wash-out” period.  You 
will also need to have certain tests repeated to make sure it is safe for you to start Part II of the 
study.   
 
Each cycle is numbered.  The chart below shows what will happen to you during Cycle 1 and 
future cycles.  The left-hand column shows the day in the cycle and the right-hand column tells 
you what will happen on that day.  This schedule lists what will happen to you after you sign the 
consent form and start the study.  The cycle numbers will start at 1 again when you begin Part II 
of the study. 
 
Cycle 1 (Part I and Part II) 
Day 
 
What to do and what will happen to you 
Before 
starting 
study 
treatment 
• Get routine blood and urine tests 
• Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider (HCP) 
• Imaging tests will be done 
• EKG and echocardiogram will be done to check your heart 
• Pregnancy test 

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Cycle 1 and Future cycles (Part I and Part II) 
Day 
 
What to do and what will happen to you 
Days 1-28 • Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider (HCP) at the start of each cycle 
• Get routine blood tests every 2 weeks for the first 2 cycles, then at the start of 
each cycle (every 3 cycles for patients on study for 2 years or longer). 
• Urine sample for routine tests at the start of each cycle 
• Have your blood pressure checked by a health care provider every 2 weeks 
during cycle 1, then at the start of each cycle (every 3 cycles for patients on study 
for 2 years or longer) 
• Take cediranib or sunitinib, as given, once a day if you have no bad side 
effects and your cancer is not getting worse.  Call the research nurse or your 
study doctor if you do not know what to do. 
• Measure your blood pressure at home every day 
• Imaging tests will be done every 2 cycles to find out how your tumor is 
responding (every 3 cycles for patients on study for 2 years or longer) 
• EKGs and echocardiograms will be done to check your heart 
• Blood samples to measure cediranib will be taken at the following time points 
before taking the drug:  before your first dose, on cycle 1 day 15, on cycle 2 
day 1, on cycle 3 day 1, and on cycle 4 day 1. 
 
Stopping Therapy 
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment (if this happens during Part I, you may still go 
on to Part II of the study, as long as the other treatment arm has not been closed) 
• if you have side effects from the treatment that your doctor thinks are too severe (if this 
happens during Part I, you may still go on to Part II of the study, as long as the other 
treatment arm has not been closed) 
• if new information shows that another treatment would be better for you 
 
In this case, you will be told the reason why cediranib or sunitinib is being stopped. 
 
You can stop taking part in the study at any time.  However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you.  However, according to FDA guidelines, 
information collected on you up to that point may still be provided to the Cancer Therapy 
Evaluation Program (CTEP) at the National Cancer Institute (NCI) or designated representatives.  
If you withdraw your consent and leave the trial, any samples of yours that have been obtained 

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for the study and stored at the NCI can be destroyed upon request.  However, any samples and 
data generated from the samples that have already been distributed to other researchers or placed 
in the research databases cannot be recalled and destroyed. 
 
 
Alternative Approaches or Treatments  
What other choices do I have if I do not take part in this study? 
Instead of being in this study, you have these options: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
 
Please talk to your doctor about these and other options. 
 
Risk or Discomforts of Participation 
What side effects or risks can you expect from being in the study?  
If you choose to take part in this study, there is a risk that the study drug(s) may not be as good 
as the usual approach for your cancer or condition at shrinking or stabilizing your cancer. 
 
You also may have the following discomforts: 
• Spend more time in the hospital or doctor’s office. 
• Be asked sensitive or private questions about things you normally do not discuss. 
• May not be able to take part in future studies. 
 
The study drug(s) used in this study may affect how different parts of your body work such as 
your liver, kidneys, heart, and blood.  The study doctor will test your blood and will let you 
know if changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
 
Here are important things to know about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, and some may never go 
away. 
• Some side effects may make it hard for you to have children. 
• Some side effects may be mild.  Other side effects may be very serious and even result in 
death. 
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem: 
• If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
• Your study doctor will work with you to treat your side effects. 

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• Your study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 
• One patient on this study experienced bleeding in his brain around his cancer.  The study 
drug may have contributed to the bleeding risk.  This condition can keep oxygen from 
reaching the brain and cause brain damage or death. 
 
Studies have shown high blood pressure to be one common side effect of cediranib and sunitinib.  
Your blood pressure will be closely watched while you are taking cediranib or sunitinib.  This 
will include having your blood pressure measured every 2 weeks by a health care provider for 
the first cycle and you checking your blood pressure at home once a day for the entire study.  If 
you have high blood pressure while taking cediranib or sunitinib, your study doctor may 
recommend follow-up with your primary care physician and/or starting or increasing medication 
to lower blood pressure. 
 
We do not know if cediranib and sunitinib will have any effect on the bone growth of patients 
who have not finished growing.  Please talk to your doctor or the research team about how this 
might affect the growth of a young patient.    
 
Grapefruit juice has been shown to affect how the body handles some drugs by blocking the 
activity of the body’s cytochrome P450 (CYP450) system.  CYP450 is important in breaking 
down substances in the body, including sunitinib and many other drugs.  Therefore, please avoid 
grapefruit juice while taking cediranib or sunitinib.  The herbal supplement St. John’s wort can 
also affect blood levels of drugs such as sunitinib, and should be avoided.  We do not know if 
taking cediranib or sunitinib will cause other drugs you may be taking to work differently.  It is 
very important that you talk to a member of the research team before beginning any new 
drugs, over-the-counter medications, vitamins, or alternative therapies.  
 
Risks and side effects related to cediranib include: 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving cediranib (AZD2171), more than 20 and up to 100 may have: 
• 
Diarrhea, nausea 
• 
Tiredness 
• 
Loss of appetite 
• 
Changes in voice 
• 
High blood pressure which may cause headaches, dizziness, blurred vision 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving cediranib (AZD2171), from 4 to 20 may have: 

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• 
Pain 
• 
Constipation, vomiting 
• 
Dry mouth 
• 
Difficulty swallowing 
• 
Sores in the mouth 
• 
Infection 
• 
Bruising, bleeding 
• 
Weight loss 
• 
Dehydration 
• 
Muscle weakness 
• 
Dizziness, headache 
• 
Cough, shortness of breath, sore throat 
• 
Redness, pain or peeling of palms and soles 
• 
Blood clot which may cause swelling, pain, shortness of breath, confusion, or paralysis 
 
RARE, AND SERIOUS 
In 100 people receiving cediranib (AZD2171), 3 or fewer may have: 
• 
Anemia, kidney problems which may cause tiredness, bruising, swelling, or may require 
dialysis 
• 
Heart failure which may cause shortness of breath, swelling of ankles, and tiredness 
• 
A tear or hole in internal organs that may require surgery 
• 
Liver damage which may cause yellowing of eyes and skin, swelling 
• 
Non-healing surgical site 
• 
Damage to the brain which may cause changes in thinking 
• 
Brain damage which may cause headache, seizure, blindness (also known as Reversible 
Posterior Leukoencephalopathy Syndrome) 
• 
Kidney damage which may require dialysis 
• 
Blood clot in artery which may cause swelling, pain, shortness of breath or change of color 
in extremity 
 
Risks and side effects related to sunitinib include:  
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving sunitinib malate (SU011248 L-malate), more than 20 and up to 
100 may have: 
• Pain 
• Constipation, diarrhea, heartburn, nausea, vomiting 
• Sores in the mouth 
• Tiredness 
• Loss of appetite 
• Changes in taste 
• Sore throat 
• Redness, pain or peeling of palms and soles 
 

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OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving sunitinib malate (SU011248 L-malate), from 4 to 20 may have: 
• Anemia which may require blood transfusion 
• Blurred vision with chance of blindness 
• Bloating, passing gas 
• Dry mouth, skin 
• Chills, fever 
• Swelling of arms, legs 
• Flu-like symptoms including body aches 
• Bruising, bleeding 
• Weight loss 
• Infection, especially when white blood cell count is low 
• Dehydration 
• Dizziness, headache 
• Feeling of "pins and needles" in arms and legs 
• Depression 
• Difficulty sleeping 
• Cough, shortness of breath 
• Nose bleed 
• Hair loss, rash, itching, skin changes 
• Change in hair color 
• High blood pressure which may cause headaches, dizziness, blurred vision 
 
RARE, AND SERIOUS 
In 100 people receiving sunitinib malate (SU011248 L-malate), 3 or fewer may have: 
• Anemia, kidney problems which may cause tiredness, bruising, swelling, or may 
require dialysis 
• Blood clot which may cause confusion, paralysis, seizures or swelling, pain, 
shortness of breath 
• Damage to organs (heart, brain, others) which may cause shortness of breath, 
swelling of ankles, and tiredness, changes in thinking 
• Heart failure, heart attack which may cause shortness of breath, swelling of ankles, 
and tiredness 
• Pain and swelling of thyroid 
• Visual loss 
• Difficulty swallowing 
• A tear or hole in or between internal organs which may cause drainage and may 
require surgery 
• Swelling of the gallbladder 
• Liver damage which may cause yellowing of eyes and skin, swelling 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness 
of breath, swelling of the face or throat 
• Flesh-eating bacteria syndrome 

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• Non-healing surgical site 
• Change in the heart rhythm 
• Kidney damage which may require dialysis  
• Damage to the jawbone which may cause loss of teeth 
• Damage to muscle which may cause muscle pain, dark red urine 
• Cancer of bone marrow caused by chemotherapy 
• Damage to the bone marrow (irreversible) which may cause infection, bleeding, 
may require transfusions 
• Stroke 
• Brain damage which may cause headache, seizure, blindness (also known as 
Reversible Posterior Leukoencephalopathy Syndrome) 
• Sores on the skin 
• Severe skin rash with blisters and peeling which can involve mouth and other parts 
of the body 
 
Reproductive Risks: If you are a woman who is breast feeding or pregnant, you may not take 
part in the study because we do not know how cediranib or sunitinib would affect your baby or 
your unborn child.  You should not become pregnant or father a baby while on this study and for 
2 months after you stop taking the drug because the drugs in this study can affect an unborn 
baby.  It is important you understand that you and your partner need to use 2 forms of effective 
birth control (examples below) while on this study and for 2 months after the study.  Check with 
your study doctor about what kind of birth control methods to use and how long to use them.  
Some methods might not be approved for use in this study.  If you think that you or your partner 
is pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include:  
• 
abstinence  
• 
intrauterine device (IUD) 
• 
hormonal [birth control pills, injections, or implants] 
• 
tubal ligation 
• 
vasectomy 
 
For more information about risks and side effects, please ask your study team. 
 
Potential Benefits of Participation 
Are there benefits to taking part in the study? 
The aim of this study is to see if either cediranib or sunitinib will cause your tumors to shrink.  
We hope that you will get personal medical benefit from taking part in this study, but we cannot 
be certain.  We do not know if you will receive personal, medical benefit from taking part in this 
study.  These potential benefits could include shrinking of your tumor or lessening of your 
symptoms, such as pain, that are caused by the cancer.  Because there is not much information 
about the drugs’ effect on your cancer, we do not know if you will benefit from taking part in 
this study, although the knowledge gained from this study may help others in the future who 
have cancer.   
 
 

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Research Subject’s Rights 
 
What are the costs of taking part in this study? 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.  
 
The study agents, cediranib and sunitinib, will be provided free of charge while you are 
participating in this study.  Even though it is unlikely, there is a possibility that at some point the 
supply of study agent may run out necessitating taking you off-study.  If this would occur, other 
possible options are: 
 
• 
You might be able to get the cediranib or sunitinib from the manufacturer or your 
pharmacy but you or your insurance company may have to pay for it. 
 
• 
If there is no cediranib or sunitinib available at all, no one will be able to get more and 
the study would close. 
 
If a problem with getting cediranib or sunitinib occurs, your study doctor will talk to you about 
these options. 
 
[If applicable, inform the patient of any tests, procedures or agents for which there is no charge. 
The explanation, when applicable, should clearly state that there are charges resulting from 
performance of the test or drug administration that will be billed to the patient and/or health 
plan. For example, “The NCI is supplying (drug) at no cost to you.  However, you or your health 
plan may need to pay for costs of the supplies and personnel who give you the (drug).”] 
 
You will not be paid for taking part in this study. 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
What happens if you are injured because you took part in this study? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.  The study will not pay for medical 
treatment.   
 

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What are your rights if you take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or to not take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.  No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  You can still get your medical care from our institution if you are eligible and 
choose to participate in another trial. 
 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.   
 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions or concerns you have about this 
study.  Contact your study doctor __________________ [name(s)] at __________________ 
[telephone number]. 
 
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group of people 
who review the research to protect your rights) at __________________ (telephone 
number).  [Note to Local Investigator: Contact information for patient representatives or other 
individuals in a local institution who are not on the IRB or research team but take calls 
regarding clinical trial questions can be listed here.]    
 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Institutes of Health Institutional Review Board 
• Qualified representatives from the pharmaceutical collaborators providing cediranib and 
sunitinib may also review the medical records. 
• Designees from other cancer centers participating in this study. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time.  
 

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Certificate of Confidentiality 
To help us protect your privacy, we have obtained a Certificate of Confidentiality.  The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena.  The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage.  These include when information will be used for auditing or program 
evaluation internally by the NIH; or  
• must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
• is necessary for your medical treatment and you have consented to this disclosure;  
• is for other research.  
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
 
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed 
by the local institution.  The regulations may or may not be included in the informed consent 
form depending on local institutional policy.] 
 
Where can I get more information? 
You may call the National Cancer Institute’s Cancer Information Service at: 1-800-4-CANCER 
(1-800-422-6237).  You may also visit the NCI Web site at http://cancer.gov/. 
• For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
• For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor.  
 

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Signature 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I 
have read it or it has been read to me.  I understand the information and have had my questions 
answered.  I agree to take part in this study. 
 
 
Participant ________________________________ 
 
 
Date _____________________________________ 
 
 
 

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Appendix N: Shipping Manifest to NCI 
 
Ship From:  
Shipping Manifest  
 
Ship To:   
Address: 
Attn: Ashley Bruns, RN 
  
Developmental Therapeutics Clinic 
National Cancer Institute 
Bldg 10 RM 8D53 
  
Bethesda, MD 20892 
Phone:  
 
Contact Name: 
Telephone: (240) 858-3162  
Fax: (301) 451-5625 
 
Clinical Site: 
E-mail: ashley.bruns@nih.gov 
Shipping Date:  
 
 
Carrier:  
  
  
 
 
 
 
Clinical Protocol: CTEP #8875 
 
  
  
  
 
  
In Package  
Unique Patient ID* 
Description  
Number of items 
Comments 
  
 
 
 
 
  
 
 
 
 
  
  
  
  
  
   
  
  
  
  
  
   
  
  
  
  
   
  
  
  
  
  
  
   
  
  
  
  
   
  
  
  
  
  
  
   
  
  
  
  
   
  
  
  
  
  
   
  
  
  
  
  
   
  
  
  
  
  
   
  
  
  
  
  
   
  
  
  
  
  
   
  
  
  
  
  
   
  
Total number of items = 
 
 
 
*Use 4-digit CTSU numbers.  Do NOT include patient identifiers. 
 

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Appendix O: PK Evaluation of Cediranib 
 
 
Pharmacokinetic analysis will be performed only on samples from patients on cediranib (both 
as upfront therapy and following cross-over).  No PK sampling and analysis will be done for 
patients receiving sunitinib.  
 
Blood samples for PK analyses will be collected in 4 cc K2 EDTA (purple top) tubes pre-
dose, and at the following time points prior to drug administration on that day: cycle 1 day 
15, C2D1, C3D1, and C4D1.  One 4 cc EDTA (purple top) tube will be obtained for each 
time point.  All samples will be centrifuged, and plasma will be separated and stored at –
70°C for analysis.  Depending on the initial results, sampling times may otherwise be 
adjusted, but neither the total number of samples nor the total amount of blood will be 
increased.   
 
 
Plasma samples for PK analysis will be sent to the laboratory for extraction and analysis c/o: 
 
Tracy W. Webb 
Office of the Associate Director 
Developmental Therapeutics Program 
Frederick National Laboratory for Cancer Research Boyles Street Building 1047 - Room 8 
Frederick, MD 21702 
 
301-846-7402 
wolfet2@mail.nih.gov