A Phase I/Randomized Phase II Study of Cediranib (NSC#732208) Versus Placebo in Combination With Cisplatin and Pemetrexed in Chemonaive Patients With Malignant Pleural Mesothelioma
Phase: PHASE1
Conditions: Epithelioid Mesothelioma, Pleural Malignant Mesothelioma, Recurrent Malignant Mesothelioma, Sarcomatoid Mesothelioma
Sponsor: National Cancer Institute (NCI)

 
 
 
 
 
 
 
Distribution Date: 
TBD 
Date of Submission 
January 5, 2017 
 
 
 
TO: 
ALL SWOG MEMBER, NCORP 
 
 
FROM: 
Dawne Wenzel, M.A., Protocol Coordinator (dwenzel@swog.org) 
 
 
RE: 
S0905, “A Phase I/Randomized Phase II Study of Cediranib (NSC # 732208) 
versus Placebo in Combination with Cisplatin and Pemetrexed in Chemonaive 
Patients with Malignant Pleural Mesothelioma”  Study Coordinators:  Drs. A.S. 
Tsao, N.J. Vogelzang and I.I. Wistuba. 
 
REVISION #10 
 
Study Coordinator:  Anne S. Tsao, M.D.   
Phone number:  713/792-6363 
E-mail:  astsao@mdanderson.org 
 
IRB Review Requirements 
(   ) Full board review required    
( √ ) Expedited review allowed 
(   ) No review required  
 
Status Change 
 
(   )  IRB Review only 
 
(   )  Activation 
(   )  Closure  
(   )  Reactivation 
  
Protocol changes 
(   )  Eligibility changes  
(   )  Treatment / Dose Modification / Study Calendar changes  
( √ )  Informed Consent changes 
( √ )  Patient notification not required 
(   ) Patient notification required  
(   )  Scientific / Statistical Consideration changes 
(   )  Specimen Submission changes 
(   )  Data Submission / Forms changes  
(   )  Editorial / Administrative changes 
( √ )  Other: Changes to drug information section 
 
Sites using the CIRB as their IRB of record:  The protocol and/or informed 
consent form changes have been approved by the CIRB and must be activated 
within 30 days of the CIRB posting of this notice. If local approval is not granted 
within 30 days, accrual must be suspended until approval is obtained. 

 
Page 2 
 
 
 
Sites not using the NCI CIRB:  Per CTMB Guidelines, the protocol updates and/or 
informed consent changes must be approved by local IRBs within 90 days of distribution 
of this notice. The changes in this revision are effective upon approval by the local IRB; 
however, any changes to eligibility become effective 6 weeks after distribution of this 
notice. If local approval is not granted within 6 weeks, accrual must be suspended until 
approval is obtained. 
 
 
REVISION #10 
 
This revision is in response to a Request for Rapid Amendment (RRA) from Dr. S. Percy Ivy 
(ivyp@ctep.nci.nih.gov), Dr. James Zwiebel (ZwiebelJ@CTEP.NCI.NIH.gov), and Dr. Meg Mooney 
(mooneym@ctep.nci.nih.gov).  
 
The above-referenced protocol has been revised as follows: 
 
1. 
The Version Date of the protocol and Model Consent Form have been updated.   
 
2. 
Page 13, Section 3.1b: CAEPR Version 2.13 (September 29, 2016) has replaced CAEPR 
Version 2.11 (November 10, 2011). 
 
• 
The SPEER grades have been updated. 
 
• 
Added New Risk:  
• 
Also Reported on Cediranib Trials But With Insufficient Evidence for 
Attribution: Acidosis; Activated partial thromboplastin time prolonged; 
Allergic reaction; Alopecia; Aspiration; Ataxia; Atrial fibrillation; Atrial 
flutter; Avascular necrosis; Bloating; Blood and lymphatic system 
disorders 
- 
Other 
(polycythemia); 
Blurred 
vision; 
Bone 
marrow 
hypocellular; Capillary leak syndrome; Cardiac disorders - Other 
(premature ventricular complexes); Cardiac disorders - Other (valvular 
heart disease); Cardiac troponin I increased; Central nervous system 
necrosis; 
Chills; 
Cholecystitis; 
Chronic 
kidney 
disease; 
Cystitis 
noninfective; Delirium; Depression; Dermatitis radiation; Duodenal ulcer; 
Ear and labyrinth disorders - Other (ears feel full/plugged); Edema face; 
Ejection fraction decreased; Esophageal necrosis; Esophageal ulcer; Eye 
disorders - Other (blindness); Eye disorders - Other (visual disturbance); 
Febrile neutropenia; Flushing; Gait disturbance; Gastric necrosis; 
Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal disorders 
- Other (hydrops); Gastrointestinal disorders - Other (tongue sensitivity); 
Gastroesophageal reflux disease; Hemoglobin increased; Hydrocephalus; 
Hypomagnesemia; Hypothermia; INR increased; Intestinal stoma leak; 
Investigations - Other (elevated ammonia level); Ischemia cerebrovascular; 
Malaise; Menorrhagia; Metabolism and nutrition disorders - Other (failure to 
thrive); Mobitz (type) II atrioventricular block; Muscle weakness left-sided; 
Muscle weakness upper limb; Musculoskeletal and connective tissue 
disorder -  Other (muscle cramps); Musculoskeletal and connective tissue 
disorder -  Other (rotator cuff injury); Myositis; Neck pain; Nervous system 
disorders - Other (coma); Nervous system disorders - Other (right 
hemiparesis); Olfactory nerve disorder; Oral cavity fistula; Palpitations; 
Pancreatitis; Papilledema; Pericardial effusion; Pericarditis; Periodontal 
disease; Peritoneal necrosis; Photophobia; Pulmonary edema; Pulmonary 
fistula; 
Pulmonary 
hypertension; 
Rash 
acneiform; 
Restrictive 
cardiomyopathy; Retinal vascular disorder; Sinus bradycardia; Sinus pain; 
Sinus tachycardia; Skin and subcutaneous tissue disorders - Other 
(petechiae); Skin and subcutaneous tissue disorders - Other (plantar 
warts); Small intestinal obstruction; Stroke; Supraventricular tachycardia; 

 
Page 3 
 
 
Syncope; Tremor; Urinary tract obstruction; Urticaria; Vaginal fistula; 
Vascular Disorders- Other (hemorrhage), Vasculitis; Venous injury; Vertigo; 
Wound complication; Wound dehiscence 
 
• 
Increase in Risk Attribution:  
• 
Changed to Likely from Less Likely: Nausea; Voice alteration 
• 
Changed to Less Likely from Also Reported on Cediranib Trials But With 
Insufficient Evidence for Attribution: Alkaline phosphatase increased; 
Lymphocyte count decreased; Neutrophil count decreased; Platelet count 
decreased 
 
• 
Decrease in Risk Attribution: 
• 
Changed to Also Reported on Cediranib Trials But With Insufficient 
Evidence for Attribution from Less Likely: Hyperthyroidism; Investigations 
- Other (increased blood erythropoietin); Seizure 
 
• 
Modified Specific Protocol Exceptions to Expedited Reporting (SPEER) reporting 
requirements: 
• 
Added: Proteinuria 
 
• 
Provided Further Clarification:  
• 
Bronchopulmonary 
hemorrhage, 
Epistaxis, 
Hepatic 
hemorrhage, 
Intracranial hemorrhage, and Rectal hemorrhage (under Also Reported on 
Cediranib Trials But With Insufficient Evidence for Attribution) are now 
reported as Vascular disorders - Other (hemorrhage) (under Less Likely). 
 
• 
The following footnote #2 was added: “Hemorrhage 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.” 
 
• 
Gastrointestinal disorders - Other (abdominal abscess) (under Also Reported on 
cediranib Trials But With Insufficient Evidence for Attribution) is now reported as 
Infection 
 
The following changes have been made to the Model Consent Form. Because this study is closed to 
accrual, sites are not required to update their informed consent. 
 
1. 
The version date has been updated. 
 
2. 
Page 6:  The “What side effects or risks can I expect from being in the study?” section has 
been changed to adhere to NCI Consent Form Template (Version May 2013) wording. 
 
3. 
Page 8:  The “risks and side effects related to the cediranib/placebo treatment we are 
studying” section has been modified to a condensed risk profile table of possible side effects 
for cediranib and categories of risk have been renamed. “Likely” is now “Common, Some May 
Be Serious,” “Less Likely” is now “Occasional, Some May Be Serious,” and “Rare but 
Serious” has been changed to “Rare and Serious.” 
 
• 
Increase in Risk Attribution:  
• 
Changed to Common from Occasional: Changes in voice; Nausea 
• 
Changed to Occasional from Also Reported on cediranib Trials But With 
Insufficient Evidence for Attribution (i.e., added to the Risk Profile): Bruising, 
bleeding 
 
• 
Decrease in Risk Attribution:  

 
Page 4 
 
 
• 
Changed to Also Reported on cediranib Trials But With Insufficient Evidence for 
Attribution from Occasional (i.e., removed from the Risk Profile): Seizure 
 
• 
Changed for clarity: 
 
• 
 “High blood pressure” has been changed to “High blood pressure which 
may cause blurred vision” in the Likely/Common category. 
 
• 
“Sores in internal organs which may cause rectal pain or throat pain” has 
been added in the Occasional/ Less Likely section and irritation or sores in 
the lining of the anus, mouth, rectum, voice box, throat, windpipe, and 
small bowel have been removed.  
 
• 
“Formation of a blood clot that plugs the blood vessel; blood clots may 
break loose and travel to another place such as the lung” has been 
changed to “blood clot which may cause swelling, pain, shortness of 
breath” in the Occasional/Less Likely category. 
 
• 
“Progressive necrosis (tissue death) of a part (the white matter) of the 
brain without inflammation (swelling an redness” and “abnormal changes 
in the brain that can cause a collection of symptoms including headache, 
confusion, seizures, and vision loss associated with MRI imaging findings 
((RPLS)” has been changed to “Brain damage which may cause headache, 
seizure, 
blindness 
(also 
known 
as 
Reversible 
Posterior 
Leukoencephalopathy Syndrome) in the Rare, and Serious/Rare but 
Serious Category., 
 
• 
Removed: 
 
• 
In the Less Likely/Occasional Category: Abnormally high level of thyroid 
gland hormone, abnormally low level of thyroid gland hormone, increased 
blood level of a liver enzyme (ALT/SGPT), increased blood level of a liver 
enzyme (AST/SGOT), increased levels of a substance involved in the 
production of red blood cells, increased levels of a substance (thyroid 
stimulating hormone) involved in the function of the thyroid gland, which 
indicated an underactive thyroid, more protein leaking in to the urine than 
usual, often a sign of kidney disease, decreased blood level of phosphate, 
convulsion,  
 
• 
In the Rare but Serious/ Rare, and Serious category: Decrease in heart’s 
ability to pump blood during “active “phase of the heartbeat (systole), and 
blood clot in a blood vessel (artery)/ 
 
• 
Added: 
 
• 
Bruising and bleeding have been added to the Occasional Category. 
 
PLEASE NOTE:  The potential risks listed in the CAEPR whose relationship to cediranib is still 
undetermined are not required by CTEP to be described in the ICD; however, they may be 
communicated to patients according to local IRB requirements. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
 
 

 
S0905 
 
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Version Date  1/5/17 
 
 
PRIVILEGED COMMUNICATION 
 
Activation Date:  March 15, 2010 
FOR INVESTIGATIONAL USE ONLY 
 
 
 
SWOG 
 
A PHASE I/RANDOMIZED PHASE II STUDY OF CEDIRANIB (NSC #732208) VERSUS PLACEBO IN 
COMBINATION WITH CISPLATIN AND PEMETREXED IN CHEMONAIVE PATIENTS WITH 
MALIGNANT PLEURAL MESOTHELIOMA 
 
PARTICIPANTS:  PHASE I:  ALL SWOG APPROVED PHASE I INSTITUTIONS AT:  UNIVERSITY OF 
ARIZONA, BROOKE ARMY MEDICAL CENTER, CITY OF HOPE, CLEVELAND CLINIC, COLUMBIA, 
LOYOLA, MD ANDERSON, MEDICAL UNIVERSITY OF SOUTH CAROLINA, UNIVERSITY OF NEW 
MEXICO, PSOC-SWEDISH MEDICAL CENTER, USC NORRIS CANCER CENTER, UC DAVIS, 
UNIVERSITY OF COLORADO, UNIVERSITY OF KANSAS, UNIVERSITY OF KENTUCKY, UNIVERSITY 
OF MICHIGAN, UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO, 
UNIVERSITY OF WASHINGTON, WAYNE STATE UNIVERSITY, SCOTT AND WHITE HOSPITAL, 
HIGHLAND ONCOLOGY GROUP 
 
PHASE II:  The Phase II portion of the study will be open to ALL SWOG MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS active effective 9/16/11. 
 
STUDY COORDINATORS: 
AGENTS: 
 
Anne S. Tsao, M.D. (Medical Oncology) 
CTEP-supplied: 
M.D. Anderson Cancer Center 
Cediranib/Placebo (RecentinTM, AZD2171)  
1515 Holcombe Boulevard Unit 432 
 
(NSC 732208; CTEP IND #72,740) 
Houston, TX 77030 
 
Phone:  713/792-6363 
Commercially available: 
FAX:  713/792-1220 
Cisplatin 
E-mail:  astsao@mdanderson.org 
Pemetrexed (AlimtaTM) 
 
 
BIOSTATISTICIANS: 
 
 
Nicholas J. Vogelzang, M.D. (Medical Oncology) 
James Moon, M.S. 
Comprehensive Cancer Centers of Nevada 
Mary W. Redman, Ph.D. 
3730 S. Eastern Avenue 
Southwest Oncology Group Statistical Center 
Las Vegas, NV  89169 
1100 Fairview Avenue N, M3-C102 
Phone:  702/952-3452 
PO Box 19024 
FAX:  702/952-3453 
Seattle, WA 98109-1024 
E-mail:  Nicholas.vogelzang@usoncology.com 
Phone:  206/667-4623 
 
FAX:  206/667-4408 
 
E-mail:  jmoon@fhcrc.org 
 
E-mail:  mredman@fhcrc.org 
 
 
 
Ignacio I. Wistuba, M.D. (Pathology)  
M.D. Anderson Cancer Center 
1515 Holcombe Boulevard, Unit 85 
Houston, TX  77030 
Phone:  713/563-9184     
FAX:  713/792-0309      
E-mail:  iiwistuba@mdanderson.org 
 

 
S0905 
 
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TABLE OF CONTENTS 
 
Page 
 
SCHEMA .................................................................................................................................. 4 
1.0 
OBJECTIVES .......................................................................................................................... 5 
1.1 
Phase I Portion ......................................................................................................................... 5 
1.2 
Phase II Portion ........................................................................................................................ 5 
2.0 
BACKGROUND ....................................................................................................................... 5 
3.0 
DRUG INFORMATION ............................................................................................................ 13 
3.1 
Cediranib (RecentinTM, AZD2171) (NSC 732208) (CTEP IND #72,740)/Placebo ................. 13 
3.2 
Cisplatin (CDDP) (Platinol®) (NSC-119875) ............................................................................ 24 
3.3 
Pemetrexed for injection (Alimta®) (NSC-698037) ................................................................... 25 
4.0 
STAGING CRITERIA ............................................................................................................... 28 
5.0 
Eligibility Criteria .................................................................................................................... 29 
5.1 
Disease Related Criteria .......................................................................................................... 29 
5.2 
Prior Therapy Criteria ............................................................................................................... 29 
5.3 
Clinical/Laboratory Criteria ....................................................................................................... 30 
5.4 
Regulatory Criteria ................................................................................................................... 31 
6.0 
STRATIFICATION FACTORS ................................................................................................. 32 
7.0 
TREATMENT PLAN ................................................................................................................ 32 
7.1 
Good Medical Practice ............................................................................................................. 32 
7.2 
Treatment Overview ................................................................................................................. 33 
7.3 
Pre-Medication ......................................................................................................................... 34 
c. 
Phase I Portion of the Study .................................................................................................... 35 
7.5 
Phase II Portion of the Study ................................................................................................... 36 
7.6 
Blood Pressure Monitoring ....................................................................................................... 37 
7.7 
Drug Compliance ..................................................................................................................... 37 
7.8 
General Concomitant Medication and Supportive Care Guidelines ........................................ 37 
7.9 
CTEP Requirements ................................................................................................................ 38 
7.10 
Criteria for Removal from Protocol Treatment ......................................................................... 38 
7.11 
Discontinuation of Treatment ................................................................................................... 38 
7.12 
Follow Up Period ...................................................................................................................... 38 
8.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS .................................. 39 
8.1 
NCI Common Terminology Criteria .......................................................................................... 39 
8.2 
General Considerations ........................................................................................................... 39 
8.3 
Dose levels ............................................................................................................................... 39 
8.4 
Hematologic toxicities .............................................................................................................. 40 
8.5 
Non-hematologic toxicities ....................................................................................................... 40 
8.6 
Proteinuria ................................................................................................................................ 42 
8.7 
Management of Abnormal Thyroid Function Tests .................................................................. 42 
8.8 
Management of Diarrhea ......................................................................................................... 42 
8.9 
Management of Hypertension .................................................................................................. 43 
8.10 
Guidelines for Reversible Posterior Leukoencephalopathy Syndrome (RPLS)....................... 44 
8.11 
Guidelines for Patients who develop Compromised Left Ventricular Ejection Fraction  
 
(LVEF) ...................................................................................................................................... 45 
8.12 
G-CSF ...................................................................................................................................... 46 
8.13 
Dose Modification Contacts ..................................................................................................... 46 
8.14 
Adverse Event Reporting ......................................................................................................... 46 

 
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9.0 
STUDY CALENDAR ................................................................................................................ 46 
9.1    
STUDY CALENDAR - Phase I Portion .................................................................................... 47 
9.2 
Phase II Portion ........................................................................................................................ 51 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS........................................... 55 
10.1  
Measurability of lesions ............................................................................................................ 55 
10.2  
Objective status at each disease evaluation ............................................................................ 56 
10.3  
Best Response ......................................................................................................................... 57 
10.4 
Performance Status ................................................................................................................. 58 
10.5 
Modified RECIST ..................................................................................................................... 58 
10.6 
Progression-free survival ......................................................................................................... 59 
10.7 
Time to Death ........................................................................................................................... 59 
11.0 
STATISTICAL CONSIDERATIONS ........................................................................................ 59 
11.1 
Phase I Run-In ......................................................................................................................... 59 
11.2 
Phase I Details ......................................................................................................................... 59 
11.3 
Phase II Trial ............................................................................................................................ 60 
11.4 
Analysis plan for Phase II study ............................................................................................... 60 
11.5  
Sample Size and Power Justification for Primary Endpoint ..................................................... 60 
11.6 
Analysis of Primary Endpoint ................................................................................................... 61 
11.7 
Data and Safety Monitoring Committee ................................................................................... 61 
12.0 
DISCIPLINE REVIEW .............................................................................................................. 61 
13.0 
REGISTRATION GUIDELINES ............................................................................................... 61 
13.1  
Registration Timing .................................................................................................................. 61 
13.2 
OPEN Registration Requirements ........................................................................................... 62 
13.3 
Registration procedures ........................................................................................................... 63 
13.4 
Exceptions ................................................................................................................................ 63 
14.0 
DATA SUBMISSION SCHEDULE .......................................................................................... 64 
14.1 
Data Submission ...................................................................................................................... 64 
14.2 
Master Forms ........................................................................................................................... 64 
14.3 
Data Submission ...................................................................................................................... 64 
14.4 
Data Submission Procedures .................................................................................................. 65 
15.0 
SPECIAL INSTRUCTIONS...................................................................................................... 67 
15.1 
Rapid Reporting ....................................................................................................................... 67 
15.2 
Specimens for Pathology Review ............................................................................................ 67 
15.3 
Specimens for Correlative Studies and Banking ..................................................................... 68 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................. 70 
16.1 
Adverse Event Reporting Requirements.................................................................................. 73 
17.0 
BIBLIOGRAPHY ...................................................................................................................... 79 
18.0 
APPENDIX ............................................................................................................................... 83 
18.1 
Determination of Expedited Adverse Event Reporting Requirements ..................................... 84 
18.2 
Appendix Deleted 11/29/10 ...................................................................................................... 86 
18.3 
Intake Calendar ........................................................................................................................ 87 
18.4 
Medications that may cause QTc prolongation ........................................................................ 88 
18.5 
New York Heart Association Class .......................................................................................... 92 
18.6 
Emergency Unblinding Guidelines ........................................................................................... 93 
18.7 
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4 ................................ 95 

 
S0905 
 
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SCHEMA 
 
 
Phase I portion (open to limited institutions as listed on the Title Page): 
 
Registration 
 
 
 
6 cycles of pemetrexed + cisplatin + cediranib  
at assigned dose level (see Section 7.4), followed by maintenance cediranib 
 
 
 
Temporary closure to assess 
the dose for Phase II 
 
 
 
 
 
Phase II portion (open to all SWOG institutions): 
 
 
Registration/Randomization 
 
 
 
6 cycles of pemetrexed  
and cisplatin 
+ 
cediranib or placebo,  
followed by maintenance cediranib/placebo 
 
 
 
 
 
 
 
 
 
A patient may be enrolled to either the Phase I portion or the Phase II portion, not both. 
 
 
 

 
S0905 
 
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1.0 
OBJECTIVES 
 
This study will be conducted in two different parts: 
 
1.1 
Phase I Portion 
 
a. 
To establish the MTD and the recommended Phase II dose of cediranib in 
combination with cisplatin and pemetrexed. 
 
b. 
To assess the safety and toxicity of the regimen. 
 
1.2 
Phase II Portion 
 
c. 
To assess whether cisplatin/pemetrexed plus cediranib as compared to 
cisplatin/pemetrexed plus placebo improves progression-free survival in patients 
with malignant pleural mesothelioma.  
 
d. 
To compare overall survival in patients treated with cisplatin/pemetrexed plus 
cediranib to those treated with cisplatin/pemetrexed plus placebo. 
 
e. 
To assess the safety and toxicity profile of the regimen. 
 
f. 
To assess response rate (confirmed and unconfirmed, complete and partial 
responses) and disease control rate (response or stable disease) in the subset of 
patients with measurable disease by RECIST criteria. 
 
g. 
To assess response rate and disease control rate using modified RECIST criteria 
for pleural tumors in the subset of patients with measurable disease by modified 
RECIST criteria for pleural tumors. 
 
h. 
To assess the rate of agreement between local and central pathology review of 
mesothelioma and its histologic subtypes. 
 
i. 
To collect specimens for banking for use in future research studies. 
 
 
2.0 
BACKGROUND 
 
Malignant Mesothelioma 
 
Unresectable malignant mesothelioma is a challenging disease that has a poor response to 
chemotherapy.  (1)  Historically, treatment with chemotherapy leads to a median time to 
progression between 3 to 4 months.  (2-3)  The current standard frontline regimen in unresectable 
mesothelioma is cisplatin-pemetrexed which yields a 12.1 month median overall survival and 5.7 
month median time to progression.  (2)  Although this regimen was an advance in mesothelioma 
treatment, there are associated toxicities and survival results remain grim. A new paradigm in 
treatment is needed with identification of new targets of therapy and novel combination regimens. 
 
Inhibition of malignant tumor angiogenesis is establishing itself as an important aspect of cancer 
therapy.  This field of work needs to be further developed in malignant mesothelioma as it is well 
established that mesothelioma cells secrete and express angiogenic factors such as vascular 
endothelial growth factor (VEGF) and receptor (VEGFR) and platelet derived growth factor 
(PDGF) and receptor (PDGFR).  (4-8) 
 
 

 
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Cediranib 
 
Cediranib (RecentinTM, AZD2171 (NSC 732208), an orally available small molecule, is a potent 
inhibitor of receptor tyrosine kinases (RTKs), which influence the effects of a key angiogenic 
factor, vascular endothelial growth factor-A (VEGF).  VEGF is implicated in tumor blood vessel 
formation and in disease progression in a wide range of solid tumor malignancies.  Expression of 
this factor is increased by diverse stimuli which include proto-oncogene activation and hypoxia, 
with the hypoxic state frequently occurring in solid tumors because of inadequate perfusion.  In 
addition to its angiogenic role, VEGF also profoundly increases the permeability of the 
vasculature and thereby potentially contributes to tumor progression – a leaky tumor endothelium 
enhances nutrient and catabolite exchange and represents less of a barrier to tumor cell 
migration during metastasis.  With the goal of suppressing neovascularization and thus inhibiting 
tumor growth and metastasis, numerous antiangiogenic agents have been developed.  In contrast 
to many of these intravenously-administered antiangiogenic agents, a recently emerging class of 
novel orally-administered VEGF TK inhibitors including cediranib has been developed.  (9-11)   
 
Two high-affinity receptors for VEGF with associated TK activity have been identified on human 
vascular endothelium, KDR (kinase insert domain-containing receptor = VEGFR2) and Flt-1 (fms-
like tyrosine kinase 1 = VEGFR1).  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.  Cediranib is a potent inhibitor of both KDR (IC50 < 0.002 microM) 
and Flt-1 (IC50 = 0.005 microM) and shows activity versus c-kit, platelet-derived growth factor 
receptor beta (PDGFRβ), and Flt-4 at nanomolar concentrations, but is selective against other 
serine/threonine kinases studied.  It has been shown that cediranib potently and selectively 
inhibits VEGF-stimulated human umbilical cord vascular endothelial cell (HUVEC) proliferation 
with an IC50 of 4 nM.  (12)  These authors have also demonstrated the agent’s profound inhibitory 
effect on vessel area, length, and branching at subnanomolar concentrations using a modified 
fibroblast/endothelial cell co-culture system.  Cediranib’s effects on hemodynamic parameters 
have been studied in an athymic rat xenograft model of human colorectal carcinoma (SW620) 
using perfusion-permeability dynamic contrast-enhanced magnetic resonance imaging.  (pp-DCE-
MRI) (13)  This method clearly demonstrated that in this model, cediranib significantly reduced 
vascular permeability by 80% (P<0.005) and vascular volume by 68% (P<0.05). 
 
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 to 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 cediranib efficacy 
studies.  (14)  In experiments incorporating a vehicle control, cediranib (at a dose of 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.  (15)  
When dosed with cediranib (0.75 to 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. 

 
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Nonclinical Pharmacology and Toxicology 
 
Nonclinical pharmacology and toxicology company-sponsored cediranib 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 PO 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 PO and intravenous administration.  Fecal excretion was the 
predominant route of elimination (> 70% of the dose) in both rat, dog 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 to 2.5 mg/kg. 
 
Protein binding of cediranib (90 to 95%) was relatively high across all species examined and was 
independent of concentration (range: 0.03 to 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 
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 to 60% reduction 
in CYP1A activity at the 2.5 mg/kg dose level.  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.  For CYP1A2, CYP2A6, 
CYP2C8, CYP2C9, CYP2C19, and CYP2E1, the IC50 values were outside the concentration 
range of cediranib examined.  As the clinically relevant plasma concentration of cediranib has not 
yet been determined, any possible effect on compound clearance and drug interaction is currently 
unknown.  
 
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, respectively. 
 
Clinical Studies 
 
The safety, tolerability, efficacy, and pharmacokinetics (PK) of cediranib are currently being 
evaluated in three Phase I monotherapy studies in patients with solid tumors and metastatic liver 
disease (Study 2171IL/0001), in relapsed or refractory acute myeloid leukemia (Study 
2171IL/0002), and in elderly patients with metastatic prostate adenocarcinoma (Study 
2171IL/0003). In addition, an ongoing company-sponsored Phase I study is currently assessing  
 

 
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the safety and tolerability of cediranib in combination with gefitinib (IRESSA) in patients with 
advanced cancer (Study 2171IL0004).  A detailed description of the preliminary data from these 
studies is provided in Section 5 of the investigator’s brochure. 
 
In Study 2171IL/0001, patients have received cediranib at doses ranging from 0.5 to 60 mg.  
Patient cohorts receive a single dose of cediranib followed by a 7-day washout period then start a 
28-day cycle of daily doses of the agent at the same dose level they received initially.  The 
company reports that preliminary safety data from this study show that cediranib appears to be 
well tolerated at doses up to and including 45 mg/day.  The 60 mg dose of cediranib appears to 
be less well tolerated and is associated with increased adverse events, dose interruptions, and 
increases in serum thyroid stimulating hormone (TSH).  The most frequently reported adverse 
events (AEs) in Study 2171IL/0001 were fatigue (13/36 [36%]), nausea (13/36 [36%]), diarrhea 
(10/36 [28%]), and vomiting (10/36 [28%]).  Three serious adverse events (SAEs) including an 
abnormal liver function test, hypertension, and hypoglycemia were considered to be related to 
cediranib.  The company reported that the patients reporting the incidences of hypertension and 
hypoglycemia recovered, while the patient with an abnormal liver function test improved while on 
trial.  Increases in mean arterial blood pressure (MAP) were observed for at least one time point 
in several patients across all of the cediranib doses studied.  No clinically relevant changes in 
electrocardiogram parameters, heart rate, or laboratory parameters have been observed.  The 
company reports that while only limited and preliminary safety data are currently available from 
the other three studies, those data also suggest that cediranib is well tolerated. 
 
Preliminary cediranib PK data from two ongoing Phase I clinical studies (Study 2171IL/0001 and 
2171IL/0003) have established that following a single dose, cediranib is orally available with Cmax 
ranging from 1 to 8 hours post dosing.  Concentrations declined in an apparent bi-exponential 
manner thereafter with a t½lz ranging from 12.5 to 35.4 hours.  Steady-state plasma 
concentrations were predicted by the single dose PK with the grand arithmetic mean temporal 
change parameter value being 1.07.  This observation supports the concept that there are no 
time-dependent PK changes.  Dose proportionate increases in Cmax, Cmax,ss, AUC, and AUCss 
provide no evidence to reject linear PK for single and multiple cediranib doses ranging from 0.5 to 
60 mg.  The PK profile of cediranib supports once-daily oral dosing. 
 
Initial assessments from the ongoing Phase I study in patients with solid tumors and metastatic 
liver disease (Study 2171IL/0001) have produced encouraging indications of potential biological 
efficacy in the patient population studied.  Reductions in blood flow in hepatic metastases have 
been detected by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and 
initial biomarker assessments (VEGF and VEGF-R2) have been encouraging.  In addition, the 
company reports that one ovarian cancer patient had a minor-partial response in lung and liver 
metastases, while a colorectal cancer patient had a minor response.   
 
Based on evidence from animal data with cediranib (vascular and renal pathology) and results in 
the ongoing Phase I clinical studies, it is possible that the agent will produce hypertension in man.  
Because hypertension seen in animals has been abrogated by nifedipine, the change is thought 
to be mechanistically related to inhibition of VEGF signaling, although a direct toxicologic effect 
on the blood vessels and kidneys cannot be ruled out.  The potential for hypertensive changes 
following cediranib administration is additionally supported by evidence from use of other 
antiangiogenic agents in the clinic.  For these reasons, patients should be monitored frequently 
for changes in blood pressure and renal function (blood urea nitrogen, creatinine, and urinary 
protein).  The potential for myocardial injury indicates that patient levels of troponin T or troponin I 
should also be measured. 
 
Certain physiologic processes other than endothelial cell growth are dependent on VEGF 
signaling, so inhibition of that growth factor may have implications for use of cediranib in selected 
patient populations.  Pediatric studies with cediranib should be undertaken with caution because 
the agent increases the zone of hypertrophy in the epiphyseal growth plates thus preventing 
ossification during long bone growth.  Cediranib interferes with normal reproductive processes  
 
 

 
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and completely prevents fetal development in rats at a dose of 2.5 mg/kg/day.  For this reason, 
women of childbearing potential should have a negative pregnancy test before treatment with 
cediranib is initiated.   In rat studies, cediranib significantly inhibited endochondral ossification and 
corpora lutea formation.  (16) 
 
VEGF/VEGFR in mesothelioma 
 
VEGF is a peptide that promotes angiogenesis via induction of vascular permeability/ proliferation 
and endothelial migration.  (17-19)  Inhibiting VEGF/VEGFR pathway in the treatment of other 
malignancies has been shown to improve clinical outcome.  (20-22)  VEGF is likely to be an 
important target in malignant mesothelioma as the tumor cells secrete and express the VEGF 
ligand and receptor.  (5)  In vitro studies have suggested a VEGF autocrine loop via tyrosine 
kinase activation which promotes mesothelioma cell line proliferation.  (6,23)  These laboratory 
findings are translated into clinical observations as patients with elevated serum VEGF levels 
have increased microvessel density in their mesothelioma tumors and an overall worse clinical 
prognosis.  (6-8,24) 
 
One recent Phase III trial, which combines chemotherapy (cisplatin, gemcitabine) with or without 
bevacizumab (monoclonal antibody targeting VEGF) presented at ASCO 2007 showed no 
improvement in survival for the patients receiving bevacizumab for the overall population of 
mesothelioma patients.  (24-25)  However, patients with lower baseline levels of VEGF appeared 
to do better (in terms of PFS, OS) when they were treated with the chemo + bevacizumab. This is 
highly suggestive that bevacizumab was ineffective in mesothelioma because it could not 
counteract the high levels of VEGF in these patients; and therefore, VEGFR tyrosine kinase 
inhibitors which target the receptor may potentially be more potent in this population of patients 
than is bevacizumab which targets only the ligand VEGF and not the receptor. 
 
PDGFR in mesothelioma 
 
PDGF/PDGFR are found on vascular endothelial cells and promote angiogenic activity consisting 
of recruitment of pericytes to capillaries, promotion of smooth muscle cells in vessels, and 
formation of mesangial cells in the renal system.  (26-27) Mesothelioma tumor cells secrete and 
express both PDGF-BB and PDGFRβ and may utilize this pathway for autocrine stimulation.  
(4,28-32)  PDGF acts as a mitogen in vitro and murine xenografts of mesothelioma cells and cell 
line experiments show that inhibiting PDGF/PDGFR pathway can prevent mesothelioma cell 
proliferation.  (4,33-34)  PDGF/PDGFR have also been reported to have a role in regulating tumor 
vascular interstitial fluid pressure and transport of molecules, i.e. increase chemotherapy uptake 
into tumors.  (26,35-36) 
 
Targeting VEGFR and PDGFR simultaneously in mesothelioma 
 
Targeting both VEGFR and PDGFR in mesothelioma is a reasonable strategy. Angiogenesis in 
malignant conditions yields disordered vasculature that is dependent on VEGF/VEGFR. It is 
hypothesized that more mature blood vessels are less dependent on VEGF possibly due to 
pericyte coverage, which can be regulated by PDGF/PDGFR.  (19,37-38)  Given that an autocrine 
loop effect may be present in malignant mesothelioma cells, it is feasible that targeting both 
pathways may provide additive cytostatic activity. 
 
To date, few agents that target VEGF/VEGFR and PDGF/PDGFR have been used in clinical trials 
in mesothelioma.  In a Phase II trial, imatinib mesylate (PDGF-R tyrosine kinase inhibitor) yielded 
a 16% disease stabilization rate > 3 months in pretreated advanced mesothelioma patients.  (39) 
CALGB has sponsored two trials that target both VEGFR and PDGFR. CALGB 30107 is a Phase 
II trial using dual tyrosine kinase inhibitor vatalanib (PTK787).  (40)  This trial reports preliminary 
results (n=47) of 44.9% progression-free survival (PFS) rate at 3 months and median PFS 2.66 
months. At IMIG 2006, the Phase II trial (CALGB 30307) using sorafenib at 400 mg twice daily in 
chemo-naïve or previously treated pemetrexed patients had a Grade 3-4 side effect profile 
inclusive of 25% fatigue and 13% hand-foot syndrome.  (41)  The overall response rate was 4.4%  
 

 
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with a 38.8% disease stabilization rate, median failure-free survival 4.1 months, and median 
overall survival 10.4 months. Patients who were chemo-naïve had worse survival outcomes 
compared to the pretreated patients. This trial did not meet its primary endpoint, but correlative 
studies are underway to determine which patients may have clinical benefit from the drug. 
 
Sunitinib (targeting VEGFR, PDGFR, c-Kit, Flt-3) has been evaluated in a Phase II single arm trial 
in patients who had failed one platinum-pemetrexed regimen.  Of 22 evaluable patients, there 
was a 15% partial response rate and 55% stable disease by modified RECIST criteria.  In 
patients without a talc pleurodesis, ten were evaluated by FDG-PET and a 30% metabolic 
response (defined as a decrease in SUV levels) was seen.  The median OS was 5.9 months, time 
to progression 3.5 months.  There was one treatment related death attributed to pulmonary 
infiltrates and respiratory failure.  (42)  
 
Rationale for combining cisplatin, pemetrexed and cediranib  
 
Cediranib (RecentinTM, AZD2171)  
 
Cediranib is a potent inhibitor of human receptor tyrosine kinases VEGFR-1, -2, -3, PDGFR-α 
and –β, c-Kit.  Cediranib acts by inhibiting the tyrosine kinase activity of VEGF receptors, hereby 
disrupting the VEGF signaling pathway in endothelial cells.  (16)  Due to its low toxicity profile, 
available biologic targets, and oral availability, this antiangiogenic agent is an ideal therapy to 
investigate in patients with unresectable malignant mesothelioma in combination with front-line 
chemotherapy. 
 
Cediranib has already been evaluated in Phase I trials (D8480C00003, D4840C00023) at 6 
different dose levels (1, 2.5, 5, 10, 20, and 30 mg). After a single dose, cediranib is orally 
available with a tmax ranging from 2 to 8 hours post dosing with a median of 2 hours. Steady state 
levels after multiple oral doses is achieved after 7 days or repeat oral daily dosing. At 30 mg daily 
dosing after 28 days of consecutive oral administration, the tmax was 3 hours. Additional trials 
(D8480C00001) determined the MTD of cediranib to be 45 mg oral daily dose. The most 
frequently observed AEs were fatigue (56.6%), diarrhea (47%), nausea (41%), dysphonia (36%), 
hypertension (34.9%), vomiting (31.3%), and anorexia (28.9%). 
 
Cediranib has been evaluated in a Phase I trial (D8480C00008) in combination with different 
chemotherapy agents (Investigator’s Brochure 16 February 2007). Preliminary PK data obtained 
after a 28-day oral daily dosing with cediranib (10, 20, and 30 mg) in combination with 
pemetrexed.  The most common AEs in the pemetrexed + 30 mg cediranib (n=8) were diarrhea 
(Grade 2 – 25%), nausea (Grade 2 – 12.5%), fatigue (Grade 1 – 50%), headache (Grade 1 – 
62.5%), hypertension (Grade 2 – 50%), and rash (Grade 1 – 25%). 
 
The preliminary data suggests that the 30mg dose of cediranib is safe and tolerable in 
combination with chemotherapy. Cediranib is being combined with platinum based doublets 
(carboplatin-paclitaxel, cisplatin-gemcitabine, FOLFOX6).  
 
Preliminary results do not demonstrate significant additional toxicity at the 30 mg daily dose in 
combination platinum based therapies. 
 
Combination of cisplatin and pemetrexed with cediranib 
 
The chemotherapeutic agents to be combined with cediranib proposed in this trial consist of 
cisplatin and pemetrexed.  Cisplatin is a platinum agent with an unclear metabolic pathway. It is 
believed that the chloride ligands of the cisplatin complex are displaced by water, forming 
positively charged platinum complexes.  Cisplatin and platinum products are highly bound to 
tissue and plasma proteins, including albumin, γ-globulins and transferrin. Pemetrexed is a novel 
antifolate antimetabolite with broad spectrum activity against cancer cell lines. This agent inhibits 
a combination of several main folate-dependent enzymes including TS, DHFR and GARFT. In 
preclinical animal models, the major route of elimination was renal with 52% + 20% of total dose  
 

 
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eliminated as the parent drug. Preliminary results from clinical studies show that the primary route 
of elimination for pemetrexed is by urinary excretion of parent drug (up to 90% of administered 
dose). Additionally, in vitro studies predicted that pemetrexed would not cause clinically 
significant inhibition of other agents metabolized via CYP 450 enzyme system including CYP3A, 
CYP2D6, CYP2C9 and CYP1A2. However, there was a 21% inhibition noted with the CYP3A 
isoenzyme. These preclinical studies were done at very high concentrations of pemetrexed (885-
1,000 μM) and the current dose of pemetrexed administered to patients would only be expected 
to reach 500 μM. 
 
Rationale for combining cisplatin, pemetrexed and cediranib in Phase I/II study design 
 
Based on prior research with the combination of pemetrexed and cediranib, there does not 
appear to be any evidence of an interaction between pemetrexed and cediranib. Also, cediranib 
combined with platinum-based doublets have not demonstrated significant antagonistic 
interaction. However, it is unclear if there will be any drug-drug interactions between the 
combination of the 3 agents cediranib, cisplatin and pemetrexed based on prior published data. 
Given the preliminary evidence, we plan on establishing the MTD and evaluating the safety and 
toxicity profile in a de-escalation Phase I study.  Once the MTD is established, we will proceed 
with a Phase II randomized trial comparing the triplet combination regimen with 
cisplatin/pemetrexed plus placebo. 
 
SWOG’s Phase I Experience 
 
In the first cohort with the cediranib 30 mg dose, one patient only received 4 days of cediranib 
during Cycle 1 and was not evaluable for DLT.  This patient misunderstood instructions and only 
took 4 days of cediranib during Cycle 1.  An additional two patients reported Grade 3 fatigue and 
one of these patients also reported Grade 3 diarrhea.  Although technically, this did not reach the 
formal stopping rule (3 or more of the first 6 patients with a DLT), the Lung Committee leadership 
and treating investigators felt that the 30 mg cediranib dose was difficult for patients to continue 
as two of the six patients required dose reductions to 20 mg of cediranib during Cycle 1.  In the 7 
patients in Cohort 1, six patients completed at least 6 cycles of the triplet regimen and five had 
nine or more cycles of therapy.  The median number of cycles from Cohort 1 is 10 cycles with 
four patients currently remaining on cediranib maintenance therapy.  The most common toxicities 
associated with therapy during Cycle 1 included: Grade 2-3 fatigue, GI symptoms (Grade 1-2 
anorexia, Grade 1-2 constipation, Grade 1-2 nausea, Grade 2 vomiting), Grade 1-2 lymphopenia, 
and one episode each of Grade 2 insomnia, Grade 2 hypertension, and Grade 1 
myelosuppression.  When assessing all cycles of therapy there were six reports of Grade 3 
toxicity: 2 diarrhea, 2 fatigue, 1 lymphopenia, and 1 weight loss.  The most common Grade 1-2 
toxicities during all cycles of therapy included:  GI complaints (abdominal pain, anorexia, 
constipation, diarrhea, nausea, vomiting), fatigue, hypomagnesemia, lymphopenia, and 
neutropenia.  There were three cases of Grade 2 hypertension.   
 
In the second cohort of patients, there were thirteen that started with cisplatin + pemetrexed + 
cediranib 20 mg daily.  One patient received only thirteen doses of cediranib during Cycle 1 due 
to a scheduling problem with drug shipment (this has since been resolved) and was not evaluable 
for toxicity.  In total, eleven patients currently remain on treatment.  In Cycle 1, there were two 
patients that experienced DLTs with two Grade 3 events: dehydration and hyponatremia.  The 
most common toxicities experienced in Cycle 1 include: Grade 1-2 fatigue, Grade 1-2 GI 
symptoms (anorexia, diarrhea, nausea, vomiting, and weight loss), Grade 1-2 hypomagnesemia, 
Grade 1-2 myelosuppression.  There was one report each of the following Grade 1 or 2 toxicity: 
alopecia, anemia, peripheral edema, hypertension, GERD, headache, hiccups, hyperglycemia, 
hyperuricemia, hypokalemia, oral pain, thrombocytopenia, presyncope, proteinuria, and rash.  For 
all cycles of therapy to date, there have been an additional ten reports of Grade 3 toxicity: 1 
anemia, 1 constipation, 1 dehydration, 1 diarrhea, 1 hypertension, 1 mucositis, 1 nausea, 1 
myelosuppression, 1 pulmonary hypertension, and 1 vomiting episode.  One Grade 4 episode of 
thrombocytopenia has been reported and one Grade 5 report occurred.  This patient with the  
 

 
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Grade 5 toxicity died after Cycle 3 of the triplet therapy – this patient is suspected to have a septic 
event with associated hypotension and delirium.  In the initial AE report, the patient was 
mistakenly graded as Grade 5 encephalopathy and this has since been amended to “nervous 
system disorder – altered mental status”. 
 
Based on the twenty patients who have been treated with cisplatin-pemetrexed-cediranib, the 
study team has been encouraged by the preliminary efficacy results and the acceptable toxicity 
profile with the cediranib at 20 mg daily. 
 
Pharmacogenetic Analyses 
 
Knowledge of variation in kdr/flk-1 (the target of cediranib) as well as other genes in this pathway 
will assist in the interpretation of biomarker data.  The proteins encoded by these other genes are 
either biomarkers themselves (VEGF-A) or they regulate the expression of biomarkers 
(HIF1α microvessel density).  Additionally, other genes regulated by this pathway include 
candidates for genetic factors predisposing to the development of hypertension in response to 
anti-angiogenic therapy.   
 
Two common (> 10% allele frequency) variants of the kdr/flk-1 gene were discovered and 
validated by an AstraZeneca polymorphism screen and have subsequently been reported in 
public domain data bases.  Both of the polymorphic amino acid residues (Val/Ile 297; Gln/His 
472) are located in the external domain of the receptor.  Single nucleotide polymorphisms have 
also been described in the promoter region of the kdr/flk-1 gene and may correlate with 
expression levels of the receptor.  While somatic mutations in the kdr/flk-1 gene have been 
described in colorectal tumors, there are no data on the functional consequences of these 
mutations and there are no reports of mutations in the kdr/flk-1 gene in other tumor types.  (43) 
 
Although no decrease in circulating VEGF was detected in a study with bevacizumab in rectal 
cancer, VEGF-A levels may be modulated by cediranib.  (44) There is a wide inter-individual 
variation in VEGF-A levels, and an understanding of the factors influencing basal levels of VEGF-
A may aid the interpretation of results.  Polymorphisms in the VEGF-A gene have been shown to 
affect expression levels of the protein both in vitro and in vivo.  (45-47) 
 
Analysis of the HIF1α gene should be included in studies where microvessel density (MVD) is 
being analyzed as a biomarker. Hypoxia inducible factor 1 (HIFα/ARNT) is a key regulator of 
cellular response to hypoxia and is thought to play an important role in tumor progression and 
metastasis through activation of genes that are involved in the regulation of angiogenesis, energy 
metabolism and other functions.  (48)  Tanimoto et al. have demonstrated a correlation between 
two polymorphic variants of HIFα and MVD in head and neck cancer.  (49) 
 
The development of hypertension has been reported in ~11% of patients treated with 
bevacizumab plus chemotherapy compared to 2% in patients treated with chemotherapy alone, 
indicating that a proportion of patients on antiangiogenic therapy may be susceptible to the 
development of hypertension.  (50)  If hypertension is observed in patients treated with cediranib, 
analysis of candidate genes such as endothelial nitric oxide synthase gene (eNOS) could be 
undertaken. Variants of eNOS have been associated with essential hypertension and renal 
disease and may correlate with the development of hypertension in patients treated with 
antiangiogenic therapy.  (51) Nitric oxide release is mediated via the activation of kdr/flk-1 through 
downstream signaling mechanisms, and components of these pathways could provide additional 
candidates. (52) 
 

 
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Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex 
categories is shown in the table below 
 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
1 
2 
3 
Not Hispanic or Latino 
58 
55 
113 
Ethnic Category: Total of all subjects 
59 
57 
116 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
1 
2 
3 
Black or African American 
6 
7 
13 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
52 
48 
100 
Racial Category: Total of all Subjects* 
59 
57 
116 
 
 
3.0 
DRUG INFORMATION 
 
3.1 
Cediranib (RecentinTM, AZD2171) (NSC 732208) (CTEP IND #72,740)/Placebo 
 
a. 
DESCRIPTION 
 
Chemical Name: 
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-
(3-pyrrolidin-1- ylpropoxy) quinazoline maleate 
 
Other Names:  
AZD2171 maleate,  Recentin™, AZD171 
 
CAS Registry Number:  
288383-20-0 (for the free base) 
 
Molecular Formula:   
C25H27FN4O3 · C4H4O4  
 
Molecular Weight:      
566.59 as maleate salt (450.52 as free base) 
 
Approximate Solubility: 
The aqueous solubility of AZD2171 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:  AZD2171 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. 
 
b. 
TOXICOLOGY 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Cediranib (AZD2171, NSC 732208) 
 
 

 
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The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. 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 via AdEERS (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification.  Frequency is provided based on 1,243 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. 
 
 

 
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Version 2.13, September 29, 20161 
 
 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 4.0 Term) 
[n= 1243] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
CARDIAC DISORDERS 
 
 
 
Left ventricular 
systolic 
dysfunction 
 
ENDOCRINE DISORDERS 
 
 
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) 
 
Mucositis oral 
 
Mucositis oral (Gr 3) 
Nausea 
 
 
Nausea (Gr 3) 
 
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) 
INVESTIGATIONS 
 
 
Alanine 
aminotransferas
e increased 
 
Alanine 
aminotransferase 
increased (Gr 3) 
 
Alkaline 
phosphatase 
increased 
 
 
 
Aspartate 
aminotrans-
ferase 
increased 
 
Aspartate 
aminotransferase 
increased (Gr 3) 
 
Investigations - 
Other 
(increased 
thyroid 
stimulating 
hormone) 
 
Investigations - Other 
(increased thyroid 
stimulating hormone) 
(Gr 2) 
 
Lymphocyte 
count 
decreased 
 
 
 
Neutrophil 
count 
decreased 
 
 

 
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 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 4.0 Term) 
[n= 1243] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
INVESTIGATIONS (contd.) 
 
 
Weight loss 
 
Weight loss (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
Anorexia (Gr 3) 
 
Dehydration 
 
Dehydration (Gr 3) 
 
Hypophosphate
mia 
 
Hypophosphatemia (Gr 
3) 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
Dizziness (Gr 2) 
 
Headache 
 
Headache (Gr 3) 
 
 
Leukoencephalopa
thy 
 
 
 
Reversible 
posterior 
leukoencephalopat
hy syndrome 
 
RENAL AND URINARY DISORDERS 
 
 
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 
erythrodysesthe
sia syndrome 
 
Palmar-plantar 
erythrodysesthesia 
syndrome (Gr 2) 
VASCULAR DISORDERS 
 
Hypertension 
 
 
Hypertension (Gr 3) 
 
Thromboemboli
c event 
 
Thromboembolic event 
(Gr 4) 
 
 
Vascular disorders 
- Other (arterial 
thrombosis) 
 
 
Vascular 
disorders - 
Other 
(hemorrhage)2 
 
 
 
1 This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of revision.  
The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 

 
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2 Hemorrhage 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. 
3 Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC. 
 
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 - Acute coronary syndrome; Atrial fibrillation; Atrial 
flutter; Cardiac arrest; Cardiac disorders - Other (premature ventricular 
complexes); Cardiac disorders - Other (valvular heart disease); Chest pain - 
cardiac; Heart failure; 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 
ENDOCRINE DISORDERS - Hyperthyroidism 
EYE DISORDERS - Blurred vision; Eye disorders - Other (blindness); Eye 
disorders - Other (visual disturbance); Papilledema; Photophobia; Retinal 
vascular disorder 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Bloating; 
Colitis; 
Colonic 
perforation; 
Duodenal 
ulcer; 
Dyspepsia; 
Enterocolitis; 
Esophageal necrosis; Esophageal ulcer; Esophagitis; Flatulence; Gastric 
necrosis; Gastric perforation; Gastric ulcer; Gastroesophageal reflux disease; 
Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal disorders - 
Other (hydrops); Gastrointestinal disorders - Other (tongue sensitivity); Ileal 
perforation; Ileus; Oral cavity fistula; Oral pain; Pancreatitis; 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 
failure; Hepatic pain; Hepatobiliary disorders - Other (bile duct obstruction); 
Hepatobiliary disorders - Other (jaundice cholestatic) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis 
INFECTIONS AND INFESTATIONS - Infection3 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; 
Dermatitis radiation; Fracture; Injury, poisoning and procedural complications - 
Other (tracheostomy malfunction); Intestinal stoma leak; Venous injury; Wound 
complication; Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood 
bilirubin 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 (elevated LDH); 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; 

 
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Metabolism and nutrition disorders - Other (failure to thrive) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; 
Avascular necrosis; Back pain; Bone pain; Chest wall pain; Generalized muscle 
weakness; Muscle weakness left-sided; Muscle weakness lower limb; Muscle 
weakness upper limb; Musculoskeletal and connective tissue disorder - Other 
(muscle cramps); Musculoskeletal and connective tissue disorder - Other (rotator 
cuff injury); Myalgia; Myositis; Neck pain; Pain in extremity 
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; 
Dysgeusia; 
Dysphasia; 
Encephalopathy; 
Hydrocephalus; 
Ischemia 
cerebrovascular; 
Lethargy; Memory impairment; Nervous system disorders - Other (coma); 
Nervous system disorders - Other (right hemiparesis); Nervous system disorders 
- Other (spinal cord compression); Olfactory nerve disorder; Peripheral motor 
neuropathy; Peripheral sensory neuropathy; Seizure; Sinus pain; Somnolence; 
Stroke; Syncope; Transient ischemic attacks; Tremor 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Depression; Insomnia; 
Suicide attempt 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney 
disease; Cystitis noninfective; Hematuria; Renal and urinary disorders - Other 
(nephrotic syndrome); 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 
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. 
 
Precautions:  Hypertension is an expected adverse event with agents that inhibit 
VEGF signaling.  In cediranib (AZD2171) studies, increases in blood pressure 
have been observed and cases of hypertension have been reported, including 
CTC grade 4 hypertension and end-organ damage related to hypertension.  
Clinical experience with cediranib (AZD2171) has shown that hypertension 
occurs at doses of 20 mg and higher.  Cediranib (AZD2171) studies include 
monitoring of blood pressure and renal function, and a hypertension monitoring 
and management protocol has been developed which will be appended to all 
future study protocols. 
 
c. 
PHARMACOLOGY 
 
How Supplied:  For this study, “AZD2171” and matched “Placebo” will be supplied 
as round, beige, film-coated tablets for oral administration.  The 30 mg tablets (and 
matched placebo) are 9 mm in diameter, the 20 mg tablets (and matched placebo) 
are 8mm in diameter, and the 15 mg tablets (and matched placebo) are 7 mm in 
diameter.  Each tamper-evident, child-resistant, 75 mL, square, white, opaque, high-
density 

 
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Version Date  1/5/17 
 
 
 
polyethylene (HDPE) bottle contains 35 tablets. 
 
For “AZD2171”, each tablet contains either 15 mg, 20 mg, or 30 mg of cediranib 
maleate with mannitol, dibasic calcium phosphate anhydrous, sodium starch 
glycollate, microcrystalline cellulose, and magnesium stearate.  For the matched 
“Placebo”, each tablet contains mannitol, dibasic calcium phosphate anhydrous, 
sodium starch glycollate, microcrystalline cellulose, and magnesium stearate.  For 
“AZD2171” and “Placebo”, the film coat consists of hypromellose 2910, 
polyethylene glycol 400, red iron oxide, yellow iron oxide, black iron oxide, and 
titanium dioxide. 
 
Storage:  AZD2171 is shipped at room temperature by U.S. Priority Mail.  On arrival, 
intact bottles should be stored at controlled room temperature [20° to 25°C (68 to 
77°F)] and protected from light. 
 
Stability:  Shelf-life studies of AZD2171 are continuing and investigators will be 
notified when lots have expired. 
 
Route of Administration:  Oral.  AZD2171 tablets should be taken either 1 hour 
before or 2 hours after meals. 
 
d. 
SUPPLIER 
 
Investigators with an affiliation with SWOG may request an Investigator’s 
Brochure by emailing the Pharmaceutical Management Branch’s IB Coordinator 
at <ibcoordinator@mail.nih.gov> and providing the following: 
 
• 
the investigator’s full name (first, middle, last) 
• 
the investigator’s NCI investigator number 
• 
the agent name (i.e., “cediranib”) 

 
S0905 
 
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• 
the NSC (i.e., “732208”) 
• 
the protocol (i.e., “S0905”) 
• 
the requestor’s name, email address, and phone number 
 
Clinical Supplies:  Cediranib (NSC 732208/CTEP IND #72,740) and, for Phase II, 
matching Placebo 
will 
be provided free of 
charge 
by 
AstraZeneca 
Pharmaceuticals and distributed by the Pharmaceutical Management Branch 
(PMB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer 
Treatment and Diagnosis (DCTD), National Cancer Institute (NCI). 
 
Phase I (Open Label, Patient-Specific Clinical Supplies) 
 
Cediranib will be supplied in bottles containing 35–30 mg tablets (Cediranib 30 
mg) with a child-resistant cap and a tamper-evident seal.  In addition, to support 
dose reductions, Cediranib will also be supplied in bottles containing 35–20 mg 
tablets (Cediranib 20 mg) and in bottles containing 35– 15 mg tablets (Cediranib 
15 mg).  Each open label, patient-specific bottle will be laeled with: 
 
• 
the protocol number (i.e., “S0905”) 
• 
the bottle number (i.e., “Bottle 1 of 2” and “Bottle 2 of 2”) 
• 
the number of tablets (i.e., “35 tablets”) 
• 
the patient ID number (e.g., “999999", where “999999” represents a unique 
patient identifier assigned by SWOG at registration) 
• 
the patient initials (i.e., last initial, first initial, middle initial [e.g., “LFM”]) 
• 
the agent identification (i.e., “Cediranib 30 mg”  OR  “Cediranib 20 mg”  OR  
“Cediranib 15 mg”) 
• 
a blank line for the pharmacist to enter the patient’s name 
• 
administration instructions (i.e., “Take 1 tablet once daily.”) 
• 
storage instructions (i.e., “Store at room temperature (20ºC to 25ºC; 66ºF to 
77ºF) and protect from light.”) 
• 
emergency contact instructions 
• 
a Julian date 
 
Phase II (Blinded, Patient Specific Clinical Supplies 
 
Cediranib and matching Placebo will be supplied in bottles containing 35–20 mg 
tablets (Cediranib 20 mg) or 35–0 mg tablets (Placebo for Cediranib 20 mg) with 
a child-resistant cap and a tamper-evident seal.  In addition, to support dose 
reductions, Cediranib and matching Placebo will also be supplied in bottles 
containing 35–15 mg tablets (Cediranib 15 mg) or 35 – 0 mg tablets (Placebo for 
Cediranib 15 mg).  Each blinded, patient-specific bottle will be labeled with: 
• 
the protocol number (i.e., “S0905”) 
• 
the bottle number (i.e., “Bottle 1 of 2” and “Bottle 2 of 2”) 
• 
the number of tablets (i.e., “35 tablets”) 
• 
the patient ID number (e.g., “999999", where “999999” represents a unique 
patient identifier assigned by SWOG at registration) 
• 
the patient initials (i.e., last initial, first initial, middle initial [e.g., “LFM”]) 
• 
the agent identification (i.e., “Cediranib 20mg or Placebo”  OR  “Cediranib 
15mg or Placebo”) 
• 
a blank line for the pharmacist to enter the patient’s name 
• 
administration instructions (i.e., “Take 1 tablet once daily.”) 
• 
storage instructions (i.e., “Store at room temperature (20ºC to 25ºC; 66ºF to 
77ºF) and protect from light.”) 
• 
emergency contact instructions 
• 
a Julian date 

 
S0905 
 
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The Julian date indicates the day the bottle was labeled and shipped and is 
composed of the last two digits of the calendar year (e.g., 2010 = 10, 2011 = 11) 
and a day count (e.g., January 1 = 001, December 31 = 365).  For example, a 
bottle labeled and shipped on January 1, 2010 would have a Julian date of 
‘10001’ and a bottle labeled and shipped on December 31, 2011 would have a 
Julian date of ‘11365’.  The Julian date will be used by PMB for recalls.  When a 
lot expires, PMB will determine the last date the expired lot was shipped and will 
recall all bottles (i.e., both cediranib and placebo) shipped on or before that date 
thus eliminating any chance of breaking the blind. 
 
Questions about drug orders, transfers, returns, or accountability should 
be addressed to the PMB by calling (301) 496-5725 Monday through Friday 
between 
8:30am 
and 
4:30pm 
Eastern 
Time 
or 
by 
emailing 
<PMBAfterHours@mail.nih.gov> anytime. 
 
Drug Orders: No open label OR blinded starter supplies will be available for 
this study. Open label (Phase I) or blinded (Phase II) patient-specific clinical 
supplies will be sent to the registering investigator at the time of registration and 
should arrive within approximately 7 to 10 days. Patients will be registered by the 
SWOG Statistical Center in Seattle, WA. The assigned patient ID number must 
be recorded by the registering institution at the time of registration for proper 
clinical supply dispersion. Once a patient has been registered, the SWOG 
Statistical Center will electronically transmit a clinical drug request for that patient 
to the PMB. This request will be entered and transmitted by the SWOG Statistical 
Center the day the patient is registered and will be processed by PMB the next 
business day and shipped the following business day. Shipments within the 
United States will be sent by US Priority Mail (generally two to three day delivery) 
and shipments to Canada will be sent by FedEx (generally one to two day 
delivery). Thus, if a patient is registered on Monday, SWOG would enter a clinical 
drug request for that patient on Monday and PMB would process that request on 
Tuesday and ship the drug on Wednesday. United States clinical sites could 
expect to receive their order approximately Friday or Monday (depending on the 
US Mail service) and Canadian clinical sites could expect to receive their order 
either Thursday or Friday. Shipments to United States clinical sites can be 
expedited (i.e., receipt on Thursday in the example above) by indicating either 
UPS or Federal Express and providing the account number to the SWOG 
Statistical Center at the time the patient is randomized. NOTE: An account 
number is not needed for regular (U.S. Priority Mail) shipments 
 
Alternatively, active CTEP-registered investigators and investigator-designated 
shipping designees and ordering designees can submit agent requests through 
the PMB Online Agent Order Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx).  
Access 
to 
OAOP 
requires 
the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” account 
status and a “current” password. 

 
S0905 
 
Page 22 
 
Version Date  1/5/17 
 
 
 
 
S0905 Shipment Schedule 
 
Patient 
Randomized  
with SWOG  
Initial e-Order 
Transmitted by 
SWOG 
Initial e-Order 
Received and 
Approved by PMB 
Initial Order 
Shipped By 
PMB 
Initial Order 
Received at 
Site 
Monday 
Monday 
Tuesday 
Wednesday 
* 
Tuesday 
Tuesday 
Wednesday 
Thursday 
* 
Wednesday 
Wednesday 
Thursday 
Friday 
* 
Thursday 
Thursday 
Friday 
Monday 
* 
Friday 
Friday 
Monday 
Tuesday 
* 
* Dependent on shipment mechanism.  See Section 3.1d/Drug Orders for additional information. 
 
Phase I (Open Label, Patient-Specific Clinical Supplies) 
 
The initial request will be for 2 – 35 tablet bottles of Cediranib 30 mg (a 3-cycle 
/ 9-week supply at a dose of one – 30 mg tablet once daily).  Six weeks after the 
initial electronic request (i.e., three weeks before needed), sites may reorder an 
additional 2 – 35 tablet bottles of Cediranib 30 mg (a 3–cycle / 9-week supply 
at a dose of one – 30 mg tablet once daily) by completing an NCI Clinical Drug 
Request form and faxing it to the PMB at 301-480-4612.  The NCI Clinical Drug 
Request form is available on the CTEP home page (http://ctep.cancer.gov).  The 
protocol number (i.e., S0905), the assigned patient ID number (e.g., “999999”), 
the patient initials (e.g., "LFM"), and the number of bottles remaining from the 
previous shipment must be recorded on each order. 
 
Special Ordering Procedures for Patients Requiring a Dose Reduction. 
 
If the patient is dose reduced from cediranib 30 mg once daily TO cediranib 20 
mg once daily (see Section 8.3), an NCI Clinical Drug Request form must be 
completed (see above) and faxed to PMB to obtain the cediranib 20 mg tablets.  
Be sure to specify “Cediranib 20 mg” in the “Strength” field.  Please indicate the 
cycle and the day of therapy (e.g., Cycle 2, Day 1) of the dose reduction in 
the comments field. 
 
If the patient is dose reduced from cediranib 20 mg once daily TO cediranib 15 
mg once daily (see Section 8.3), an NCI Clinical Drug Request form must be 
completed (see above) and faxed to PMB to obtain the cediranib 15 mg tablets.  
Be sure to specify “Cediranib 15 mg” in the “Strength” field.  Please indicate the 
cycle and the day of therapy (e.g., Cycle 2, Day 1) of the dose reduction in 
the comments field. 
 
Phase II (Blinded, Patient-Specific Clinical Supplies) 
 
The initial request will be for 2 – 35 tablet bottles of Cediranib 20 mg or 
matched placebo (a 3-cycle / 9-week supply at a dose of one – 20 mg tablet 
once daily).  Six weeks after the initial electronic request (i.e., three weeks before 
needed), sites may reorder an additional 2 – 35 tablet bottles of Cediranib 20 
mg or matched placebo (a 3–cycle / 9-week supply at a dose of one – 20 mg 
tablet once daily) by completing an NCI Clinical Drug Request form and faxing it 
to the PMB at 301-480-4612.  The NCI Clinical Drug Request form is available on 
the CTEP home page (http://ctep.cancer.gov).  The protocol number (i.e., 
S0905), the assigned patient ID number (e.g., “999999”), the patient initials (e.g., 
"LFM"), and the number of bottles remaining from the previous shipment must be 
recorded on each order. 

 
S0905 
 
Page 23 
 
Version Date  1/5/17 
 
 
 
 
Special Ordering Procedures for Patients Requiring a Dose Reduction. 
 
If the patient is dose reduced from cediranib 20 mg once daily TO cediranib 15 
mg once daily (see Section 8.3), an NCI Clinical Drug Request form must be 
completed (see above) and faxed to PMB to obtain the cediranib 15 mg tablets.  
Be sure to specify “Cediranib 15 mg / Placebo” in the “Strength” field.  Please 
indicate the cycle and the day of therapy (e.g., Cycle 2, Day 1) of the dose 
reduction in the comments field. 
 
All drug orders will be shipped directly to the registering physician at the shipping 
address provided on their current Supplemental Investigator Data Form (IDF) on 
file with CTEP.  The registering investigator must maintain an active investigator 
registration status with CTEP, DCTD through the annual submission of an FDA 
Form 1572 (Statement of Investigator), a Curriculum Vitae, a Supplemental 
Investigator Data Form (IDF), and a Financial Disclosure Form (FDF). 
 
Drug Transfers:  Bottles may NOT be transferred from one patient to another 
patient or from one protocol to another protocol.  All other transfers (e.g., a 
patient moves from one participating clinical site to another participating clinical 
site, the registering investigator for a given patient changes) must be approved in 
advance by the PMB.  To obtain an approval for transfer, investigators should 
complete and submit to the PMB (fax number 301-480-4612) a Transfer 
Investigational 
Agent 
Form 
available 
on 
the 
CTEP 
home 
page 
(http://ctep.cancer.gov).  The patient ID number (e.g., “999999”) and the patient 
initials (e.g., "LFM”) should be entered in the "Received on NCI Protocol No." and 
the "Transferred to NCI Protocol No." fields in addition to the protocol number 
(i.e., " S0905").  The julian date/order number (e.g., 10001-9999) should be 
entered in the “Lot Number” field. 
 
Drug Returns:  Only undispensed clinical supplies should be returned to the 
PMB.  When it is necessary to return study drug (e.g., sealed bottles remaining 
when a patient permanently discontinues protocol treatment, expired bottles 
recalled by the PMB), investigators should return the study drug to the PMB 
using the NCI Return Drug List available on the CTEP home page 
(http://ctep.cancer.gov).  The patient ID number (e.g., “999999”), the patient 
initials (e.g., "LFM"), and the julian date/order number (e.g., 10001-9999) should 
be entered in the "Lot Number" field.  A separate line item is required for each 
patient ID (e.g., “999999”) and for each strength (e.g., “30 mg”, “20 mg”, “15 mg”) 
being returned.  Dispensed bottles with remaining tablets should be 
documented 
in 
the 
patient-specific 
NCI 
Investigational 
Agent 
Accountability Record (i.e., logged is as “returned by patient” and logged 
out as “destroyed on site”) and destroyed on site in accordance with 
institutional policy. 
 
Drug Accountability:  The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return 
of all drugs received from the PMB using the NCI Investigational Agent 
Accountability Record available on the CTEP home page (http://ctep.cancer.gov).  
A separate NCI Investigational Agent Accountability Record must be maintained 
for each patient ID number (e.g., “999999”) and for each strength (e.g., “30 mg”, 
“20 mg”, “15 mg”) on this protocol.  The combination julian date/order number in 
the upper right hand corner of the patient-specific bottle label (e.g., 10001-9999) 
should be recorded as the lot number. 
 

 
S0905 
 
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Emergency Unblinding:  In the event of an emergency or severe adverse reaction 
necessitating identification of the medication for the welfare of the patient, please 
contact the Washington Poison Center (WPC) at 206-526-2121 (see Appendix 
18.6).  This service is available 24 hours a day, 365 days a year.  The WPC will 
require the protocol number (i.e., “S0905”), the patient ID number (e.g., 
“999999”), and the patient initials (e.g., “LFM”) to unblind the patient.  Please 
note that, if a patient is emergently unblinded, he/she is considered to be off-
therapy and must discontinue protocol treatment. 
 
Compliance:  Patients will be required to return all bottles of study medication at the 
end of each cycle.  The number of tablets remaining should be documented and 
recorded on the Intake Calendar (see Appendix 18.3). 
 
3.2 
Cisplatin (CDDP) (Platinol®) (NSC-119875) 
 
b. 
DESCRIPTION 
 
Cis-diamminedichloroplatinum (Platinol® or cisplatin) is a heavy metal complex 
and is water soluble.  It is a white lyophilized powder with a molecular weight of 
300.1. 
 
Mechanism of Action:  It acts as a bifunctional alkylating agent. 
 
b. 
TOXICOLOGY 
 
Human Toxicology:  Human toxicity includes anorexia, nausea, vomiting, renal 
toxicity (with an elevation of BUN, creatinine, serum uric acid and impairment of 
endogenous creatinine clearance, as well as renal tubular damage), ototoxicity 
(with hearing loss which initially is in the high-frequency range, as well as 
tinnitus), peripheral neuropathy and hyperuricemia.  Much more severe and 
prolonged toxicity has been observed in patients with abnormal or obstructed 
urinary excretory tracts.  Raynaud’s phenomena and digital ischemia has been 
described. 
 
Anaphylactic-like 
reactions 
including 
facial 
edema, 
bronchoconstriction, tachycardia and hypotension may occur within minutes of 
administration.  Myelosuppression, often with delayed erythrosuppression, is 
expected.  In the high-dose treatment regimen with osmotic diuresis, the nadir of 
white cells and platelets occurred regularly at about two weeks with recovery 
generally at about three weeks after the initiation of therapy.  Alopecia, malaise 
and asthenia have been reported.  Rare complications are alopecia, seizures, 
loss of taste and allergic reactions.  Tetany may occur due to hypomagnesemia 
and/or hypocalcemia.  Other electrolyte disturbances may occur.  At high doses 
patients have experienced optic neuritis, emetrexed, cerebral blindness, 
blurred vision, and altered color perception.  Patients have also experienced 
cardiac abnormalities, elevated SGOT and rash.  Subsequent courses should not 
be given until serum creatinine returns to normal if elevated.  Audiometric 
analyses should be monitored and courses withheld until auditory acuity is within 
normal limits.  The occurrence of acute leukemia has been reported rarely in 
patients treated with anthracycline/alkylator combination chemotherapy. 
 
Pregnancy and Lactation:  Cisplatin can cause fetal harm when administered to a 
pregnant woman.  In mice, cisplatin is teratogenic and embryotoxic.  This drug 
has been found to be excreted in human milk and because of the potential for 
serious adverse reactions in nursing infants, patients receiving cisplatin should 
not breast feed. 
 

 
S0905 
 
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c. 
PHARMACOLOGY 
 
Kinetics:  After a single IV dose, increased concentration is found in the liver, 
kidneys and small and large intestines.  Plasma levels of cisplatin decay in a 
biphasic mode with an initial half-life of 25 to 49 minutes, and a secondary phase 
ranging from 58 to 73 hours.  This prolonged phase is due to protein binding 
which exceeds 90% of the radioactivity in the second phase.  Urinary excretion is 
incomplete with only 27 to 43% of the radioactivity excreted in the first five days.  
The initial fractions of radioactivity are largely unchanged drugs.  Although this 
drug seems to act as an alkylating agent, there are data to indicate that its mode 
and sites of action are different from those of nitrogen mustard and the standard 
alkylating agents.  Cisplatin penetrates into CNS poorly. 
 
Formulation:  Cisplatin is available as 10 mg and 50 mg vials of dry powder 
which are reconstituted with 10 ml and 50 ml of Sterile Water for Injection USP, 
respectively.  Cisplatin is also available as an aqueous solution, 1 mg/ml, in 50 or 
100 ml vials. 
 
Storage and Stability:  The intact vials may be stored at room temperature (15–
25°C) for the lot life indicated on the package.  Do not refrigerate.  Once 
reconstituted, the solution should be kept at room temperature to avoid 
precipitation.  The reconstituted solution is stable for 20 hours at room 
temperature, although, due to a lack of preservatives, the solution should be 
used within eight hours of reconstitution.  The solution may be further diluted in a 
chloride-containing vehicle such as D5NS, NS, or D5-1/2NS (precipitate occurs 
in D5W). 
 
If cisplatin contacts the skin or mucosa, immediately and thoroughly wash the 
skin with soap and water and flush the mucosa with water. 
 
Administration:  In this protocol, cisplatin will be given immediately after 
preparation as an intravenous infusion over a 2 hour period.  Needles or 
intravenous sets containing aluminum parts that may come in contact with 
cisplatin (Platinol) should not be used for preparation or administration, as 
a black precipitate is formed within 30 minutes. 
 
d. 
SUPPLIER 
 
Cisplatin is commercially available, and should therefore be purchased by a third 
party.  This drug will not be supplied by the NCI. 
 
Please refer to the Physician Desk Reference and package insert for complete 
information. 
 
3.3 
Pemetrexed for injection (Alimta®) (NSC-698037) 
 
b. 
DESCRIPTION 
 
Pemetrexed for injection is an antifolate antineoplastic agent that exerts its action 
by disrupting folate-dependent metabolic processes essential for cell replication. 
Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, N-
[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, 
disodium salt, heptahydrate. It is a white to almost-white solid with a molecular 
formula of C20H19N5Na2O6•7H2O and a molecular weight of 597.49.  
 

 
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c. 
TOXICOLOGY 
 
The following toxicities occurred in > 10% of patients: 
 
Cardiovascular:  Chest paint (38 to 40%); edema (19%) 
 
Central nervous system:  Fatigue (80 to 87%); fever (17 to 26%); depression (11 
to 14%) 
 
Dermatologic:  Rash (17 to 22%); alopecia (11%) 
 
Gastrointestinal:  Nausea (39 to 84%; grade 3-4 in 12%); vomiting (25 to 58%; 
Grade 3-4 in 11%); constipation (30 to 44%); anorexia (35 to 62%); 
stomatitis/pharyngitis (20 to 28%); diarrhea (21 to 26%) 
 
Hematologic:  Neutropenia (11 to 58%); leucopenia (13 to 55%); anemia (33%); 
thrombocytopenia (9 to 27%).  Nadir: 8-10 days, Recovery:  12-17 days. 
 
Neuromuscular and skeletal:  Neuropathy (17 to 29%); myalgia (13%) 
 
Renal:  Creatinine increased (3 to 16%) 
 
Respiratory:  Dyspnea (66%) 
 
Miscellaneous:  Infection (17 to 23% 
 
The following toxicities occurred in 1% to 10% of patients: 
 
Cardiovascular:  Thrombosis/embolism (4 to 7%); cardiac ischemia (3%) 
 
Endocrine and metabolic:  Dehydration (3 to 7%) 
 
Gastrointestinal:  Dysphagia/esophagitis/odynophagia (5 to 6%) 
 
Renal:  Renal failure (< 1 to 2%) 
 
Miscellaneous:  Allergic reaction (2 to 8%) 
 
Neuromuscular and skeletal:  Arthralgia (8%) 
 
Drug Interactions:  Pemetrexed is primarily eliminated unchanged renally as a 
result of glomerular filtration and tubular secretion.  Concomitant administration 
of nephrotoxic drugs could result in delayed clearance of emetrexed. 
Concomitant administration of substances that are also tubularly secreted (e.g., 
probenecid) could potentially result in delayed clearance of emetrexed.  
Although ibuprofen (400 mg qid) can be administered with emetrexed in 
patients with normal renal function (creatinine clearance ≥ 80 mL/min), caution 
should be used when administering ibuprofen concurrently with emetrexed to 
patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 
79 mL/min).  Patients with mild to moderate renal insufficiency should avoid 
taking NSAIDs with short elimination half-lives for a period of 2 days before, the 
day of, and 2 days following administration of emetrexed.  In the absence of 
data regarding potential interaction between emetrexed and NSAIDs with 
longer half-lives, all patients taking these NSAIDs should interrupt dosing for at 
least 5 days before, the day of, and 2 days following emetrexed administration.  
If concomitant administration of an NSAID is necessary, patients should be 
monitored closely for toxicity, especially myelosuppression, renal, and 
gastrointestinal toxicity. 

 
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Decreased Renal Function:  Pemetrexed is primarily eliminated unchanged by 
renal excretion. No dosage adjustment is needed in patients with creatinine 
clearance ≥ 45 mL/min.  Insufficient numbers of patients have been studied with 
creatinine clearance < 45 mL/min to give a dose recommendation.  Therefore, 
emetrexed should not be administered to patients whose creatinine clearance 
is < 45 mL/min. 
 
Pregnancy Category D:  Pemetrexed may cause fetal harm when administered to 
a pregnant woman.  Pemetrexed was fetotoxic and teratogenic in mice at i.p. 
doses of 0.2 mg/kg (0.6 mg/m2) or 5 mg/kg (15 mg/m2) when given on gestation 
days 6 through 15.  Pemetrexed caused fetal malformations (incomplete 
ossification of talus and skull bone) at 0.2 mg/kg (about 1/833 the recommended 
i.v. human dose on a mg/m2 basis), and cleft palate at 5 mg/kg (about 1/33 the 
recommended i.v. human dose on a mg/m2 basis).  Embryotoxicity was 
characterized by increased embryo-fetal deaths and reduced litter sizes.  There 
are no studies of emetrexed in pregnant women.  Patients should be advised to 
avoid becoming pregnant.  If emetrexed is used during pregnancy, or if the 
patient becomes pregnant while taking emetrexed, the patient should be 
apprised of the potential hazard to the fetus. 
 
Nursing Mothers:  It is not known whether emetrexed or its metabolites are 
excreted in human milk.  Because many drugs are excreted in human milk, and 
because of the potential for serious adverse reactions in nursing infants from 
emetrexed, it is recommended that nursing be discontinued if the mother is 
treated with emetrexed. 
 
d. 
PHARMACOLOGY 
 
Kinetics:  The pharmacokinetics of emetrexed administered as a single agent in 
doses ranging from 0.2 to 838 mg/m2 infused over a 10-minute period have been 
evaluated in 426 cancer patients with a variety of solid tumors.  Pemetrexed is 
not metabolized to an appreciable extent and is primarily eliminated in the urine, 
with 70% to 90% of the dose recovered unchanged within the first 24 hours 
following administration.  The total systemic clearance of emetrexed is 91.8 
mL/min and the elimination half-life of emetrexed is 3.5 hours in patients with 
normal renal function (creatinine clearance of 90 mL/min).  The clearance 
decreases, and exposure (AUC) increases, as renal function decreases. 
Pemetrexed total systemic exposure (AUC) and maximum plasma concentration 
(Cmax) increase proportionally with dose.  The pharmacokinetics of emetrexed 
do not change over multiple treatment cycles.  Pemetrexed has a steady-state 
volume of distribution of 16.1 liters. In vitro studies indicate that emetrexed is 
approximately 81% bound to plasma proteins.  Binding is not affected by degree 
of renal impairment. 
 
Formulation:  Pemetrexed is supplied as a sterile lyophilized powder for 
intravenous infusion available in single-dose vials.  The product is a white to 
either light yellow or green-yellow lyophilized solid.  Each 500-mg vial contains 
emetrexed disodium equivalent to 500 mg emetrexed and 500 mg of 
mannitol. Hydrochloric acid and/or sodium hydroxide may have been added to 
adjust pH. 
 
Storage and Stability:  Pemetrexed for injection should be stored at 25°C (77°F); 
excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room 
Temperature].  Chemical and physical stability of reconstituted and infusion 
solutions of emetrexed were demonstrated for up to 24 hours following initial 
reconstitution, when stored refrigerated, 2-8°C (36-46°F), or at 25°C (77°F),  

 
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excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room 
Temperature]. When prepared as directed, reconstituted and infusion solutions of 
emetrexed contain no antimicrobial preservatives. Discard unused portion.  
Pemetrexed is not light sensitive. 
 
Administration:  
 
1. 
Use aseptic technique during the reconstitution and further dilution of 
emetrexed for intravenous infusion administration. 
 
2. 
Calculate the dose and the number of emetrexed vials needed.  Each 
vial contains 500 mg of emetrexed.  The vial contains an excess of 
emetrexed to facilitate delivery of label amount. 
 
3. 
Reconstitute 500-mg vials with 20 mL of 0.9% Sodium Chloride Injection 
(preservative free) to give a solution containing 25 mg/mL emetrexed. 
Gently swirl each vial until the powder is completely dissolved.  The 
resulting solution is clear and ranges in color from colorless to yellow or 
green-yellow without adversely affecting product quality.  The pH of the 
reconstituted emetrexed solution is between 6.6 and 7.8.  FURTHER 
DILUTION IS REQUIRED. 
 
4. 
Parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to administration.  If particulate matter is 
observed, do not administer. 
 
5. 
The appropriate volume of reconstituted emetrexed solution should be 
further diluted to 100 mL with 0.9% Sodium Chloride Injection 
(preservative free) and administered as an intravenous infusion over 10 
minutes. 
 
6. 
Chemical and physical stability of reconstituted and infusion solutions of 
emetrexed were demonstrated for up to 24 hours following initial 
reconstitution, when stored at refrigerated or ambient room temperature 
(see USP Controlled Room Temperature) and lighting.  When prepared 
as directed, reconstitution and infusion solutions of emetrexed contain 
no antimicrobial preservatives. Discard any unused portion. 
 
Reconstitution and further dilution prior to intravenous infusion is only 
recommended with 0.9% Sodium Chloride Injection (preservative free). 
Pemetrexed is physically incompatible with diluents containing calcium, including 
Lactated Ringer’s Injection, USP and Ringer’s Injection, USP and therefore these 
should not be used.  Co-administration of emetrexed with other drugs and 
diluents has not been studied, and therefore is not recommended. 
 
d. 
SUPPLIER 
 
Pemetrexed is commercially available and should be purchased by a third party.  
Pemetrexed will not be supplied by the NCI.   
 
Please refer to the Physician's Desk Reference and package insert for complete 
information.   
 
 
4.0 
STAGING CRITERIA 
 
Staging criteria are not applicable to this protocol. 
 

 
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5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration.  Use the spaces provided to confirm a patient's eligibility.  For each criterion requiring test 
results and dates, please record this information on the S0905 Prestudy Form (Form #39381) and submit 
to the Data Operations Center in Seattle (see Section 14.0).  Any potential eligibility issues should be 
addressed to the Data Operations Center in Seattle at 206/652-2267 prior to registration. 
  
In calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be considered Day 28.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 28 or 42 falls on a 
weekend or holiday, the limit may be extended to the next working day. 
 
SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
5.1 
Disease Related Criteria 
 
 
 a. 
Patient must have histologically or cytologically confirmed diagnosis of malignant 
pleural mesothelioma.  Surgical resection must not be planned.   
 
 
 b. 
Patients must have measurable or non-measurable disease by both RECIST 
(see Section 10.1) and modified RECIST criteria for pleural tumors (see Section 
10.5) as documented by CT scan.  Examinations for assessment of measurable 
disease must have been completed within 28 days prior to registration.  
Examinations for assessment of non-measurable disease must have been 
performed within 42 days prior to registration.  All disease must be assessed and 
documented on the RECIST 1.1 and Modified RECIST Baseline Tumor 
Assessment Form (Form #35990).  
 
 
 c. 
Patients must not have received any prior systemic therapy (chemotherapy or 
other biologic therapy) for their unresectable malignant pleural mesothelioma.  
Prior systemic chemotherapy or biologic therapy is allowed as neoadjuvant or 
adjuvant treatment, disease has now recurred, and all systemic treatment was 
completed > 6 months prior registration.  Prior therapy must not have included 
cediranib.  
 
 
 d. 
Patients may have received prior surgery (e.g., pleurectomy, pleurodeisis) 
provided at least 28 days have elapsed since surgery (thoracic or other major 
surgeries) and patients have recovered from all associated toxicities at the time 
of registration. There must be no anticipated need for major surgical procedures 
during protocol treatment.   
 
5.2 
Prior Therapy Criteria 
 
 
 e. 
Patients may have received prior radiation therapy provided at least 28 days 
have elapsed since the last treatment and patients have recovered from all 
associated toxicities at the time of registration.   
 
 
 f. 
Institutions must seek additional patient consent for the banking and future use of 
specimens as described in Section 15.3. 
 

 
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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
5.3 
Clinical/Laboratory Criteria 
 
 
 g. 
Patient must have Zubrod performance status 0-2 (see Section 10.4).  
 
 
 h. 
Patient must have adequate bone marrow function as evidenced by all of the 
following:  absolute neutrophil count ≥ 1,500 mcl; platelets ≥ 100,000/ml; 
hemoglobin ≥ 9.0 g/dl (may be reached by transfusion).  These results must have 
been obtained within 28 days prior to registration. 
 
 
 i. 
Patient must have adequate hepatic function as defined by total bilirubin ≤ 1.5 x 
Institutional Upper Limit of Normal (IULN) and SGOT or SGPT ≤ 2.5 x IULN (if 
liver metastases are present, SGOT or SGPT must be ≤ 5.0 x IULN).  These 
results must be obtained within 28 days prior to registration. 
 
 
 j. 
Patient must have adequate renal function as evidenced by BOTH of the 
following: 
 
• 
Serum creatinine ≤ 1.5 x IULN.  Must be obtained within 28 days prior to 
registration. 
 
• 
Calculated creatinine clearance ≥ 60 mL/min.  Creatinine level (mg/dl) used 
in calculation must be obtained within 28 days prior to registration. 
 
Calculated creatinine clearance = (140-age) x weight (kg) x 0.85 (if female) 
 
72 x creatinine (mg/dl) 
 
 
 k. 
Urine protein must be screened by urine analysis within 28 days prior to 
registration.  Patient must not have greater than +1 proteinuria on two 
consecutive dipsticks taken no less than 7 days apart.  However, if the first 
urinalysis shows no protein, then a repeat urinalysis is not required. 
 
 
 l. 
Patient must have an ECG performed within 42 days prior to registration.  Patient 
must not have mean QTc > 500 msec (with Bazett’s correction) in screening 
electrocardiogram, or other significant ECG abnormality, NYHA classification III 
or IV (see Appendix 18.5).  Patient must not require concurrent use of drugs or 
biologics with proarrhythmic potential (see Appendix 18.4 for list of agents). 
 
 
 m. 
Patient must not be receiving any medication that may markedly affect renal 
function (e.g., vancomycin, amphotericin, pentamidine).  
 
 
 n. 
Patient must not have had clinically significant hemoptysis, defined as greater 
than 1 tablespoon of bright red blood, within one year prior to registration.  
Although hemoptysis has not been associated with cediranib, it may be a class 
effect for anti-angiogenic agents and therefore a risk factor for this experimental 
agent.  
 
 
 o. 
Patient must be able to swallow oral medications. 
 
 
 p. 
Patients must not have known HIV infection because their immune system may 
not tolerate the investigational treatment and because antiretroviral treatment 
may interact with the study agents. 

 
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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
 
 q. 
Patients must not be pregnant or nursing because of increased risk of harm to a 
nursing infant or fetus including fetal death from the chemotherapeutic and 
biologic agents.  Women/men of reproductive potential must have agreed to use 
an effective contraceptive method.  A woman is considered to be of "reproductive 
potential" if she has had menses at any time in the preceding 12 consecutive 
months.  In 
addition 
to 
routine 
contraceptive 
methods, 
"effective 
contraception" also includes heterosexual celibacy and surgery intended to 
prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a 
hysterectomy, bilateral oophorectomy or bilateral tubal ligation.  However, if at 
any point a previously celibate patient chooses to become heterosexually active 
during the time period for use of contraceptive measures outlined in the protocol, 
he/she is responsible for beginning contraceptive measures. 
 
 
 r. 
Patient must have no plans to receive concurrent chemotherapy, hormonal 
therapy, radiotherapy, immunotherapy or any other type of therapy for treatment 
of cancer while on this protocol treatment.   
 
 
 s. 
No other prior malignancy is allowed except for the following:  adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately 
treated Stage I or II cancer from which the patient is currently in complete 
remission, or any other cancer from which the patient has been disease free for 
five years. 
 
5.4 
Regulatory Criteria 
 
 
 t. 
All patients must be informed of the investigational nature of this study and must 
sign and give written informed consent in accordance with institutional and 
federal guidelines. 
 
 
 u. 
As a part of the OPEN registration process (see Section 13.2 for OPEN access 
instructions) the treating institution’s identity is provided in order to ensure that 
the current (within 365 days) date of institutional review board approval for this 
study has been entered in the system. 
 

 
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6.0 
STRATIFICATION FACTORS 
 
For the Phase II portion of the trial, patients will be randomized using a dynamic balancing 
algorithm with stratification based on (53): 
 
6.1 
Performance status: 0 or 1 versus 2 
 
6.2 
Histologic subtype: epitheliod versus biphasic/sarcomatoid 
  
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Dr. Tsao at 713/792-6363 or Dr. 
Vogelzang at 702/952-3452.  For dosing principles or questions, please consult the Southwest 
Oncology Group Policy #38 "Dosing Principles for Patients on Clinical Trials" at http://swog.org 
(then click on "Policies and Manuals" under the "Visitors" menu and choose Policy 38). 
 
7.1 
Good Medical Practice 
 
The following tests (and/or assessments) are recommended within 28 days prior to 
registration in accordance with Good Medical Practice.  Results of these tests do not 
determine eligibility and minor deviations from normal limits would be acceptable if they 
do not affect patient safety in the clinical judgment of the treating physician.  If there are 
significant deviations in these tests/assessments that could impact patient safety, 
it is highly recommended that the registering investigator discuss the patient with 
the Study Coordinator prior to registering. 
 
a. 
Uric acid 
 
b. 
Serum mesothelin-related peptide 
 
c. 
Patients at an increased risk for compromised left ventricular ejection fraction 
(LVEF) should have a baseline ECHO/MUGA and troponins to help identify 
compromised LVEF should it occur.  Investigators should consider patients who 
have the following risk factors at an increased risk for compromised LVEF: 
 
1. 
New York Heart Association classification of II (see Appendix 18.5) 
 
2. 
Prior central thoracic radiation therapy (RT), including RT to the heart 
 
3. 
History of myocardial infarction within 12 months 
 
d. 
Any non-required baseline test result ≥ Grade 3 should be noted in the patient’s 
medical record as an abnormality with an indication that the treating investigator 
feels it is safe for the patient to enroll on the study. 
 
e. 
Performance of an audiogram is recommended to document baseline hearing 
loss status in the event of possible hearing loss due to cisplatin administration.  
Patients with significant clinical hearing loss should be willing to accept the 
potential for worsening of symptoms. 
 
f. 
Patient should not have resting blood pressure > 150/90 in the presence or 
absence of anti-hypertensive therapy. 
 
 
 

 
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g. 
Patient should not have symptomatic congestive heart failure resulting in a 
resting O2 saturation of < 92% on room air.  Patient should not have unstable 
angina pectoris.  Patient should not have cardiac arrhythmia requiring 
maintenance medication.  Patient should not require oxygen at rest.  Patients 
with hypoxia from mesothelioma disease and not from congestive heart failure 
are allowed on the trial. 
 
h. 
Patients should have chemistry tests including serum chemistry for potassium, 
magnesium, albumin, electrolytes (sodium, chloride, bicarbonate), glucose, 
calcium, LDH, phosphorus, total protein, alkaline, phosphatase, and BUN. 
Results should be within normal limits. These should be obtained within 28 days 
prior to registration. 
 
i. 
Patients should have a thyroid function test (TSH, free T4) with results within 
normal limits within 28 days prior to registration. 
 
j. 
Patient should not have suffered an arterial thromboembolic event within the 
previous 1 year.  Although arterial thrombotic events have not been associated 
with cediranib, it may be a class effect for anti-angiogenic agents and therefore a 
risk factor for this experimental agent.  
 
k. 
Patient should not have > Grade 2 neuropathy. 
 
l. 
Patient should not have chronic diarrhea ≥ Grade 1.   
 
m. 
Patient should not have ongoing or active infection requiring parenteral therapy 
at the time of registration. 
 
n. 
Patients on anticoagulants should have INR performed. 
 
7.2 
Treatment Overview 
 
The study will be conducted in two sequential parts.  A patient may be enrolled to 
either the Phase I portion or the Phase II portion, but not both. 
 
Phase I – Details are in Section 7.4. 
 
Phase II – Details are in Section 7.5. 
 
 

 
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7.3 
Pre-Medication 
 
Pre-Medication – applicable to both the Phase I and Phase II portions of the study 
 
Pre-medication for pemetrexed and cisplatin is required as detailed below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Agent 
Dose 
Route 
Schedule 
Folic Acid 
400-1,000 
mcg or 
equivalent a 
PO 
Daily; beginning 7 days before 
first dose of pemetrexed and 
continuing until 3 weeks after the 
last dose of pemetrexed 
Vitamin B12 
1,000 mcg 
IM 
q 9 weeks; beginning 7 days 
before first dose of pemetrexed 
and continuing until 3 weeks after 
the last dose of pemetrexed b 
Dexamethasone 
4 mg c 
PO twice per 
day (or as 8 
mg every 
morning) 
 
Day before, day of, and day after 
all doses of pemetrexed unless 
clinically contraindicated 
Aprepitant  d 
125 mg 
PO 
One hour before each cisplatin 
dose 
Aprepitant  d 
80 mg 
PO 
Daily on Days 2, 3, 4 of each 
cycle 
Ondansetron d 
8 mg 
IVPB in 50 
mL NS 
 
Day 1 of each cycle 
Ondansetron  d 
8 mg 
PO 
Daily on Days 2, 3, 4 of each 
cycle 
a 
An acceptable range of folic acid intake is given above.  If patient is already on 
vitamin supplement that includes 400-600 mcg folic acid daily, this is acceptable 
and no additional folic acid needs to be taken. 
b  
i.e., if a scheduled vitamin B12 dose falls within 3 weeks following pemetrexed, it 
should be given. 
c 
Higher or additional doses are permitted for reasons other than routine rash 
prophylaxis (e.g., antiemetic prophylaxis) 
d   Or acceptable alternative 

 
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c. 
Phase I Portion of the Study 
 
NOTE:  No open label starter supplies will be available for this study.  Initial open 
label, patient-specific clinical supplies of cediranib will be shipped from the 
Pharmaceutical Management Branch (PMB) to the registering investigator at the time of 
patient registration and should arrive within 7 to 10 days (see Section 3.1). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMPORTANT NOTE: The Phase I portion of this trial is now closed. Rapid reporting 
of dose-limiting toxicities (Section 15.1) is no longer required. 
 
a.  
Dose Determination Rules 
 
1.  
Dose Limiting Toxicity (DLT) is defined in Section 7.4b. 
 
2.  
Only DLTs occurring during Cycle 1 will be used to guide dosing 
determination of cediranib.  
 
3.  
Patients will be considered evaluable for DLT if they received at least 14 
doses of cediranib at the assigned dose during Cycle 1 and at least one 
dose each of emetrexed and cisplatin, or if they developed a DLT. If a 
patient does not develop a DLT but does not complete at least 14 doses 
of cediranib and one dose each of emetrexed and cisplatin during 
Cycle 1 due to any reason, the patient will be considered not evaluable 
for DLT and will be replaced.  
 
b. 
The following dosing scheme will be used for dose determination:  
 
Cohort 1: 
Evaluate up to 10 patients at Dose Level 0 (30 mg daily):   
• 
Enroll 6 patients, evaluate for toxicity, enroll additional patients 
as required 
• 
If 3 or more of the initial 6 patients have DLT at Dose Level 0 
stop enrollment at this dose and continue to Dose Level -1. 
• 
If in initial 6 patients, 2 or fewer patients have DLT at Dose Level 
0 enroll 4 additional patients. 
• 
If 3/10 or fewer patients have DLT this will be the MTD for the 
Phase II trial.   
• 
If more than 3/10 patients have DLT at Dose Level 0 stop 
enrollment at this dose after the 4th patient with DLT and 
continue to Dose Level -1. 
 
 
Agent* 
Dose 
Route 
Schedule* 
Pemetrexed 
500 mg/m2 
IV over 10 
minutes 
Day 1 of each cycle, for 
6 cycles only 
Cisplatin 
75 mg/m2 
in 1 L NS 
IVPB with 25 
grams 
mannitol over 
2 hours 
Day 1 of each cycle, for 
6 cycles only 
Cediranib 
Cohort 1 (Dose 
Level 0):  30 mg   
Cohort 2 (Dose 
Level -1):  20 mg   
PO 
Daily until meeting one 
of the criteria in Section 
7.10** 
*    Each cycle is 21 days long. 
**  Cediranib should be taken either one hour before or two hours after eating. 

 
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Cohort 2: 
If Dose Level 0 is not the MTD, evaluate up to 10 patients at Dose Level 
-1 (20 mg daily):   
• 
Enroll 6 patients, evaluate for toxicity, enroll additional patients 
as required 
• 
If 3 or more of the initial 6 patients have DLT at Dose Level -1 
stop enrollment at this dose and conclude neither dose is the 
MTD.  Further testing will need to be discussed. 
• 
If in initial 6 patients, 2 or fewer patients have DLT at Dose Level 
-1 enroll 4 additional patients,  
• 
If 3/10 or fewer patients have DLT this will be the dose for the 
Phase II trial.  
• 
If more than 3/10 patients have DLT at Dose Level -1 stop 
enrollment at this dose after the 4th patient with DLT and 
conclude neither dose is the MTD.  Further testing will need to 
be discussed.  
 
c. 
Definition of Dose-Limiting Toxicity  
 
Toxicities will be graded according to the CTEP Active Version of the NCI 
Common Terminology Criteria for Adverse Events. This can be reviewed at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Dose-limiting toxicities (DLT) apply only during Cycle 1 and must be drug-related 
(i.e. possibly, probably or definitely related to one of the 3 study drugs). The 
following events occurring in the first cycle of treatment are considered dose 
limiting.  
 
1. 
Febrile neutropenia 
 
2. 
Grade 4 neutrophil count decrease for more than 7 days’ duration 
 
3. 
Grade 4 platelet count decrease 
 
4. 
Grade 3 or 4 non-hematologic toxicity (excluding alopecia)  
 
7.5 
Phase II Portion of the Study 
 
NOTE:  No blinded starter supplies will be available for this study.  Initial blinded, 
patient-specific clinical supplies of cediranib / placebo will be shipped from the 
Pharmaceutical Management Branch (PMB) to the registering investigator at the time of 
patient registration and should arrive within 7 to 10 days (see Section 3.1). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Agent* 
Dose 
Route 
Schedule* 
Pemetrexed 
500 mg/m2 
IV over 10 minutes 
Day 1 of each cycle, for 6 
cycles only 
 
Cisplatin 
75 mg/m2 
in 1 L NS IVPB with 
25 grams mannitol 
over 2 hours 
 
Day 1 of each cycle, for 6 
cycles only 
Cediranib or 
Placebo 
20 mg 
PO 
Daily until meeting one of 
the criteria in Section 7.10** 
*  Each cycle is 21 days long. 
** Cediranib should be taken either one hour before or two hours after eating. 

 
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7.6 
Blood Pressure Monitoring 
 
Blood pressure monitoring is required for all patients on this study according to the 
schedule indicated in Section 9.0.   
 
Patients should have their blood pressure checked at routine visits.   
 
Experience 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.  Patients should therefore be encouraged to seek medical advice 
should they be concerned with any symptoms that may be associated with high blood 
pressure. 
 
7.7 
Drug Compliance 
 
Drug compliance will be recorded by patients in the Intake Calendar (see Appendix 18.3). 
Institutional CRAs will review and ascertain patient adherence with protocol therapy at 
the end of treatment for each cycle.  Calendar should be kept in the patient's clinic chart.  
Note that the Intake Calendar is provided only as a tool for tracking patient compliance.  
Sites may utilize institutional pill diaries or other source documentation in place of the 
Intake Calendar at the discretion of the treating physician. 
 
7.8 
General Concomitant Medication and Supportive Care Guidelines 
 
a. 
Any medication that is considered necessary for the patient’s safety and well-
being may be given at the discretion of the treating investigator(s).  
 
b. 
Caution should be exercised in concomitant use of any medication that may 
significantly affect hepatic CYP450 drug metabolizing activity by way of enzyme 
induction (e.g. phenytoin) or inhibition (e.g. ketoconazole, ritonavir, erythromycin) 
within 2 weeks of the first dose of cediranib and throughout the study period.  
(See Appendix 18.7 for a list of medications.) 
 
c. 
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 
 
Ibuprofen (400 mg qid) can be administered with pemetrexed in patients with 
normal renal function (creatinine clearance ≥ 80 mL/min), but caution should be 
used when administering ibuprofen concurrently with pemetrexed to patients with 
mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). 
Patients with mild to moderate renal insufficiency should avoid taking NSAIDs 
with short elimination half-lives for a period of 2 days before, the day of and 2 
days following administration of pemetrexed. 
 
In the absence of data regarding potential interaction between pemetrexed and 
NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt 
dosing for at least 5 days before, the day of and 5 days following pemetrexed 
administration. If concomitant administration of an NSAID is necessary, patients 
should be monitored closely for toxicity, especially myelosuppression, renal and 
gastrointestinal toxicity. 
 
NSAIDs with short half-lives include:  diclofenac (Volteran), indomethacin 
(Indocin), tolmetin (Tolectin), meclofenamaic acid (Meclomen), mefenamic acid 
(Ponstel), fenoprefen (Nalfon), flurbiprofen (Ansaid), ibuprofen (Motrin), 
ketoproten (Orudis). 
 

 
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NSAIDs with long half-lives include:  etodolac (Iodine), ketordac (Toradol), 
sulindac (Clinoril), naproxen (Naprosyn), naproxen sodium (Anaprox), oxaprozin 
(Daypro), nabumetone (Relafen), diflunisal (Dolobid), salsalate, celecoxib 
(Celebrex), rofecoxib (Vioxx), valdecoxib (Bextra), meloxicam (Mobic), piroxicam 
(Feldene). 
 
d. 
For elective surgery during the study it is recommended that all protocol 
treatment be stopped for 2 consecutive weeks prior to the surgical procedure. 
Treatment can be restarted when the surgical wound has healed.   If emergency 
surgery is performed, precautions should be taken to minimize the potential risk 
of bleeding and thrombosis associated with this class of agents, all protocol 
treatment should be stopped and close monitoring for bleeding, wound healing 
and thromboembolic complications should be initiated.  If patients are off protocol 
treatment for more than 4 weeks due to elective or emergent surgery, they will be 
removed permanently from protocol treatment. 
 
7.9 
CTEP Requirements 
 
Because this study contains an investigational drug for which CTEP holds the IND, it falls 
under CTEP requirements for full reporting.  This involves required submission of cycle-
specific toxicity and dose information (see Section 14.8, the S0905 Treatment Form 
[Form #39146] and the S0905 Adverse Event Form [Form #19062]).  A cycle is defined 
as 21 days. 
 
7.10 
Criteria for Removal from Protocol Treatment 
 
a. 
Progression of disease or symptomatic deterioration (as defined in Section 10.2). 
 
b. 
Unacceptable toxicity. 
 
c.   
Treatment delay of all 3 drugs for any reason > 2 weeks during the first 6 cycles 
of concurrent treatment.  (EXCEPTION:  protocol treatment may be delayed up 
to 4 weeks for elective or emergent surgery as described in Section 7.8.) 
 
d. 
Treatment delay for any reason > 2 weeks during maintenance treatment with 
single agent cediranib/placebo.  (EXCEPTION:  cediranib/placebo may be 
delayed up to 4 weeks for elective or emergent surgery as described in Section 
7.8.) 
 
e. 
The patient may withdraw from the study at any time for any reason. 
 
7.11 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice (Form #52393). 
 
7.12 
Follow Up Period 
 
All patients will be followed until death or 3 years after registration, whichever occurs first. 
 
 
 

 
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8.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria 
 
The CTEP Version 4.0 of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE), will be utilized for AE reporting.  The CTEP Active Version of the CTCAE is 
identified and located at the CTEP website at  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
All appropriate treatment areas should have access to a copy of the CTEP Active Version 
of the CTCAE. 
 
8.2 
General Considerations 
 
a. 
If a patient requires a treatment delay of all 3 drugs for any reason > 2 weeks 
during the first 6 cycles of concurrent treatment, they must be removed from 
protocol treatment.  (EXCEPTION:  protocol treatment may be delayed up to 4 
weeks for elective or emergent surgery as described in Section 7.8.) 
 
b. 
If a patient requires a treatment delay for any reason > 2 weeks during 
maintenance treatment with single agent cediranib/placebo, they must be 
removed from protocol treatment.  (EXCEPTION:  cediranib/placebo may be 
delayed up to 4 weeks for elective or emergent surgery as described in Section 
7.8.) 
 
c. 
There are no dose escalations.  If a dose reduction is mandated by toxicity, there 
will be no dose re-escalation even if toxicity resolves. 
 
d. 
If multiple toxicities are experienced, dose modification will be based on the 
toxicity requiring the largest dose reduction. 
 
8.3 
Dose levels  
 
NOTE:  Please see Section 3.1d (“Special Ordering Procedures for Patients 
Requiring a Dose Reduction”) for instructions on ordering replacement “Cediranib 
20 mg” or “Cediranib 15mg” clinical supplies if your patient is dose reduced. 
 
a. 
Cediranib - Phase I portion of the study 
 
Dose level 0 
30 mg 
Dose level -1 
20 mg 
Dose level -2 
15 mg 
Dose level -3 
Permanently remove patient from protocol treatment 
 
b. 
Cediranib - Phase II portion of the study 
 
The following dose de-escalation schema will be used: 
 
Dose level 0 
20 mg 
Dose level -1 
15 mg 
Dose level -2 
Permanently remove patient from protocol treatment 
 
 

 
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c. 
Cisplatin 
 
Dose level 0 
75 mg/m2  
Dose level -1 
60 mg/m2 or change to carboplatin AUC 6 
Dose level -2 
Carboplatin AUC 5 
Dose level -3 
Permanently remove patient from protocol treatment 
 
d. 
Pemetrexed 
 
No dose modifications are allowed for pemetrexed. 
 
8.4 
Hematologic toxicities 
 
Grade 1-2 
 
No dose modifications 
 
Grade 3-4 
 
Hold all treatment until toxicities resolve to ≤ Grade 2.  If patient experiences Grade 4 
myelosuppression and growth factor support was not given, patients should receive 
growth factor support in all subsequent cycles of therapy (see Section 8.9).  If growth 
factor support was given yet Grade 4 myelosuppression still occurs, then dose -1* should 
be instituted once the toxicity resolves.  Patients should continue to receive growth factor 
support in all subsequent cycles of therapy.  Patients unable to continue cediranib whose 
symptoms do not resolve within 2 weeks will be permanently removed from cediranib.   
 
*Cediranib/placebo and cisplatin may be modified singly or as a doublet at the 
investigator’s discretion. 
 
8.5 
Non-hematologic toxicities 
 
NOTE:  This section refers to toxicities other than those listed in Sections 8.6-8.8. 
 
Grade 1-2, or Grade 3 unrelated to chemotherapy 
 
No dose modifications 
 
Grade 3 and related to chemotherapy 
 
Cisplatin and pemetrexed may be held for 1 week to allow for toxicities to resolve.  During 
that time, cediranib will be continued.  When the toxicity resolves to ≤ Grade 1, patient's 
treatment will be resumed at the same dose level.  If patient continues to have Grade 2-3 
non-hematologic toxicity, a decrease to dose -1* can be made.  However, if the toxicity is 
related to cisplatin induced renal dysfunction or neuropathy or nausea/vomiting, patient 
may be switched from the cisplatin to carboplatin (AUC 6). 
 
*Cediranib/placebo and cisplatin may be modified singly or as a doublet at the 
investigator’s discretion. 
 
Grade 4 
 
Hold all treatment until toxicities resolve to ≤ Grade 2.  Upon resolution resume treatment 
at dose -1*.  Patients unable to continue cediranib whose symptoms do not resolve within 
2 weeks will be permanently removed cediranib.   
 

 
S0905 
 
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* Cediranib/placebo and cisplatin may be modified singly or as a doublet at the 
investigator’s discretion. 

 
S0905 
 
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8.6 
Proteinuria 
 
Although patients with > 1+ proteinuria at entry are ineligible, increases in proteinuria 
may occur during treatment and should be managed as follows. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.7 
Management of Abnormal Thyroid Function Tests 
 
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 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 should be given when clinically indicated to 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 should be 
monitored frequently and the dose of levothyroxine should be titrated as required. 
 
8.8 
Management of Diarrhea 
 
Diarrhea should be treated as an early stage (Grade 1) with loperamide or similar agent.  
The patient should be given a prescription to take as required at home. 
 
 
Proteinuria Value 
Monitoring 
Dose modification 
≥ 1+ (dipstick or 
equivalent routine 
laboratory analysis) 
Perform the following tests: 
• 24-hour urine collection for total 
protein and creatinine 
• microscopic examination of fresh 
urine 
• urine protein electrophoresis (at 
first occurrence of > 1+ proteinuria 
only) 
See below. 
Based on results of the 24-hour urine collection: 
< 1g protein 
(24-hour collection) 
Continue dipstick or equivalent routine 
laboratory analysis 
Continue planned dose 
≥ 1g but ≤ 2g protein 
(24-hour collection) 
Perform 24-hour urine collection (total 
protein, creatinine) prior to day 1 of 
each subsequent cycle of therapy 
(q4w) until total protein is < 500 mg/24 
hours. 
Decrease one dose level; 
continue treatment 
> 2 g protein 
(24-hour collection) 
Perform 24-hour urine collection (total 
protein, creatinine) weekly until 
proteinuria is < 2g.  
 
Hold cediranib. 
 
When protein is < 2g/24 
hours, resume treatment at 
one lower dose level. 
Perform 24-hour urine collection (total 
protein, creatinine) prior to day 1 of 
each subsequent cycle of therapy 
(q4w). 
Continue until patient is off 
protocol treatment. 

 
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For Grade 3-4 diarrhea refractory to oral and anti-diarrheal medication all treatment will 
be held.  If ≥ Grade 3 diarrhea persists after 2 weeks, both loperamide and study 
medication should be discontinued.  If the toxicity resolves to ≤ Grade 1, then the 
loperamide will be restarted and the dose reduced, study medication may also be 
restarted at a reduced dose.  If ≥ Grade 3 diarrhea recurs loperamide and study 
medication should be discontinued. 
 
8.9 
Management of Hypertension 
 
Increases in blood pressure 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/placebo treatment has been seen in animal studies as well as clinical trials.  
Specific guidance for management of this AE is provided below. 
 
When managing mild to moderate hypertension, the following principles must be noted: 
 
• 
Cediranib may cause rapid increase in BP in some patients. 
• 
Calcium-channel antagonists are the first line agents of choice. 
• 
If calcium channel antagonists are contraindicated, β-blockers are second choice 
agents. 
• 
Increase nti-hypertensives to maximum doses and add additional agents as required. 
• 
It is recommended that no more than 2 drugs are added in a 48-hour period before 
temporarily stopping cediranib. 
 
The following cautions and contraindications should be noted: 
 
• 
Calcium-channel blockers:  use with caution in patient with tachyarrhythmia aortic 
stenosis, unstable angina or congestive cardiac failure and may cause headache. 
• 
Short-acting dihydropyridines should be avoided since they may precipitate abrupt 
fall in BP and increase of myocardial ischemia, infarction or stroke 
• 
Beta-blockers:  contraindicated in patients with asthma, chronic obstructive 
pulmonary disease and A-V block, they should be used with caution in patients with 
peripheral vascular disease and glucose intolerance and may cause fatigue. 
• 
If diuretics are to be used, thiazides rather than loop diuretics are recommended. 

 
S0905 
 
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BP measurements - 
systolic/diastolic 
 
Interval 
 
Treatment/Dose Modification 
Patients not receiving maximal antihypertensive therapy: 
≥ 150 mmHg (systolic) 
OR 
≥ 90 mmHg (diastolic) 
 
Two BP readings at 
least 1 hour apart 
• Add new or additional antihypertensive meds 
or increase dose of existing meds 
 
• Maintain dose of cediranib 
> 200 mmHg (systolic) 
OR 
> 110 mmHg (diastolic) 
Two BP readings 
during a 1-week 
period 
• Hold cediranib 
 
• Monitor patient closely for hypotension (if on 
antihypertensive meds) until cediranib is 
restarted. 
 
• Resume treatment at same dose level when 
BP falls to < 150/90. 
Patients receiving maximal antihypertensive therapy*: 
> 160 mmHg (systolic) 
OR 
> 105 mmHg (diastolic) 
2 BP readings at 
least 1 hour apart 
• Hold cediranib 
 
• Maintain antihypertensive meds and monitor 
patient closely for hypotension until cediranib 
is restarted. 
 
• Resume treatment at one lower dose level 
when BP falls to < 150/90 
* Maximal antihypertensive therapy is defined as four antihypertensive medications given for 2 
weeks. 
 
Notes: 
 
• 
While patients are receiving treatment with cediranib, the early initiation of 
antihypertensive treatment for Grade 1 or 2 hypertension to minimize more severe or 
persistent hypertension is not considered a Grade 3 adverse event. 
 
• 
Decisions to hold or decrease the cediranib dose during treatment must be based on 
BP readings taken in the clinic by a medical professional. 
 
8.10 
Guidelines for Reversible Posterior Leukoencephalopathy Syndrome (RPLS) 
 
Cediranib/placebo should be held in patients with symptoms/signs suggestive of RPLS, 
pending 
work-up 
and 
management, 
including 
control 
of 
blood 
pressure.  
Cediranib/placebo should be discontinued upon diagnosis of RPLS.  After consultation 
with the principal investigator and the NCI, consideration of restarting the study may be 
evaluated in light of any clinical benefit. 
 

 
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8.11 
Guidelines for Patients who develop Compromised Left Ventricular Ejection Fraction 
(LVEF) 
 
a. 
Asymptomatic Decrease in LVEF 
 
The decision to continue or hold cediranib/placebo is based on the LVEF as it 
relates to the institution’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  
MUGA/ECHO 
within 1-2 cycles 
1-5% below LLN 
 
Continue and 
repeat 
MUGA/ECHO 
within 1-2 
cycles 
Continue and 
repeat 
MUGA/ECHO 
within 1-2 
cycles 
HOLD cediranib/ 
placebo and 
repeat  
MUGA/ECHO 
within 1-2 cycles 
≥ 6% below LLN 
 
Continue and 
repeat 
MUGA/ECHO 
within 1-2 
cycles 
HOLD 
cediranib/ 
placebo and 
repeat 
MUGA/ECHO 
within 1-2 
cycles 
HOLD cediranib/ 
placebo and 
repeat  
MUGA/ECHO 
within 1-2 cycles 
 
Permanently discontinue all protocol treatment if: 
 
• 
Two consecutive HOLD categories occur. 
 
• 
Three intermittent HOLD categories occur (at the discretion of the 
investigator, cediranib/placebo may also be permanently discontinued prior 
to the occurrence of 3 intermittent HOLD categories).  
 
IF LVEF is maintained at a "Continue and repeat MUGA/ECHO" or improves 
from a HOLD to a "Continue and repeat MUGA/ECHO" category, additional 
MUGA scans/echocardiograms prior to the next scheduled MUGA/ECHO will be 
at the discretion of the treating investigator.  
 
b. 
Symptomatic Cardiac Events 
 
Discontinue all protocol treatment if: 
 
• 
a patient has symptoms of congestive heart failure (CHF) and a diagnosis of 
CHF is confirmed. 
 
• 
a patient has a myocardial infarction. 

 
S0905 
 
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8.12 
G-CSF 
 
Prophylactic use of G-CSF for myelosuppression is recommended.  However, use of G-
CSF is at the discretion of the treating physician.  If used, it must be used in accordance 
with the ASCO guidelines (http://www.jco.org/cgi/content/full/18/20/3558).  The use of 
erythropoietin simulating agents is NOT recommended. 
 
8.13 
Dose Modification Contacts 
 
For treatment or dose modification questions, please contact Dr. Tsao at 713/792-6363 
or Dr. Vogelzang at 709/952-3452.   
 
8.14 
Adverse Event Reporting  
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Coordinator and NCI via AdEERS, and to the IRB per local IRB requirements. 
 
 
9.0 
STUDY CALENDAR 
 
 

 
S0905 
 
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9.1    
STUDY CALENDAR - Phase I Portion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MAINTE-
NANCE $ 
& 
√  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F/U After 
Off 
Treatment  
Prior 
  
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycles  7+ 
F/U
Afte
REQUIRED 
STUDIES 
PRE 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
  Pro
  
STUDY 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
 to Prog 
  
PHYSICAL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History and 
Physical Exam  
¢ 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
Blood 
Pressure 
Monitoring   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X # 
X #
Weight and 
Performance 
Status ¢  
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
Disease 
Assessment   
X 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
X 
  
Baseline 
Abnormality 
Assessment 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Toxicity 
Notation     
  
X% 
X% 
X% 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X # 
X #
Review intake 
calendar ¢ 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
LAB  ¢ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC/     
Differential/   
Platelets   
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
Bilirubin   
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
Calendar continued on next page. 
 

 
S0905 
 
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SGOT or 
SGPT    
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
Serum 
Creatinine  
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
Urine dipstick 
(protein) 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
ECG  £ 
X 
  
  
  
X 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum 
Chemistry  ¥ 
X 
  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
TSH,  Free T4 
X 
  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
Uric acid ¥ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum 
mesothelin-
related peptide 
¥ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ECHO/MUGA  
┼ 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
Troponin T or 
Troponin I   ┼ 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
INR for 
patients on 
anticoagulants 
¥ 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
Audiogram ¥ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
SCANS   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Chest CT ¶ 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
X 
  
CT or MRI of 
the brain 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Calendar continued on next page. 
 
 

 
S0905 
 
Page 49 
 
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SPECIMEN 
SUBMISSION  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Slides for 
pathology 
review (see 
Section 15.2a) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum, 
plasma and 
buffy coat (see 
Section 
15.3a.1)  €   
  
X 
X 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
Whole blood 
(see Section 
15.3a.2)  €   
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Paraffin-
embedded 
tissue (see 
Section 
15.3a.3)  €   
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
TREATMENT 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Folic Acid 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
Vitamin B12 
X 
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
Dexa-
methasone 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
Aprepitant 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
Ondansetron 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
Pemetrexed 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
Cisplatin 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
Cediranib  ∆ 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
Calendar continued on next page. 
 

 
S0905 
 
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Version Date  1/5/17 
 
 
 
NOTE:  Forms are found in Section 18.0.  Forms submission guidelines may be found in Section 14.0. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
¢    Physical exams, weight, performance status and laboratory tests must be done prior to the start of every cycle. 
 
£     Required for all patients at baseline (see Section 5.12).  Suggested at other time points if clinically indicated. 
 
¥    Results of these tests do not determine eligibility but are recommended prior to registration and during treatment in  
       accordance with Good Medical Practice (see Section 7.1). 
 
 
 
 
 
 
 
 
 
 
 
 
 
┼    Only applicable to patients at increased risk for compromised LVEF (as defined in Section 7.1c).  These tests are required  
 
       prestudy for Good Medical Practice (see Section  7.1 for guidance on timing and interpretation of those test results) and are  
       recommended during treatment where indicated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
¶    Chest CT must be performed prior to the start of every other cycle.  If patient is removed from protocol treatment prior to  
      progression, scans must continue every 6 weeks until progression or symptomatic deterioration.  Scans must be  
 
      documented on the Follow-Up Tumor Assessment Form - RECIST 1.1 and Modified RECIST (Form #23757).  RESPONSE  
      SHOULD BE CONFIRMED BY A SECOND DETERMINATION AT LEAST 4 WEEKS AFTER A COMPLETE OR PARTIAL  
      RESPONSE HAS BEEN NOTED.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
€     If additional consent is granted. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
∆    Continuous oral daily dosing (see Section 7.4). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
%   Dose-limiting toxicities must be reported weekly during Cycle 1 (see Section 15.1). 
 
 
 
 
 
 
&    If patient is removed from protocol treatment prior to disease progression, scans for disease assessment and physical  
      assessments (with lab tests performed at the discretion of the treating physician) must take place every 6 weeks until progression 
√    After disease progression, follow-up will occur (with lab tests performed at the discretion of the treating investigator) every  
      6 months for the first two years and then at the end of the third year after registration. 
 
 
 
 
 
 
#    Toxicity notation will continue until resolution of any adverse events.  Blood pressure monitoring will continue until the 
       resolution of any hypertension.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
$     During maintenance therapy, items marked under physical and laboratory should be performed every 6 weeks until patient  
 
       meets one of the criteria in Section 7.10. Disease assessments and CT scans are to take place every 6 weeks.  
 
       NOTE: Blood pressure monitoring must continue at the noted interval (weekly) for safety purposes. 
 
 
 
 
 

 
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9.2 
Phase II Portion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MAINTE-
NANCE $ 
& 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F/U 
After 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycles  7+ 
Off  
REQUIRED STUDIES 
PRE 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
Treat  
Prior to
  
STUDY 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Prog 
PHYSICAL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History and Physical 
Exam ¢  
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
Blood Pressure 
Monitoring   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X # 
Weight and Performance 
Status ¢  
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
Disease Assessment   
X 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
X 
Baseline Abnormality 
Assessment 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Toxicity Notation     
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X # 
Review intake calendar ¢ 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
LABORATORY  ¢ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC/Differential/Platelets   
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
Bilirubin   
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
SGOT or SGPT    
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
Serum Creatinine  
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
Urine dipstick (protein) 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
Calendar continued on next page. 
 

 
S0905 
 
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ECG  £ 
X 
  
  
  
X 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum Chemistry  ¥ 
X 
  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
TSH,  Free T4 
X 
  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
Uric acid ¥ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum mesothelin-
related peptide ¥ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ECHO/MUGA  ┼ 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
Troponin T or Troponin 
I   ┼ 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
INR for patients on 
anticoagulants ¥ 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
Audiogram ¥ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
SCANS   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Chest CT ¶ 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
X 
CT or MRI of the brain 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
SPECIMEN 
SUBMISSION  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Slides for pathology 
review (see Section 
15.2a) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum, plasma and buffy 
coat (see Section 
15.3a.1)  €   
  
X 
X 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
Whole blood (see 
Section 15.3a.2)  €   
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
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S0905 
 
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Paraffin-embedded 
tissue (see Section 
15.3a.3)   €  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
TREATMENT 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Folic Acid 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
Vitamin B12 
X 
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
X 
  
  
  
  
Dexamethasone 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
Aprepitant 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
Ondansetron 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
Pemetrexed 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
Cisplatin 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
Cediranib / Placebo  ∆ 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Calendar continued on next page. 
 
 

 
S0905 
 
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Version Date  1/5/17 
 
 
 
NOTE:  Forms are found in Section 18.0.  Forms submission guidelines may be found in Section 14.0. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
¢    Physical exams, weight, performance status and laboratory tests must be done prior to the start of every cycle. 
£     Required for all patients at baseline (see Section 5.12).  Suggested at other time points if clinically indicated. 
¥    Results of these tests do not determine eligibility but are recommended prior to registration and during treatment in  
       accordance with Good Medical Practice (see Section 7.1). 
 
 
 
 
 
 
 
 
 
 
 
 
 
┼    Only applicable to patients at increased risk for compromised LVEF (as defined in Section 7.1c).  These tests are required prestudy for Good  
       Medical Practice (see Section 7.1 for guidance on timing and interpretation of those test results) and are recommended  
       during treatment where indicated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
¶    Chest CT must be performed prior to the start of every other cycle.  If patient is removed from protocol treatment prior to  
      progression, scans must continue every 6 weeks until progression or symptomatic deterioration.  Scans must be   
      documented on the Follow-Up Tumor Assessment Form - RECIST 1.1 and Modified RECIST (Form #23757).   
      RESPONSE SHOULD BE CONFIRMED BY A SECOND DETERMINATION AT LEAST 4 WEEKS AFTER A COMPLETE  
       OR PARTIAL RESPONSE HAS BEEN NOTED.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
€     If additional consent is granted. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
∆    Continuous oral daily dosing (see Section 7.5). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
&     If patient is removed from protocol treatment prior to disease progression, scans for disease assessment and 
       physical assessments (with lab tests performed at the discretion of the treating physician) must take place every 6 weeks  
       until progression. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√    After disease progression, follow-up will occur (with lab tests performed at the discretion of the treating investigator)  
      every 6 months for the first two years and then at the end of the third year after registration. 
 
 
 
 
 
#    Toxicity notation will continue until resolution of any adverse events.  Blood pressure monitoring will continue until the  
       resolution of any hypertension.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
$    During maintenance therapy, items marked under physical and laboratory should be performed every 6 weeks until patient meets one of the  
       criteria in Section 7.10. Disease assessments and CT scans are to take place every 6 weeks. NOTE: Blood pressure  
       monitoring must continue at the noted interval (weekly) for safety purposes. 
 
 
 
 
 
 
 
 
 
 
 
 

 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
In this study, disease is to be assessed using both RECIST 1.1 and the Modified RECIST for 
Pleural Tumors. This means that pleural tumors must be assessed using BOTH methods. 
RECIST 1.1 criteria are outlined in Sections 10.1-10.2. In addition, modified RECIST 
measurements as determined by six pleural thickness measurements perpendicular to the chest 
wall are to be obtained and incorporated into determination of objective status as outlined in 
Section 10.5. (55) 
 
10.1  
Measurability of lesions 
 
a.  
Measurable disease  
 
Measurable disease is defined differently for lymph nodes compared with other 
disease and will be addressed in a separate section below. 
 
1. 
Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 2.0 cm  by chest x-ray, by ≥ 1.0 
cm  with CT or MRI scans, or ≥ 1.0 cm with calipers by clinical exam. All 
tumor measurements must be recorded in decimal fractions of 
centimeters (or millimeters). 
 
The defined measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 0.5 cm or less.  If CT scans have 
slice thickness greater than 0.5 cm, the minimum size for a measurable 
lesion should be twice the slice thickness.   
 
2. 
Malignant lymph nodes are to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 
perpendicular to the long axis of the lymph node) when assessed by 
scan (CT scan slice recommended being no greater than 0.5 cm). 
 
b.    
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to 
<1.5 cm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered non-measurable as are previously 
radiated lesions that have not progressed. 
 
c. 
Notes on measurability 
 
1. 
For CT and MRIs, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to 
prior scans.  Body scans should by performed with breath-hold scanning 
techniques, if possible.  
2. 
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT, then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with 
conventional CT. 
3. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. 
4. 
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. 

 
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5. 
If a target lesion becomes very small some radiologists indicate that it is 
too small to measure.  If the lesion is actually still present, a default 
measurement of 0.5 cm should be applied.  If the radiologist believes the 
lesion has gone, a default measurement of 0.0cm should be recorded. 
 
10.2  
Objective status at each disease evaluation   
 
Objective Status is to be recorded at each evaluation. All measurable lesions up to a 
maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, 
should be identified as target lesions at baseline. All other lesions (or sites of disease) 
including any measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions.  Measurements must be provided for target measurable lesions, 
while presence or absence must be noted for non-target measurable and non-
measurable disease.   
 
For studies that use disease progression as an endpoint, whole body scanning at specific 
intervals is necessary to determine that progression is NOT present outside of the 
“target” areas. Therefore, in these studies it is not acceptable to image only the “target” 
areas of the body in follow-up scans. For study-specific imaging requirements, see the 
Study Calendar in Section 9.0.   
 
a.  
Complete Response (CR):  Complete disappearance of all target and non-
target lesions (with the exception of lymph nodes mentioned below).  No new 
lesions.  No disease related symptoms.   Any lymph nodes (whether target or 
non-target) must have reduction in short axis to < 1.0 cm.  All disease must be 
assessed using the same technique as baseline. 
 
b. 
Partial Response (PR): Applies only to patients with at least one measurable 
lesion. Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target measurable lesions.  No unequivocal 
progression of non-measurable disease.  No new lesions.  All target measurable 
lesions must be assessed using the same techniques as baseline. 
 
c.  
Stable: Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as 
baseline. 
 
 
 
d.  
Progression: One or more of the following must occur:  20% increase in the sum 
of appropriate diameters of target measurable lesions over smallest sum 
observed (over baseline if no decrease during therapy) using the same 
techniques as baseline, as well as an absolute increase of at least 0.5 cm.  
Unequivocal progression of non-measurable disease in the opinion of the treating 
physician (an explanation must be provided).  Appearance of any new lesion/site.  
Death due to disease without prior documentation of progression and without 
symptomatic deterioration (see Section 10.2e). 
 
 
Notes regarding new lesions:  FDG-PET imaging can complement regular scans 
in identifying new lesions according to the following algorithm.  
 
1. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is 
a sign of progression based on a new lesion. 
2. 
No FDG-PET at baseline and a positive FDG-PET at follow-up 
corresponding to a potential new site of disease must have a 
confirmation by anatomical assessment (e.g. CT, MRI, x-ray) as new site 
of disease to be considered progressive disease.  In such a case, the 
date of progressive disease will be the date of the initial abnormal FDG-
PET.   

 
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e. 
Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts 
should be made to obtain objective evidence of progression after discontinuation. 
 
f.  
Assessment inadequate, objective status unknown.  Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment 
methods were used. 
 
g.  
Objective status notes: 
 
1.  
Non-measurable and non-target measurable disease do not affect 
Objective Status  in determination of CR (must be absent--a patient who 
otherwise has a CR, but who has non-measurable or non-target 
measurable disease present or not assessed, will be classified as having 
a PR). However, non-measurable and non-target lesions are included in 
determination of progression (if new sites of disease develop or if 
unequivocal progression occurs in the opinion of the treating physician).  
2.   
An objective status of PR or stable cannot follow one of CR.  Stable can 
follow PR only in the rare case that tumor increases too little to qualify as 
progression, but enough that a previously documented 30% decrease no 
longer holds. 
3.    
In cases for which initial flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), objective status is not 
progression unless either symptoms persist beyond 4 weeks or there is 
additional evidence of progression.   
4.  
Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed.  
5.   
For bone disease documented on bone scan only, increased uptake 
does not constitute unequivocal progression. However, increase in the 
soft tissue component of a lesion as measured by CT or MRI would 
constitute progression. 
6.   
Appearance of new pleural effusions does not constitute unequivocal 
progression unless cytologically proven of neoplastic origin, since some 
effusions are a toxicity related to therapy or other medical conditions. 
Increase in the size of an existing effusion does not constitute 
unequivocal progression, since the fluid status of the patient could alter 
the size of the effusion.  
7.   
If CR determination depends on a lesion for which the status is unclear 
by the required tests, it is recommended the residual lesion be 
investigated with biopsy or fine needle aspirate.   
 
10.3  
Best Response 
 
This is calculated from the sequence of objective statuses. 
 
a. 
CR:  Two or more objective statuses of CR a minimum of four weeks apart 
documented before progression or symptomatic deterioration. 
 
b.  
PR: Two or more objective statuses of PR or better a minimum of four weeks 
apart documented before progression or symptomatic deterioration, but not 
qualifying as CR. 
 
c.  
Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 
 

 
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d.  
Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 
 
e.  
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before progression or 
symptomatic deterioration, but not qualifying as anything else above. 
 
f. 
Increasing disease:  Objective status of progression within 12 weeks of 
registration, not qualifying as anything else above.   
 
g. 
Symptomatic deterioration: Objective status of symptomatic deterioration within 
12 weeks of registration, not qualifying as anything else above.   
 
h. 
Inadequate assessment, response unknown:  Progression or symptomatic 
deterioration greater than 12 weeks after registration and no other response 
category applies. 
 
10.4 
Performance Status  
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
housework, office work.   
 
2 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours.   
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours.   
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair.   
 
 
10.5 
Modified RECIST  
 
Modified RECIST for Pleural Tumors:  Response is to be assessed both via RECIST 
and modified RECIST for pleural tumors.  (54) 
 
For RECIST 1.1, the definitions outlined in Section 10.1 must be followed. The longest 
diameter of the pleural lesion, as defined in Section 10.1.a.1,  must be recorded in the 
target lesion section of the RECIST and Modified RECIST Baseline Tumor Assessment 
Form (Form #35990) and the Follow Up Tumor Assessment Form-RECIST and Modified 
RECIST (Form #23757). If a longest diameter that fulfills the criteria outlined in Section 
10.1.a.1 cannot be obtained, then it should be recorded in the non-target lesion section of 
the respective forms. 
 
In addition, for modified RECIST, measurements based on the sum of 6 CT cuts in the 
pleura perpendicular to the chest wall are to be obtained via the description below and 
applied (along with unidimensional measurements from other non-pleural lesions) to  

 
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standard RECIST criteria (sum of 6 = one univariate diameter).  The six pleural thickness 
measurements are to be documented on the RECIST and Modified RECIST Baseline 
Tumor Assessment Form (Form #35990) and the Follow Up Tumor Assessment Form-
RECIST and Modified RECIST (Form #23757).  
 
Tumor thickness perpendicular to the chest wall or mediastinum should be measured in 
two positions at three separate levels on transverse cuts of the CT scan. The sum of the 
six measurements defines a pleural unidimensional measure. Transverse cuts at least 1 
cm apart and related to anatomical landmarks in the thorax should be chosen to allow for 
reproducible assessment at later time points. If measurable tumor is present, transverse 
cuts in the upper thorax, above the level of the division of the main bronchi are preferred. 
At reassessment, pleural thickness should be measured at the same position at the same 
level and by the same observer. This is not necessarily the greatest tumor thickness at 
that level. Nodal, subcutaneous and other measurable lesions should be measured 
unidimensionally as per the RECIST criteria. Unidimensional measurements are added to 
obtain the total tumor measurement. 
 
10.6 
Progression-free survival 
 
From date of registration to date of first documentation of progression or symptomatic 
deterioration (as defined in above), or death due to any cause.  Patients last known to be 
alive and progression free are censored at date of last contact. 
 
10.7 
Time to Death 
 
From date of registration to date of death due to any cause.  Patients last known to be 
alive are censored at date of last contact. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Phase I Run-In 
 
This study will initially be open in limited institutions, with an expected accrual of 10-20 
patients in the Phase I portion of the trial.  The Phase II portion of the trial will be initiated 
Groupwide.  Based on data from M.D. Anderson in similar patient populations the 
estimated accrual rate is 4 patients/month. 
 
11.2 
Phase I Details 
 
Phase I Study:  Section 7.4 provides the details of the study design for the Phase I 
portion of the study.  The Phase I study will be a limited dose-de-escalation study with 
two possible doses of cediranib: 
 
Dose levels 
0 
-1 
Cediranib (mg/daily) 
30 
20 
 
The primary objective of this study is to determine the maximum tolerated dose (MTD) of 
cediranib used in combination with cisplatin and pemetrexed (CP) in chemonaive patients 
with malignant pleural mesothelioma (MPM).  The regimen will be considered safe and 
the MTD determined if the dose-limiting toxicity rate of cediranib + CP is ≤ 33%.   
 

 
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11.3 
Phase II Trial 
 
Phase II Study:  The primary objective of the Phase II portion of this study is to evaluate 
the efficacy of cediranib in combination with cisplatin and pemetrexed in comparison with 
cisplatin, pemetrexed and placebo in chemonaive patients with malignant pleural 
mesothelioma (MPM).  Based on a previous study it is assumed that the regimen would 
not be promising if the true median PFS were ≤ 6 months, but would be of considerable 
interest if the true median PFS were ≥ 10 months (corresponding to a 1.66 hazard ratio). 
(2) Ninety-six patients will be accrued over an estimated 24 months.  With an additional 9 
months of follow-up, this design has 83% power to detect 66% improvement in median 
PFS at the 0.1 level. 
 
11.4 
Analysis plan for Phase II study 
 
Primary analyses will be performed on an intent-to-treat basis.  A stratified log-rank test 
at the 0.1 level will be used to test the primary hypothesis. 
 
Once 50% of the expected events in the control arm have occurred (21 events at ~ 18 
months after study opens), an interim analysis of the primary endpoint will be performed 
with the intent of testing the alternative hypothesis (e.g. terminate early if a 1.66 hazard 
ratio is deemed to be highly unlikely [p<0.005]). 
 
Secondary analyses include the comparison of overall survival, response, and toxicity 
between study arms.  A stratified log-rank test will be used to compare overall survival; a 
stratified chi-square test will be used to compare response and toxicity between the two 
arms.  This design has 73% power to detect a 66% improvement in median survival time 
from 12 to 20 months using a 0.10 level test.   
 
Additionally, this design has 83% power to detect > 20% difference in toxicity rates 
assuming an unacceptable toxicity rate > 33%, for any given toxicity (also using a 1-sided 
0.1 level test).  Within each arm, any toxicity occurring with at least a 5% probability is 
likely to be seen at least once (91% chance).   
 
Forty-eight patients/arm will be sufficient to estimate the 6-month overall survival 
probability and individual toxicity proportions to within at least 14% (95% confidence 
interval).   
 
Assuming 80% of participants will have measurable disease (as defined by RECIST), 
approximately 38 patients/arm will be evaluable for response.  Seventy-six patients with 
measurable disease has 81% power to detect at least a 27% increase in response rates 
with cediranib using a 1-sided 0.10 level test.  Thirty-eight patients/arm will be sufficient 
to estimate the response rate (confirmed and unconfirmed complete and partial 
responses) to within at least 16% (95% confidence interval).  The disease control rate 
(confirmed and unconfirmed complete and partial responses and stable disease) will also 
be assessed. 
 
In addition, an exploratory analysis of response and progression-free survival using 
definitions per modified RECIST criteria for pleural tumors will be performed. 
 
11.5  
Sample Size and Power Justification for Primary Endpoint 
 
Assuming sufficient tissue for pathology review is received from 90 patients, this would 
be sufficient to estimate the rate of agreement between the local pathologist and the 
central pathology reviewer to within at least 11% (95% confidence interval).   
 

 
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Correlative studies will assess potential relationships between potential biomarkers (yet 
to be defined) involving angiogenesis, cediranib, pemetrexed and cisplatin and clinical 
and toxicity outcomes, utilizing available tumor tissue and plasma specimens.  Due to the 
limited sample size in a Phase II setting, correlative studies will be considered exploratory 
in nature and will be used to formulate hypotheses that can be tested using correlative 
data in larger patient cohorts. 
 
11.6 
Analysis of Primary Endpoint 
 
The Phase I portion of the trial will employ careful adverse event monitoring as previously 
established for regimens where there are limited or no pre-existing data for the specific 
combination under study, but where combination data for the targeted agent plus other 
chemotherapy regimens suggest that full doses of the study combination can be safely 
administered.  Adverse event monitoring will performed by the Study Coordinator, Study 
Statistician and the Disease Committee Chair and include weekly toxicity reports and bi-
weekly conference calls.   A temporary closure will occur prior to opening this study for 
the Phase II portion in order to assess dose and to evaluate the safety profile more fully 
prior to implementation of the Phase II trial. 
 
11.7 
Data and Safety Monitoring Committee  
 
A Data and Safety Monitoring Committee will oversee the conduct of the randomized 
Phase II portion of the study.  The Committee consists of four members from outside of 
the Southwest Oncology Group, 3 Southwest Oncology Group members, 3 non-voting 
representatives from the National Cancer Institute (NCI), and the Group Statistician (non-
voting).  The members of this Committee will receive confidential reports every 6 months 
from the Southwest Oncology Group Statistical Center, and will meet at the Group's bi-
annual meetings as necessary.  The Committee will be responsible for decisions 
regarding possible termination and/or early reporting of the study. 
 
 
12.0 
DISCIPLINE REVIEW 
 
Central pathology review will be performed on this study.  The purpose of this review is to confirm 
diagnosis. 
 
All patients are required to submit tissue for the purpose of this review.  Instructions for tissue 
submission are located in Section 15.2a. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1  
Registration Timing 
 
Patients must be registered prior to initiation of treatment (no more than ten working days 
prior to planned start of treatment).  NOTE:  No open label OR blinded starter supplies 
will be available for this study.  Initial patient-specific clinical supplies of cediranib 
(Phase I) or cediranib/placebo (Phase II) will be shipped from the Pharmaceutical 
Management Branch (PMB) to the registering investigator at the time of patient 
registration and should arrive within 7 to 10 days (see Section 3.1d). 
 

 
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13.2 
OPEN Registration Requirements  
 
The individual registering the patient must have completed the S0905 Registration 
Worksheet (Form #44837).  The completed form must be referred to during the 
registration but should not be submitted as part of the patient data. 
 
OPEN will also ask additional questions that are not present on the S0905 Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
l. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 

 
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n. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
13.3 
Registration procedures 
 
a. 
All site staff will use OPEN to enroll patients to this study.  OPEN is a web-based 
application and can be accessed from the CTSU members' web site OPEN tab, 
or from the OPEN Patient Registration link on the SWOG CRA Workbench.  
 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated 
timeframes. Site staff should refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
 
c. 
Access requirements for OPEN: 
 
• 
Site staff will need to be registered with CTEP and have a valid and 
active CTEP-IAM account. This is the same account (user ID and 
password) used for the CTSU members' web site.  
 
• 
To perform registrations on SWOG protocols you must have an 
equivalent 'Registrar' role on the SWOG roster.  Role assignments are 
handled through SWOG.  
 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.   Please print this confirmation for your 
records.   
 
d. 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL. For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
13.4 
Exceptions  
 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 

 
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14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission 
 
Data must be submitted according to the protocol requirements for ALL patients 
registered, whether or not assigned treatment is administered, including patients deemed 
to be ineligible.  Patients for whom documentation is inadequate to determine eligibility 
will generally be deemed ineligible. 
 
14.2 
Master Forms 
 
Master forms are included in Section 18.0 and (with the exception of the sample consent 
form and the Registration Worksheet) must be submitted to the Data Operations Center 
in Seattle.  Data from approved SWOG institutions must be submitted on-line via the 
Web; see Section 14.3a for details.  Exceptions to online data submission are patient-
completed 
(e.g. 
Quality 
of 
Life) 
forms 
and 
source 
documents 
(e.g. 
pathology/operative/lab reports). 
 
14.3 
Data Submission  
 
a. 
SWOG institutions must submit data electronically via the Web by using the 
SWOG CRA Workbench.  To access the CRA Workbench, go to the SWOG Web 
site (http://swog.org) and logon to the Members Area.  After you have logged on, 
click on the CRA Workbench link to access the home page for CRA Workbench 
website.  Next, click on the Data Submission link and follow the instructions.  For 
new users, the link to a "Starter Kit" of help files may be found by clicking on the 
Starter Kit link at the Members’ logon page. 
 
To submit data via the web the following must be done (in order): 
 
1.  
You are entered into the Southwest Oncology Group Roster and issued 
a SWOG Roster ID Number, 
2.  
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, and 
3.  
Your Web User Administrator has added you as a web user and has 
given you the appropriate system permissions to submit data for that 
institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  
For point 3, contact your local Web User Administrator (refer to the "Who is my 
Web User Administrator?" function on the swog.org Members logon page).  For 
other 
difficulties 
with 
the 
CRA 
Workbench, 
please 
email 
technicalquestion@crab.org.   
 
 
b. 
If you need to submit data that are not available for online data submission, the 
only alternative is via facsimile.  Should the need for this occur, institutions may 
submit data via facsimile to 800/892-4007 or 206/342-1680 locally. Please do not 
use cover sheet for faxed data.  Please make sure that each page of all faxed 
data includes the SWOG patient number, study ID and patient initials. 
 

 
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14.4 
Data Submission Procedures 
 
a. 
WITHIN 7 DAYS AFTER REGISTRATION: 
 
Submit the following: 
 
S0905 Prestudy Form (Form #39381) 
 
RECIST 1.1 and Modified RECIST Baseline Tumor Assessment Form (Form 
#35990) 
 
S0905 Baseline Abnormalities Form (Form #41007) 
 
Radiology reports from all scans used to assess disease and document 
eligibility* 
 
Pathology report* 
 
*NOTE:  These must be faxed (see Section 14.3b) 
 
b. 
WITHIN 14 DAYS AFTER REGISTRATION: 
 
Submit the following: 
 
Tissue for pathology review (see Section 15.2a) 
 
c. 
IF PATIENT CONSENTS, SUBMIT SPECIMENS FOR RESEARCH: 
 
Submit the following: 
 
Serum, plasma and buffy coat – samples may be batched (see Section 15.3a.1) 
 
Whole blood – submit within 30 days after beginning treatment (see Section 
15.3a.2) 
 
Paraffin-embedded tissue - submit within 30 days after beginning treatment (see 
Section 15.3a.3) 
 
d. 
PHASE I PORTION ONLY:  AFTER EVERY WEEK DURING CYCLE 1: 
 
Submit the web-based S0905 Phase I Dose-Limiting Toxicity Rapid Reporting 
Form (Form #31896), which can be found on the CRA workbench (see Section 
14.3).  For further details regarding the rapid reporting system, see Section 15.1. 
 
e. 
AFTER EVERY CYCLE ON TREATMENT: 
 
Submit the following: 
 
S0905 Treatment Form (Form #39146) 
 
S0905 Adverse Event Form (Form #19062) 
 
Patients on the Phase I portion will begin submitting the S0905 Adverse Event 
Form (Form #19062) after Cycle 2 then after every cycle thereafter.  Adverse 
events for Cycle 1 must be reported weekly using the S0905 Phase I Dose-
Limiting Toxicity Rapid Reporting Form (Form #31896). 
 

 
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f. 
AFTER EVERY DISEASE ASSESSMENT (see Section 9.0): 
 
Submit the following: 
 
Follow Up Tumor Assessment Form - RECIST 1.1 and Modified RECIST (Form 
#23757) 
 
Radiology reports from all scans used to assess disease 
 
g. 
ONCE OFF TREATMENT SUBMIT EVERY 6 MONTHS FOR THE FIRST 2 
YEARS, THEN AT THE END OF YEAR 3: 
 
Submit the following: 
 
Lung Carcinoma Follow Up Form (Form #32426). 
 
Follow Up Tumor Assessment Form - RECIST 1.1 and Modified RECIST (Form 
#23757) until progression of disease 
 
Radiology reports from all scans used to assess disease 
 
h. 
WITHIN 14 DAYS AFTER PROGRESSION/RELAPSE: 
 
Submit the following: 
 
Lung Carcinoma First Site(s) of Progression or Relapse Form (Form #9469) 
 
Follow-Up Tumor Assessment Form - RECIST 1.1 and Modified RECIST (Form 
#23757) documenting date, site and method used to determine relapse. 
 
If the patient is off protocol treatment, submit the Lung Carcinoma Follow Up 
Form (Form #32426) with notice of first relapse or progression section 
completed. 
 
i. 
WITHIN 14 DAYS AFTER DISCONTINUATION OF TREATMENT: 
 
Submit the following: 
 
Off Treatment Notice (Form #52393) 
 
S0905 Treatment Form (Form #39146) 
 
S0905 Adverse Event Form (Form #19062) 
 
S0905 Phase I Dose-Limiting Toxicity Rapid Reporting Form (Form #31896) – if 
patient is on the Phase I portion and did not begin Cycle 2 of treatment 
 
j. 
WITHIN 4 WEEKS AFTER KNOWLEDGE OF DEATH: 
 
Submit the following: 
 
Notice of Death (Form #49467) 
 
Off Treatment Notice (Form #52393) – if patient is still on treatment 
 
Lung Carcinoma Follow Up Form (Form #32426) – if patient is already off 
treatment 

 
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15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Rapid Reporting  
 
RAPID REPORTING OF TREATMENT-RELATED DOSE-LIMITING TOXICITIES FOR 
PHASE I PORTION OF TRIAL 
 
Participation in the Phase I portion of the trial requires weekly reporting of dose-limiting 
toxicities on patients who have initiated treatment.  These toxicities must be reported 
using the web-based S0905 Phase I Dose-Limiting Toxicity Rapid Reporting Form 
(Form #31896), which can be found on the CRA workbench (see Section 14.3). 
 
Institutional participation in the Phase I portion of the trial requires the identification of a 
contact CRA and back-up CRA.  Prior to registration of the first patient, each 
institution must provide the contact and back-up CRA names, e-mail addresses, 
and phone numbers to the SWOG Data Operations Center.  Institutions will be 
responsible for keeping this information up-to-date and must notify the study Data 
Coordinator (Brian Zeller, brianz@crab.org, 206/652-2267) of any changes.  
 
The contact CRA and back-up CRA will receive weekly e-mails including a list of the 
dose-limiting toxicity forms that are overdue, currently due, or due in the next week.  
These e-mails will include a reply-to address and phone number to contact the Data 
Operations Center when questions arise. 
 
Upon activation of the Phase I portion of the study, participating institutions will receive 
an e-mail with information on current dose level, as well as specifications for e-mail and 
conference call communication among investigators participating in the Phase I portion. 
 
15.2 
Specimens for Pathology Review  
 
Specimens for pathology review specimens for pathology review (submitted to the 
SWOG Specimen Repository – Solid Tissue, Myeloma and Lymphoma Division, Lab 
#201) (Required): 
 
a.  
Specimens must be collected for central pathology review (see Section 12.0) at 
the following times and submitted (see Sections 9.1-9.2): 
 
1. 
Submit 1-2 stained slides containing tumor tissue from surgery or biopsy, 
or malignant pleural mesothelioma tissue cells from a pleural effusion (a 
cell button in paraffin) within 14 days after registration. With additional 
patient consent, cell buttons submitted for pathology review may be 
banked for future use. 
 
b. 
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage 
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp),  
or via the link on the S0905 protocol abstract page on the SWOG website 
(www.swog.org). 
 
 
c. 
Specimen collection kits are not being provided for this submission; sites will 
use institutional supplies. 
 

 
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15.3 
Specimens for Correlative Studies and Banking  
 
Specimens for correlative studies and banking (submitted to the SWOG Specimen 
Repository – Solid Tissue, Myeloma and Lymphoma Division, Lab #201)(Optional): 
 
a.  
With patient’s consent, specimens must be collected at the following times and 
submitted (see Sections 9.1-9.2): 
 
1. 
Instructions for serum, plasma and buffy coat: 
 
Collect blood at the following time points: 
 
• 
Prior to initiating treatment on Day 1 and, if possible, 8 hours after 
first dosing 
• 
Days 8 and/or 15  
• 
Day 22 (Cycle 2, Day 1), then every 21 days up to and including 
Cycle 6, Day 1 
• 
Cycle 7, Day 1, and then every 6 weeks while on maintenance 
cediranib/placebo 
• 
When the patient is removed from protocol treatment 
 
Serum collection 
 
• 
Collect 7.5 mL of blood in a S-Monovette 
• 
After allowing 30 minutes for blood coagulation (no longer than 60 
minutes), the sample is centrifuged at 3000 G for 15 minutes. 
• 
Serum is pipetted in 1mL aliquots into three white labeled Nalgene 
cryovials. 
• 
Clearly label tubes as "serum". 
• 
Note:  Sample must be processed within 2 hours of collection.  
Hemolyzed, lipemic, or icteric specimens may cause erroneous 
results. 
 
Plasma and buffy coat collection 
 
• 
Collect two (2) x 5 mL of blood into two (2) K2-EDTA DB Vacutainer 
collection tubes pre-cooled in an ice bath. 
• 
Gently invert five to six times to ensure adequate mixing and prevent 
coagulation. 
• 
Cool the tubes immediately in an ice bath. 
• 
Centrifuge at 800 G for 10 minutes within 30 minutes of collection. 
• 
Plasma is pipetted in 1 mL aliquots into four (4) red labeled Nalgene 
cryovials. 
• 
Buffy coat cells should be removed separately from the plasma and 
placed in a labeled cryo tube.   
• 
Clearly label tubes as "buffy coat" or "plasma". 
 
Storage and Shipment 
 
Samples must be stored as soon as possible at -70°C until shipment.  
Specimens may be batched.  They must be shipped frozen on dry ice by 
overnight carrier.  Follow the general submission instructions located in 
Section 15.3b below. 
 

 
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2. 
Instructions for whole blood: 
 
Collect blood at the following time point: 
 
Prior to initiating treatment on Day 1 
 
Collection 
 
• 
Collect blood in 9 or 10 mL polypropylene tubes containing the 
anticoagulant EDTA 
- 
SARSTEDT Monovette® EDTA KE (9 mL), Part # 02.1333.001 
 
Or 
 
- 
Becton-Dickinson VacutainerTM K2E (10 mL), Part # 367525  
 
or 
 
- 
Greiner Bio-One Vacuette® K3E EDTA K3 (9 mL), Part 455036 
 
• 
Blood tubes must be gently inverted several times after collection to 
ensure thorough mixing of EDTA with the sample to prevent clotting. 
• 
Glass tubes MUST NOT be used as they may break transport and 
freeze-thaw cycles. 
• 
Heparin MUST NOT be used as an anticoagulant as it may interfere 
with downstream genotyping methodology. 
 
Storage and Shipment 
 
Samples must be refrigerated or frozen as soon as possible until 
shipment.  See the chart below for options regarding storage and 
shipping.  Also follow the general submission instructions located in 
Section 15.3b below. 
 
  
Option 
 
Storage 
Temperature 
at Treatment 
Site 
 
Maximum 
Duration of 
Storage at 
Treatment Site 
 
Transport 
Temperature 
 
Delivery 
Time 
1 
+ 4°C (fridge) 
24 hours 
0 - 4°C  
(ice blocks) 
24 hours 
2 
+ 4°C (fridge) 
24 hours 
Less 
than 
-
20°C  
(dry ice) 
24-72 
hours 
3 
-20°C (freezer)  
or -70°C 
Up to 1 month 
Less 
than 
-
20°C  
(dry ice) 
24-72 
hours 
 
• 
If blood samples are to be frozen for storage at -20°C or less, non-
frost free freezers must be used to prevent repeated freeze-thaw of 
blood which may reduce yield and quality of the DNA obtained. 
• 
Samples must not be thawed and then re-frozen at any point. 
 

 
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3. 
Instructions for paraffin embedded tissue: 
 
Submit 1-2 paraffin-embedded tissue blocks containing formalin-fixed 
tumor from time of diagnosis (or subsequent, but prior to therapy).  
Paraffin blocks may be processed according to standard institutional 
protocols.  If a tissue block is unavailable or unable to be sent, 10-15 
unstained slides or malignant pleural mesothelioma cells from a pleural 
effusion (a cell button in paraffin) are acceptable as an alternate. 
 
Archival paraffin blocks/slides should be sent at ambient temperature 
following the general specimen submission instructions located in 
Section 15.3b, within 30 days after beginning treatment. 
 
b. 
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage 
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp),  
or via the link on the S0905 protocol abstract page on the SWOG website 
(www.swog.org). 
 
 
c. 
Specimen collection kits are not being provided for this submission; sites will 
use institutional supplies. 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46). 
 
Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312. 
 
 
Publication and Industry Contact 
 
The agent (hereinafter referred to as "Agent"), cediranib/placebo, used in this protocol is provided 
to the NCI under a Clinical Trials Agreement (CTA) between AstraZeneca (hereinafter referred to 
as "Collaborator") and the NCI Division of Cancer Treatment and Diagnosis.  Therefore, the 
following obligations/guidelines apply to the use of the Agent in this study: 

 
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1. 
Agent may not be used outside the scope of this protocol, nor can Agent be transferred 
or licensed to any party not participating in the clinical study.  Collaborator data for Agent 
are confidential and proprietary to the Collaborator and should 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 or patient’s 
family member participating on the study, the individual should sign a confidentiality 
agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
another investigational Agent, each the subject of different CTAs or CRADAs, 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 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 which 
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 to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party 
Data 
solely 
for 
development, 
regulatory 
approval, 
and 
commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, 
as appropriate and unless additional disclosure is required by law or court order.  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection 
of human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for cooperative 
group studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. 
Any data provided to the Collaborator for Phase III 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 the Collaborator for advisory review and comment prior to 
submission for publication.  Collaborator will have 30 days from the date of receipt for 
review.  Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days in order to ensure that Collaborator's confidential and proprietary 
data, in addition to the Collaborator's intellectual property rights, are protected.  Copies of 
abstracts must be provided to CTEP for forwarding to the Collaborator 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 presentation must also be forwarded to CTEP prior to release.  

 
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Copies of any manuscript, abstract and/or press release/media presentation should be 
sent to: 

 
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Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX:  301/402-1584 
E-mail:  anshers@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to the Collaborator.  No 
publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information. 
 
Monitoring 
 
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. 
 
16.1 
Adverse Event Reporting Requirements  
 
a. 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as 
well as those who will enroll in future studies using similar agents. Adverse 
events are reported in a routine manner at scheduled times during a trial. 
(Directions for routine reporting are provided in Section 14.0.) Additionally, 
certain adverse events must be reported in an expedited manner to allow for 
more timely monitoring of patient safety and care. The following guidelines 
prescribe expedited adverse event reporting for this protocol. See also Appendix 
18.1 for general and background information about expedited reporting. 
 
b. 
Reporting methods 
 
This study requires that expedited adverse event reporting use the NCI’s 
Adverse Event Expedited Reporting System (AdEERS). The NCI’s guidelines for 
AdEERS can be found at http://ctep.cancer.gov. An AdEERS report must be 
submitted to the SWOG Operations Office by one of the following methods: 
 
Electronically submit the report via the AdEERS Web-based application located 
at http://ctep.cancer.gov, or 
 
In the rare event when Internet connectivity is disrupted a 24-hour notification is 
to be made to NCI by telephone at:  301-897-7497.  An electronic report MUST 
be submitted immediately upon re-establishment of internet connection.  Please 
note that all paper AdEERS forms have been removed from the CTEP website 
and will NO LONGER be accepted. 
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via 
AdEERS. When Internet connectivity is disrupted, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is 
restored, a 24-hour notification phoned in, must be entered electronically into 
AdEERS by the original submitter at the site. 

 
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When the adverse event requires expedited reporting, submit the report within 
the number of calendar days of learning of the event specified in Table 16.1 or 
16.2, as applicable.  
 
d. 
Other recipients of adverse event reports 
 
The Operations Office will forward reports and documentation to the appropriate 
regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable must also be reported according to 
local policy and procedures to the Institutional Review Board responsible for 
oversight of the patient. 
 
e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agent as part of the trial. Reporting requirements are provided in 
Table 16.1 for the Phase I portion and Table 16.2 for the Phase II portion. The 
investigational agent used in this study is cediranib/placebo.  If there is any 
question about the reportability of an adverse event or if on-line AdEERS cannot 
be used, please telephone or email the SAE Specialist at the Operations Office, 
210/614-8808 or adr@swog.org, before preparing the report. 
 

 
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Table 16.1: 
 
Phase I Trials Utilizing an Agent under a CTEP IND or Non-CTEP IND:  AdEERS Expedited 
Reporting Requirements for Adverse Events that Occur within 30 Days1 of the Last Dose of an 
Investigational Agent (cediranib/placebo) in this study (Phase I portion). 
 
 
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause must be provided. 
 
Phase I Trials 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Unexpecte
d  
and 
Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected  
and 
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
24-Hour; 
5 
Calendar 
Days 
24-Hour; 
5 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days 
after the last dose of treatment with an agent under a CTEP IND or non-CTEP IND require reporting 
as follows: 
AdEERS 24-hour notification (via AdEERS for CTEP IND agents; via email to [Group] AE Coordinator 
for agents in non-CTEP IND studies) followed by complete report within 5 calendar days for: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 4 unexpected events  
• 
Grade 5 expected events and unexpected events 
 
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a 
full report is required as outlined in the table. 
 
   Please see exceptions below under section entitled "Additional Instructions or Exceptions." 
March 2005

 
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Table 16.2: 
 
Phase II and III Trials Utilizing an Agent under a CTEP IND or Non-CTEP IND:  AdEERS Expedited 
Reporting Requirements for Adverse Events that Occur within 30 Days1 of the Last Dose of an 
Investigational Agent (cediranib/placebo) in this Study (Phase II portion). 
 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpec-
ted 
and 
Expected 
Unex-
pected 
Expected 
Unexpected 
Expected 
Unex-
pected 
Expected 
with 
Hospitali-
zation 
without 
Hospitali- 
zation 
with 
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 
Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the 
last dose of treatment with an agent under a CTEP IND or Non-CTEP IND require reporting as follows: 
 AdEERS 24-hour notification (via AdEERS for CTEP IND agents; via email to adr@swog.org for agents in 
non-CTEP IND studies) followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 unexpected events  
AdEERS 10 calendar day report: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events    
 
2  Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full 
report is  
required as outlined in the table. 
 
   Please see exceptions in f. below, "Additional Instructions or Exceptions." 
March 2005 
 
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause must be provided. 
 
Expedited AE reporting timelines defined: 
• 
"24 hours; 5 calendar days" – The investigator must initially report 
the AE via AdEERS within 24 hours of learning of the event followed 
by a complete AdEERS report within 5 calendar days of the initial 24-
hour report. 
• 
"10 calendar days" - A complete AdEERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the 
event.  
 
Any medical event equivalent to CTCAE Grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse event 
reporting exclusions.   
 

 
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Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via AdEERS if the event 
occurs following treatment with an agent under a CTEP IND. 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during 
trial registration on all reports. 
 
f. 
Additional Instructions or Exceptions to AdEERS Expedited Reporting 
Requirements for Phase II and III Trials Utilizing an Agent under a CTEP-IND: 
 
1) 
Group-specific instructions. 
 
Submission of the on-line AdEERS report plus any necessary 
amendments generally completes the reporting requirements. You may, 
however, be asked to submit supporting clinical data to the Operations 
Office in order to complete the evaluation of the event. If requested, the 
specified data should be sent by fax to 210-614-0006. Note, however, 
that any documents checked in the Additional Information section of the 
AdEERS report must be submitted to CTEP per the instructions on that 
AdEERS web page. 
 
2) 
For this study, the adverse events listed below do not require expedited 
reporting via AdEERS: 
• 
Grade 4 myelosuppression 
 
g. 
Reporting secondary AML/ALL/MDS 
 
1. 
All cases of acute myeloid leukemia (AML), acute lymphocytic leukemia 
(ALL), and myelodysplastic syndrome (MDS) that occur in patients on 
NCI-sponsored trials following chemotherapy for cancer must be 
reported in AdEERS.  
 
i. 
In protocols using CTCAE Version 4.0 for SAE reporting, three 
options are available to describe treatment-related events: 
 
• 
Leukemia secondary to oncology chemotherapy 
• 
Myelodysplastic syndrome.  NOTE:  The only grading option 
for "Myelodysplastic syndrome" is Grade 4, life-threatening. 
If reporting MDS that is other than Grade 4, use “Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - 
Other, (specify,__)” and insert MDS as the specify term. 
• 
Treatment related secondary malignancy 
 
ii. 
In protocols using CTCAE Version 3.0 for SAE reporting, the 
event(s) can be reported as “Secondary malignancy-Other 
(specify, ___)”.  Report MDS as “Myelodysplasia,” in the 
BLOOD/BONE MARROW category. 
 
iii. 
Secondary malignancies other than AML/ALL/MDS that are 
related to protocol treatment must also be reported in AdEERS. 
 

 
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iv. 
Non-treatment related cases of AML/ALL/MDS must be reported 
as follows: 
 
In protocols using CTCAE Version 4.0 for SAE reporting, report 
as “Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) - Other, specify” 
 
In protocols using CTCAE Version 3.0 for SAE reporting, report 
MDS as “Myelodysplasia” and Leukemias as “Blood/Bone 
Marrow - Other (Specify, __)” 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/default.htm#adverse_events
_adeers 
 
2. 
The following supporting documentation must also be submitted within 
30 days: 
 
• 
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis 
• 
(if available) a copy of the cytogenetics report   
 
Submit the Report and documentation to: 
 
Investigational Drug Branch    and 
SWOG 
by electronically submitting  
 
ATTN: SAE Program 
the report via the AdEERS  
4201 Medical Drive, Suite 250 
web-based application located 
San Antonio, Texas 78229 
at http://ctep.cancer.gov, or 
in the rare event when Internet 
connectivity is disrupted a 24-hour 
notification is to be made to NCI by 
telephone at:  301-897-7497.  An 
electronic report MUST be submitted 
immediately upon re-establishment 
of internet connection.  Please note 
that all paper AdEERS forms have  
been removed from the CTEP website 
and will NO LONGER be accepted. 
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial. 
 
 
 

 
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17.0 
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18.0 
APPENDIX 
 
18.1 
Determination of Expedited Adverse Event Reporting Requirements 
 
18.2 
Appendix Deleted 11/29/10 
 
18.3 
Intake Calendar 
 
18.4 
Medications that may cause QTC prolongation 
 
18.5 
New York Heart Association Class 
 
18.6 
Emergency Unblinding Guidelines 
 
18.7 
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4 
 
 

 
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18.1 
Determination of Expedited Adverse Event Reporting Requirements 
 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial. (Directions for routine reporting are provided in 
Section 14.0.) Additionally, certain adverse events must be reported in an expedited 
manner to allow for more timely monitoring of patient safety and care. Expedited adverse 
event reporting principles and general guidelines follow; specific guidelines for expedited 
adverse event reporting on this protocol are found in Section 16.0. 
 
All serious adverse events must also be reported to the local Institutional Review Board 
(IRB).  Documentation of this reporting should be maintained for possible inspection 
during quality assurance audits. 
 
Reporting requirements may include the following considerations: 1) whether the patient 
has received an investigational or commercial agent; 2) the characteristics of the adverse 
event including the grade (severity), the relationship to the study therapy (attribution), and 
the prior experience (expectedness) of the adverse event; 3) the Phase (1, 2, or 3) of the 
trial; and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event.  
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Submission (IND). In some instances, the investigational agent may be available 
commercially, but is actually being tested for indications not included in the approved 
package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead 
from a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules 
apply. 
• 
Concurrent administration: When an investigational agent(s) is used in 
combination with a commercial agent(s), the combination is considered to be 
investigational and expedited reporting of adverse events would follow the 
guidelines for investigational agents. 
• 
Sequential administration: When a study includes an investigational agent(s) and 
a commercial agent(s) on the same study arm, but the commercial agent(s) is 
given for a period of time prior to starting the investigational agent(s), expedited 
reporting of adverse events that occur prior to starting the investigational agent(s) 
would follow the guidelines for commercial agents. Once therapy with the 
investigational agent(s) is initiated, all expedited reporting of adverse events 
should follow the investigational guidelines. 
 
Steps to determine if an adverse event is to be reported in an expedited manner 
 
Step 1: Identify the type of event using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE). The CTCAE provides descriptive terminology and a grading 
scale for each adverse event listed. A copy of the CTCAE can be downloaded from the 
CTEP home page (http://ctep.cancer.gov). Additionally, if assistance is needed, the NCI 
has an Index to the CTCAE that provides help for classifying and locating terms. All 
appropriate treatment locations should have access to a copy of the CTCAE. 
 
Step 2:  Grade the event using the NCI CTCAE version specified. 
 

 
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Step 3:  Determine whether the adverse event is related to the protocol therapy 
(investigational or commercial). Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite. 
 
Step 4:  Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in  
• 
the current NCI Agent-Specific Adverse Event List (for treatments using agents 
provided under an NCI-held IND); 
• 
the drug package insert (for treatments with commercial agents only); 
• 
Section 3.0 of this protocol. 
 
Step 5:  Review Tables 16.1 and 16.2 in the protocol to determine if there are any 
protocol-specific requirements for expedited reporting of specific adverse events that 
require special monitoring.  
 
Step 6:  Determine if the protocol treatment given prior to the adverse event included an 
investigational agent(s), a commercial agent(s), or a combination of investigational and 
commercial agents. 
 
NOTE:  This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed possibly, probably, or definitely to the agent(s) must be reported according to 
the instructions in Table 16.1 (Phase I) or Table 16.2 (Phase II). 
 

 
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18.2 
Appendix Deleted 11/29/10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THIS PAGE IS BEING LEFT BLANK 
TO PREVENT EXTENSIVE REPAGINATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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18.3 
Intake Calendar 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Signature: 
 
SWOG Patient ID________  Patient Initials (L, F, M) ________ SWOG Study #__________
 
 
 
Institution/Affiliate _______________________  Physician _____________________________ 
Instructions for the participant: 
 
This is a monthly calendar on which you are to record the number of tablets/pills/capsules you 
take each day.  Be sure you have enough calendars to last until your next appointment.  If you 
develop any side effects from the tablets/pills/capsules, mark this on the calendar on the day 
you note the effect.  Bring your calendars with you each time you have an appointment. 
 
If you have questions contact: ____________________ Telephone: _____________________ 
 
Your next appointment is: _______________________ 
Special instructions: 
Month: 
 
Year: 
 

 
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18.4 
Medications that may cause QTc prolongation 
 
This table lists drugs that may prolong the QTc interval.  Cediranib may be administered 
after a 5 half-life washout period elapses following discontinuation of prohibited drugs.  
Drugs labeled "Use discretion" may be co-administered in the absence of other risk 
factors and with appropriate monitoring.  Drugs with a weak association may be 
administered at usual doses with appropriate monitoring. 
 
 
Compound 
 
Compound Half 
Life 
QTc 
Prolongation 
Association/ 
Concurrent 
Administration 
Possible 
Washout 
Period - Hours 
Possible 
Washout 
Period - 
Days 
Alfuzocin 
~10 hours 
Some/Use 
Discretion 
 
7 
Amantadine 
17 +/- 4 hours (10-
25) 
Some/Use 
Discretion 
 
4 
Amiodarone ** 
(cordarone) 
58 days (15-142) 
36 days (active 
metabolite) 
Strong/Prohibited 
 
14 
Amitriptyline* 
> 24 hours, wide 
interpatient 
variability 
Weak/At usual 
doses 
 
 
Amoxapine 
~ 8 hours 
Weak/At usual 
doses 
40 hours 
2 days 
Ampicillin 
1 to 1.5 hours 
Weak/At usual 
doses 
 
 
Arsenic trioxide 
Not characterized; 
may be weeks 
Strong/Prohibited 
 
 
Azithromycin 
40 hours 
Some/Use 
Discretion 
 
 
Bepridil 
42 hr (26-64) 
Strong/Prohibited 
 
10 
Chloral hydrate 
Readily converted to 
Trichloroethanol 
(active metabolite 
T1/2=7-10 hour) 
Some/Use 
Discretion 
48 
 
Chloroquine 
1. 6 to 60 days; 
mean 20 days 
Strong/Prohibited 
 
 
Chlorpromazine 
2. 30 +/- 7 
hours 
Strong/Prohibited 
 
7 
Ciprofloxacin 
3.5 to 4.5 hours 
Weak/At usual 
doses 
 
 
Cisapride 
6 – 12 hour, up to 
20 hour 
Strong/Prohibited 
60 
 
Citalopram 
 
Weak/At usual doses 
 
 
Clarithromycin 
Non linear PK3-4 hr 
(250mg Q12) 
5-7 hr (500mg Q12) 
Strong/Prohibited 
36 
3 
Clomipramine 
~ 21 hours 
Weak/At usual doses 
 
 
Clozapine 
12 hours at steady 
state 
Some/Use 
Discretion 
 
 
Desipramine* 
> 24 hours, wide 
interpatient 
variability 
Weak/At usual 
doses 
 
 
Disopyramide 
6.7 hr (4-10) 
Strong/Prohibited 
36 
 
Dofetilide 
10 hr 
Strong/Prohibited 
48 
 
Dolesetron 
8.1 hr 
Some/Use 
Discretion 
 
 
 

 
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Page 89 
 
 
 
Domperidone 
7-8 hr 
Strong/Prohibited 
48 
 
Doxepin* 
> 24 hours, wide 
interpatient 
variability 
Weak/At usual 
doses 
 
 
Droperidol 
2.2 hours 
Strong/Prohibited 
10 
 
Erythromycin 
* Each salt form 
has different Half 
life* 
Strong/Prohibited 
 
 
Felbamate 
20-23 hr 
Some/Use 
Discretion 
 
5 
Flecainide 
20 hr (12-27) 
Some/Use 
Discretion 
 
5 
Fluconazole 
~ 30  hours 
Weak/At usual doses 
 
 
Foscarnet  
87.5+/-41.8 hours 
*distribution and 
release from bone* 
Some/Use 
Discretion 
 
20 
Fosphenytoin 
12-29 hr 
Some/Use 
Discretion 
 
6 
Galantamine 
 
Weak/At usual doses 
 
 
Gatifloxacin 
7-14 hr 
Some/Use 
Discretion 
48 
 
Gemifloxacin 
7 hours 
Some/Use 
Discretion 
48 
 
Granisetron 
3 to 4 hours 
Some/Use 
Discretion 
 
 
Grepafloxacin 
16 hr 
Some/Use 
Discretion 
 
3 
Halofantrine 
6-10 days ( 
variable among 
individual) 
Strong/Prohibited 
 
45 
Haloperidol 
18 +/-5 hr 
Strong/Prohibited 
 
5 
Ibutilide 
6 hours (2-12) * 
variable among 
subject* 
Strong/Prohibited 
36 
3 
Imipramine* 
> 24 hours, wide 
interpatient 
variability 
Weak/At usual 
doses 
 
 
Indapamide 
14 hours (biphasic 
elimination) 
Some/Use 
Discretion 
 
3 
Isradipine 
8 hours ( multiple 
metabolites) 
Some/Use 
Discretion 
48 
 
Itraconazole 
20 hours, increasing 
to 40 hours 
Weak/At usual doses 
 
 
Ketoconazole 
2 hours, increasing 
to 8 hours 
Weak/At usual doses 
 
 
Levofloxacin 
6-8 hours 
Some/Use 
Discretion 
48 
 
Levomethadyl 
Multiple 
compartment PK 
with active 
metabolite 
2.6 day for LAAM, 
2 day for nor-
LAAM, 4 day for 
dinor-LAAM 
3. 
Strong/Prohibited 
4.  
5. 
20 
Lithium 
24 hour (10-50) 
Some/Use Discretion 
 
7 
Mefloquine 
13 to 24 days 
Weak/At usual doses 
 
 
 

 
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Mesoridazine 
24-48 hours ( 
animal study) 
Strong/Prohibited 
 
10 
Methadone 
15-30 hours 
Strong/Prohibited 
 
7 
Mexiletine 
>10 hours 
Weak/At usual doses 
 
 
Moexipril/HCTZ 
2-9 hour (include 
active metabolite) 
for moexipril; 5.6-
14.8 hours for HCTZ  
Some/Use Discretion 
48 
 
Moxifloxacin 
12 +/-1.3 hours 
6. 
Some/Use Discretion 
7. 72 
8.  
Naratriptan 
6 hours 
 
36 
 
Nicardipine 
~ 2 hour post IV 
infusion 
Some/Use Discretion 
12 
 
Nortriptyline* 
> 24 hours, wide 
interpatient 
variability 
Weak/At usual doses 
 
 
Octreotide 
1.7 hours 
Some/Use Discretion 
12 
 
Ofloxacin 
5 to 7.5 hours 
Some/Use Discretion 
 
2 
Ondansetron 
4 hours (IV/IM); 3 
hours (PO) 
Some/Use Discretion 
 
1 to 3 
Paroxetine 
 
Weak/At usual doses 
 
 
Pentamidine 
6.4+/-1.3 hours 
Strong/Prohibited 
36 
 
Pimozide 
55 hours 
Strong/Prohibited 
 
10 
Procainamide 
3-4 hour for PA 
and NAPA (active 
metabolite) 
Strong/Prohibited 
24 
3 
Protiptyline* 
> 24 hours, wide 
interpatient 
variability 
Weak/At usual doses 
 
 
Quetiapine 
6 hours 
Some/Use Discretion 
36 
 
Quinidine 
6-8 hours in adult; 
3-4 hours in 
children 
Strong/Prohibited 
36 
 
Quinine 
4-5 hours 
Weak/At usual doses 
 
 
Risperidone 
3-20 hours 
(extensive to poor 
metabolizer) 
9-
hydroxyrisperidone 
(active metabolite) T 
½ =21-30 hours 
(extensive to poor 
metabolizer) 
Some/Use Discretion 
 
4 
Roxithromycin 
 
Some/Use Discretion 
 
 
Salmeterol 
5.5 hours ( only one 
datum) 
Some/Use Discretion 
36 
 
Sertraline 
~ 26 hours 
Weak/At usual doses 
 
 
Solifenacin 
40 to 68 hours 
Weak/At usual doses 
 
 
Sotalol 
12 hours 
Strong/Prohibited 
72 
 
 

 
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Sparfloxacin 
20 hours (16-30) 
Strong/Prohibited 
 
4 
Sumatriptan 
2.5 hours 
 
12 
 
Tacrolimus 
~34 hours in 
healthy; ~19 hours 
in Kidney transplant 
Some/Use Discretion 
 
7 
Tamoxifen 
5-7 days (biphasic) 
Some/Use Discretion 
 
30 
Telithromycin 
2-3 hr 
Some/Use Discretion 
24 
 
Thioridazine 
20-40 hours 
(Phenothiazines) 
Strong/Prohibited 
 
7 
Tizanidine 
2.5 hours 
Some/Use Discretion 
12 
 
Trimethoprim/sulfa 
6 to 17 hours 
Weak/At usual doses 
 
 
Trimipramine 
~ 23 hours 
Weak/At usual doses 
 
 
Vardenifil 
4 to 5 hours 
Some/Use Discretion 
 
 
Venlaflaxine 
5 +/-2 hours for 
parent comp. 
11+-2 hours for 
OVD (active 
metabolite) 
Some/Use Discretion 
60 
 
Voriconizole 
6 hours; dose 
dependent 
Some/Use Discretion 
 
 
Ziprasidone 
7 hr 
Some/Use Discretion 
36 
 
Zolmitriptan 
2.8-3.7 hours 
(higher in female) 
Weak/At usual doses 
18 
 
* These agents are tricyclic antidepressants; traditionally, they have only been associated with 
QTc interval prolongation at serum levels approaching or into the range of toxicity. Special 
caution is advised is the elderly and children/adolescents. 
** Patients should discontinue amiodarone and switch to an anti-arrhythmic agent that does not 
interfere with the protocol.  Prior to and after the 14 day washout period, baseline EKG’s should 
be checked.  If the QTc interval is normal, then proceed to enroll the patient onto the trial. 
 
References: 
1. Physician’s Desk Reference 2002 
2. Facts and Comparisons ( update to June 2005) 
3. The Pharmacological Basis of Therapeutics 9th Edition, 1996 
4. ArizonaCERT Center for Education and Research on Therapeutics, 
http://torsades.org/medical-pros/drug-lists/drug-lists.htm 
 
Disclaimer:  This chart was updated on August 23, 2005.  It may not include all drugs associated with 
QTc prolongation.  Prescribers are advised to do further research if they have additional questions. 
 

 
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18.5 
New York Heart Association Class 
 
 
 
 
 
Need for 
Physical Ability 
 
Class 
Cardiac Symptoms 
Limitations 
Additional Rest* 
To Work** 
 
 
I 
None 
None 
None 
Full Time 
 
II 
Only moderate 
Slight 
Usually only slight 
Usually full time 
 
 
 
or occasional 
 
III 
Defined, with less 
Marked 
Usually moderate 
Usually part time 
 
than ordinary 
 
activity 
 
IV 
May be present 
Extreme 
Marked 
Unable to work 
 
even at rest, & any 
 
activity increases 
 
discomfort 
 
 
 
 
 
* 
To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician. 
 
** 
At accustomed occupation or usual tasks. 
 
 
 
 

 
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18.6 
Emergency Unblinding Guidelines 
 
a. 
General Considerations 
 
The randomized regimen for this study includes a blinded drug, which is either 
cediranib or placebo.  During the course of this study it may become necessary 
to identify (or unblind) a patient's treatment assignment.  The circumstances that 
will warrant emergency unblinding and the procedure for emergency unblinding 
are described in this Appendix. 
 
b. 
Criteria for Emergency Unblinding 
 
In general, treatment assignments will not be emergency unblinded unless there 
is a compelling medical or ethical reason that the treatment should be identified.  
In most circumstances it will be appropriate to treat the patient or person who 
received blinded drug as though he or she received cediranib, irrespective of the 
drug actually received.  Therefore, emergency unblinding should seldom be 
necessary. 
 
The following events MAY require emergency unblinding of treatment 
assignments in this study: 
 
1. 
A compelling medical need as determined by a physician, e.g., existence 
of a condition for which knowledge of the patient's treatment assignment 
is necessary for the selection of appropriate care. 
 
2. 
Administration of blinded drug to a person other than the patient. 
 
c. 
Procedure for Emergency Unblinding 
 
Emergency unblinding of treatment assignments for patients on this study will be 
performed by the Washington Poison Center (WPC), upon approval from a 
designated physician (either one of the WPC's resource physicians or Dr. Anne 
Tsao).  The procedure for emergency unblinding the treatment assignment for a 
patient on this study is as follows: 
 
1. 
All requests for emergency unblinding must be made by the registering 
physician or his/her designee. 
 
2. 
Call the WPC collect at 206/526-2121 from outside Washington State or 
toll free at 800/222-1222 from within Washington State.  The WPC is 
accessible 24 hours per day, 365 days per year. 
 
3. 
The person calling the WPC must be prepared to provide the following 
information: 
 
Study number (S0905) 
 
Southwest Oncology Group Patient Number (e.g., "999999") 
 
Patient Initials 
 
Name and telephone number of the caller 
 
Reason emergency unblinding is thought to be required 
 

 
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4. 
The WPC will contact one of its resource physicians and provide the information 
received from the caller.  If none of the WPC's resource physicians can be 
contacted, then the WPC will contact Dr. Anne Tsao.  The contacted physician 
will evaluate the need for emergency unblinding and provide the WPC either 
approval to unblind or a recommendation for treatment, if any, while maintaining 
blinding.  The WPC will then call the person who initiated the unblinding request 
and tell him/her either the treatment assignment or the resource physician's 
treatment recommendation. 
 
5. 
If the WPC is unable to contact any of its resource physicians or Dr. Tsao within 
three hours after receiving the request for emergency unblinding, then the WPC 
will notify the person who initiated the unblinding request that treatment 
assignment will not be unblinded at that time and treatment of the patient or 
person who received blinded drug should proceed as if the blinded drug is 
cediranib.  In such cases, the WPC will continue to attempt to contact the 
resource physicians, and when one of them is contacted, will proceed as in #4 
above. 
 
6. 
Any patient whose treatment assignment is emergency unblinded will receive no 
further blinded drug, but should continue all other protocol treatment if his/her 
medical condition permits. 
 
7. 
Unblinding of treatment assignments for any reason must be documented on the 
Off Treatment Notice. 
 
Questions regarding the unblinding may be directed to any of the following 
resource physicians: 
 
Anne S. Tsao, M.D. 
MD Anderson Cancer Center 
1515 Holcombe Boulevard 
Unit 432 
Houston, Tx 77030 
Phone:  713/792-6363 
E-mail:  astsao@mdanderson.org 
 
Anne Schott, M.D. 
Southwest Oncology Group  
24 Frank Lloyd Wright Drive 
P.O. Box 483 
Ann Arbor, MI  48106 
Phone:  734/998- 7172 
E-mail:  aschott@umich.edu 
 
Washington Poison Center 
Phone:  206/526-2121 
 

 
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18.7 
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4 
 
 
CYP2D6 
SUBSTRATES 
Amitriptyline (hydroxylation) 
Amphetamine 
Betaxolol 
Bisoprolol 
Brofaromine 
Buturolol 
Bupropion 
Captopril 
Carvedilol 
Cevimeline 
Chlorpheniramine 
Chlorpromazine 
Cinnarizine 
 
Clomipramine (hydroxylation) 
Clozapine (minor pathway) 
Codeine (hydroxylation, o-demelhylation) 
Cyclobenzaprine (hydroxylation) 
Cyclophosphamide 
Debrisoquin 
Delavirdine 
Desipramine 
Dexfenfluramine 
Dextromethorphan (o-demethylation) 
Dihydrocodeine 
Diphenhydramine 
Dolasetron 
Donepezil 
Doxepin 
Encainide 
Fenlluramine 
Flecainide 
Fluosetine (minor pathway) 
Fluphenazine 
Haiofantrine 
Haioperidol (minor pathway) 
Hydrocodone 
Hydrocortisone 
Hydroxyamphetamine 
lmipramine (hydroxylation) 
Labetalol 
Loratadine 
Maprotiline 
m-Chlorophenylpiperazine (m-CPP) 
Meperidine 
Methadone 
 
Methamphetamine 
Metoclopramide 
Metoprolol 
Mexitetine 
Mianserin 
Mirtazapine (hydroxylation) 
Molindone 
Morphine 
Nortriptyline (hydroxylation) 
Olanzapine (minor, hydroxymethylation) 
Ondansetron 
Orphenadrine 
Oxycodone 
Papaverine 
Paroxetine (minor pathway) 
Penbutolol 
Pentazocine 
Perhexiline 
Perphenazine 
Phenformin 
Pindolol 
Promethazine 
Propafenone 
Propranolol 
Quetiapine 
Remoxipride 
Risperidone 
Ritonavir (minor) 
Ropivacaine 
Selegiline 
Sertindole 
Sertratine (minor pathway) 
Sparteine 
Tamoxifen 
Thioridazine 
Tiagabine 
Timolol 
Tolterodine 
Tramadol 
Trazodone 
Trimipramine 
Tropisetron 
Venlafaxine (o-desmethylation) 
Yohimbine 
 

 
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INHIBITORS 
Amiodarone 
Celecoxib 
Chloroquine 
Chlorpromazine 
Cimelidine 
Citalopram 
Clomipramine 
Codeine 
Deiavirdine 
Desipramine 
Dextropropoxyphene 
Diitiazem 
Doxorubicin 
Entacapone (high dose) 
Fluoxetine 
Fluphenazine 
Fluvoxamine 
Haloperidol 
Labetalol 
Lobeline 
Lomustine 
Methadone 
Mibefradil 
Moclobemide 
Nortluoxeline 
Paroxetine 
Perphenazine 
Propafenone 
Quinacrine 
Quinidine 
Ranitidine 
Risperidone (weak) 
Ritonavir 
Sertindole 
Sertraline (weak) 
Thioridazine 
Vaiprolc acid 
Venlafaxine (weak) 
Vinblastine 
Vincristine 
Vinorelbine 
Yohimbine 
CYP3A3/4 
Substrates 
Acetaminophen 
Aifentanil 
Alosetron 
Alprazolam 
Amiodarone 
Amitriptyline (minor) 
Amlodipine 
Anastrozole 
Androsterone 
Antipyrine 
Astemizole 
Atorvastatin 
Benzphetamine 
Bepridil 
Bexarotene 
Bromazepam 
Bromocriptine 
Budesonide 
Bupropion (minor) 
Buspirone 
Busutfan 
Caffeine 
Cannabinoids 
Carbamazepine 
Cevimeline 
Cerivastatin 
Digitoxin 
Diltiazem 
Disopyramide 
Docetaxel 
Dolasetron 
Donepezil 
 
Chlorpromazine 
Cimetidine 
Cisapride 
Citałopram 
Clarithromycin 
Clindamycin 
Clomipramine 
Clonazepam 
Clozapine 
Cocaine 
Codeine (demethylation) 
Cortisol 
Cortisone 
Cyclobenzaprine (demethylation) 
Cyclophosphamide 
Cyclosporine 
Dapsone 
Dehydroepiandrostendione 
Delavirdine 
Desmethyldiazepam 
Dexamethasone 
Dextromethorphan (minor, N-
demethylation)  
Diazepam (minor; hydroxylation, N-
demethylation) 
 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Niludipine 
 

 
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Doxorubicin 
Doxycycline 
Dronabinol 
Enalapril 
Erylhromycin 
Estradiol 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestene 
Dofetilide (minor) 
Felodipine 
Fentanyl 
Fexotenadine 
Finaxteride 
Fluoxetine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Omeprazole (sulfonation) 
Ondansetron 
Oral contraceptives 
Orphenadrine 
Paclitaxel 
Pantoprazole 
Pimozide 
Pioglitazone 
Pravastatin 
Prednisone 
Progesterone 
Proguanil 
Propafenone 
FLUTAMIDE 
Substrates 
Glyburide 
Granisetron 
Halofantrine 
Hydrocortixone 
Hydroxyarginine 
lfosfamide 
lmipramine 
lndinavir 
lsradipine 
ltraconazole 
Ketoconazole 
Lansoprazole (minor) 
Letrozole 
Levobupivicaine 
Lidocaine 
Loratadine 
Losartan 
Lovastatin 
Methadone 
Mibefradil 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine (N-demethylation) 
Montelukast 
Navelbine 
Toremifene 
Trazodone 
Tretinoin 
Triazolam 
Troglitazone 
Troleandomycin 
Venlafaxine (N-demethylation) 
Verapamil 
Vinblastine 
 
Quercetin 
Quetiapine 
Quinidine 
Quinine 
Repaglinide 
Retinoic acid 
Rifampin 
Risperidone 
Ritonavir 
Salmeterol 
Saquinavir 
Sertindole 
Sertraline 
Sibutramine 
Sildenafil citrate 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Temazepam 
Teniposide 
Terfenadine 
Testosterone 
Tetrahydrocannabinol 
Theophylline 
Tiagabine 
Tolterodine 
Vincristine 
Warfarin (R-warfarin) 
Yohimbine 
Zaleplon (minor pathway) 
Zatoestron 
Zileuton 
Ziprasidone 
Zolpidem 
Zonisamide 

 
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INDUCERS 
Carbamazepine 
Dexamethasone 
Ethosuximide 
Glucocorticoids 
Griseofulvin 
Nafcillin 
Nelfinavir 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifampin 
Rofecoxib (mild) 
St John’s wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
INHIBITORS 
Amiodarone 
Anastrozole 
Azithromycin 
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (weak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
lndinavir 
lsoniazid 
ltraconazole  
 
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole (moderate) 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole (weak) 
Oxiconazole 
Paroxetine (weak) 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Troglitazone 
Troleandomycin 
Valproic acid (weak) 
Verapamil 
Zafirlukast 
Zileuton 
 
 
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In : Lacy CF, Armstrong LL, 
Goldman MP, Lance LL eds. Drug Information Handbook 8th ed. Hudson, OH; LexiComp Inc. 
2000: 1364-1371