Prospective Randomized Phase II Trial of Pazopanib (NSC #737754) Versus Placebo in Patients With Progressive Carcinoid Tumors
Phase: PHASE2
Conditions: Foregut Neuroendocrine Tumor, Hindgut Neuroendocrine Tumor, Metastatic Digestive System Neuroendocrine Tumor G1, Metastatic Neuroendocrine Tumor, Midgut Neuroendocrine Tumor G1, Neuroendocrine Tumor G2, Recurrent Digestive System Neuroendocrine Tumor G1, Regional Digestive System Neuroendocrine Tumor G1
Sponsor: National Cancer Institute (NCI)

 
1 
Protocol Update #12 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
_________________________________________ 
PROTOCOL UPDATE TO ALLIANCE A021202 
_________________________________________ 
 
PROSPECTIVE RANDOMIZED PHASE II TRIAL OF PAZOPANIB (NSC # 737754, IND 75648) VERSUS 
PLACEBO IN PATIENTS WITH PROGRESSIVE CARCINOID TUMORS 
 
Pazopanib and matching placebo will be supplied by Novartis and distributed by CTEP. 
 
 
 
 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
 
Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
X Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
 
Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
 
Data Submission / Forms changes 
 
 
 
 
 
 
 
 
X Editorial / Administrative changes 
 
 
 
 
 
 
 
 
X Other: Updated CAEPR for Pazopanib 
 
 
 
 
The CAEPR and Risk List changes included in this update to A021202 have been made in 
response to the NCI Request for Amendment from Dr. Fernanda Arnaldez. A revised 
CAEPR for pazopanib with new risks has been added to the protocol. Therefore, the model 
consent form has been revised to incorporate these new risks, consistent with the NCI Model 
Consent Template instructions. There are no changes to the risk/benefit ratio. 
 
Expedited review is allowed. IRB approval (or disapproval) is required within 90 days. Please 
follow your IRB of record guidelines. 
 
UPDATES TO THE PROTOCOL: 
 
Cover Page 
Brandon Bright has replaced Luke Wilson as the Data Manager; all contact information has been updated. 
 
Section 5.5 (Re-Registration [Step 2] at the Time of Progression) 
A new second paragraph has been added for clarity. It reads: “Note: As of 03/14/2019, patients who were 
initially assigned to placebo were given the option to receive open-label pazopanib due to the release of 
study results. 
 
 
 

 
2 
Section 16.2 (Comprehensive Adverse Events and Potential Risks list [CAEPR] for Pazopanib 
[GW786034, NSC 737754]) 
This section has been revised to include the updated pazopanib CAEPR (Version 2.8, January 31, 2019) 
provided by CTEP. Changes from Version 2.7 to Version 2.8 include the following: 
• 
Added New Risk: 
o Also Reported on Pazopanib Trials But With Insufficient Evidence for Attribution: 
Muscle cramp. 
• 
Deleted Risk: 
o Also Reported on Pazopanib Trials But With Insufficient Evidence for Attribution: Acute 
coronary syndrome; Musculoskeletal and connective tissue disorder - Other (muscle 
spasms). 
• 
Provided Further Clarification: 
o Eye disorders - Other (eye/retinal hemorrhage) (CTCAE 4.0 language) is now reported as 
Eye disorders - Other (eye hemorrhage, retinal hemorrhage). 
o Female genital tract fistula (CTCAE 4.0 language) is now reported as Reproductive 
system and breast disorders - Other (female genital tract fistula). 
o Skin and subcutaneous tissue disorders - Other (hair color change/hair depigmentation) 
(CTCAE 4.0 language) is now reported as Hair color changes. 
o Vascular disorders - Other (arterial thromboembolic event) (CTCAE 4.0 language) is now 
reported as Arterial thromboembolism. 
o Gastrointestinal disorders - Other (oropharyngeal pain), previously listed under the 
GASTROINTESTINAL DISORDERS SOC (CTCAE 4.0 language), is now reported as 
Oropharyngeal pain and is now listed under the RESPIRATORY, THORACIC AND 
MEDIASTINAL DISORDERS SOC. 
o Investigations - Other (blood lactate dehydrogenase increased) (CTCAE 4.0 language) is 
now reported as Blood lactate dehydrogenase increased. 
 
 
UPDATES TO THE MODEL CONSENT: 
 
What side effects or risks can I expect from being in the study? 
Based on the updated CAEPR described above, the following changes have been made to the NCI 
condensed risk profile for pazopanib: 
• 
Added New Risk: 
o Rare: Blood clot in artery which may cause swelling, pain, shortness of breath or change 
of color in extremity. 
• 
Deleted Risk: 
o Rare: Bleeding of the eye which may cause blurred vision with a chance of blindness. 
• 
Provided Further Clarification: 
o High blood pressure which may cause blurred vision (under Common) is now reported as 
High blood pressure which may cause headaches, dizziness, blurred vision (under 
Common). 
o Bleeding from multiple sites including the nose or vagina (under Occasional) is now 
reported as Bleeding from multiple sites including the nose or vagina which may cause 
blurred vision with a chance of blindness (under Occasional). 

 
3 
o Anemia, kidney problems which may require dialysis (under Rare) is now reported as 
Anemia, kidney problems which may cause tiredness, bruising, swellings, or may require 
dialysis (under Rare). 
o Blood clot which may cause confusion, paralysis, swelling, pain, or shortness of breath 
(under Rare) is now reported as Blood clot which may cause confusion, paralysis, 
seizures and blindness, swelling pain, shortness of breath (under Rare). 
 
Replacement protocol and informed consent documents have been issued. 
This protocol remains permanently closed to new patient accrual. 
_________________________________________________________ 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
_________________________________________________________

 
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Version Date: 04/08/2019 
 
 
 
 
 
 
 
Update #12 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
ALLIANCE A021202 
 
PROSPECTIVE RANDOMIZED PHASE II TRIAL OF PAZOPANIB (NSC #737754, IND #75648) VERSUS 
PLACEBO IN PATIENTS WITH PROGRESSIVE CARCINOID TUMORS 
ClinicalTrials.gov Identifier: NCT01841736 
 
Pazopanib and matching placebo will be supplied by Novartis and distributed by CTEP. 
 
Study Chair 
Emily Bergsland, M.D. 
UCSF Helen Diller Family Comprehensive Cancer Center 
Mission Hall, 550 16th Street, Box 3211 
San Francisco, CA 94143 
Tel: 415-353-9888 Fax: 415-353-9959 
emily.bergsland@ucsf.edu  
 
Community Oncology Co-Chair 
J. Phil Kuebler, MD, PhD 
Population Pharmacology and 
Pharmacogenomics Co-Chair 
Correlative Science Co-Chair 
and GI Correlative Vice-Chair 
Columbus Oncology and 
Michael Maitland, MD, PhD 
Andrew Nixon, PhD 
Hematology Associates 
Tel: 614-488-2118 
Inova Schar Cancer Institute 
Tel: 703-208-6646 
Duke University 
Tel: 919-613-7883 
pkuebler1@gmail.com 
michael.maitland@inova.org 
anixon@duke.edu 
 
Health Outcomes Co-Chair 
Imaging Co-Chair 
Imaging Committee Chair 
Jeff Sloan, PhD 
Nathan Hall, MD, PhD 
Lawrence Schwartz, MD 
Mayo Clinic 
Tel: 507-261-4268 
University of Pennsylvania 
Tel: 215-662-3091 
Columbia University 
Tel: 212-305-8994 
jsloan@mayo.edu 
nathan.hall@uphs.upenn.edu 
lhs2120@cumc.columbia.edu 
 
Alliance GI Committee Co-Chairs 
Jeffrey Meyerhardt, MD, MPH 
Eileen O’Reilly, MD 
Dana-Farber Cancer Institute 
Tel: 617-632-6855 
MSKCC 
Tel: 646-888-4182 
jeffrey_meyerhardt@dfci.harvard.edu 
oreillye@mskcc.org 
 
Primary Statistician 
Data Manager 
Protocol Coordinator 
Michelle Mahoney, MS 
Brandon Bright 
Alexandra LeVasseur 
Tel: 507-266-4456 
Tel: 507-538-1484 
Tel: 773-834-4518 
Fax: 507-266-2477 
Fax: 507-284-1902 
Fax: 312-345-0117 
mahoneym@mayo.edu 
bright.brandon@mayo.edu 
alevasseur@uchicago.edu 
 
CCTG Champion 
SWOG Champion 
Tim Asmis, M.D. 
Alexandria T. Phan, MD 
Tel: 613-737-7700 
Tel: 713-441-8324 
tasmis@ottawahospital.on.ca 
atphan@tmhs.org 
 
Participating Organizations: ALLIANCE / Alliance for Clinical Trials in Oncology (lead), 
ECOG/ACRIN / ECOG-ACRIN Cancer Research Group, CCTG / Canadian Clinical Trials Group, NRG / 
NRG Oncology, SWOG / SWOG 

ALLIANCE A021202 
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Update #12 
Study Contacts: 
Alliance Statistics and Data Center 
Mayo Clinic 
200 First St. SW 
Rochester MN 55905 
Expedited Adverse Event Reporting 
https://eapps-ctep.nci.nih.gov/ctepaers 
Medidata Rave iMedidata Portal 
https://login.imedidata.com 
OPEN (Oncology Patient Enrollment Network) 
https://open.ctsu.org 
 
Protocol Resources: 
A021202 Nursing Contact 
Barbara Kleiber, RN, OCN, CCRC 
The Ohio State University 
Tel: 614-297-2378 
barbara.kleiber@osumc.edu 
A021202 Pharmacy Liaison 
Zoe Ngo, PharmD 
UCSF 
Tel: 415-514-3878 
zoe.ngo@ucsf.edu 
Alliance Biorepository at Ohio State University 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073  Fax: 614-293-7967 
path.calgb@osumc.edu 
Alliance Imaging Core Lab 
The Ohio State University 
Wright Center of Innovation 
395 W. 12th Ave., RM #414 
Columbus, OH 43240 
Tel: 614-293-2929  Fax: 614-293-9275 
Alliance021202@imagingcorelab.com 
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, Protocol 
Coordinator, or (where available) Data Manager  
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol and model 
informed consent: 
Protocol Coordinator 
Questions related to IRB review: 
Regulatory Affairs Manager  
regulatory@alliancenctn.org 
Questions regarding CTEP-AERS reporting: 
Pharmacovigilance Inbox 
pharmacovigilance@alliancenctn.org 
 
 
 

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Update #12 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
 For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.) 
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support.  
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN) 
which can be accessed at 
https://www.ctsu.org/OPEN_S
YSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com. 
 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Please see the 
data submission section of the 
protocol for further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires user log on with 
CTEP-IAM username and password. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS. 
For clinical questions (i.e. patient eligibility or treatment-related) see the Protocol Contacts, Page 2 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Update #12 
PROSPECTIVE RANDOMIZED PHASE II TRIAL OF PAZOPANIB (NSC #737754, IND #75648) VERSUS 
PLACEBO IN PATIENTS WITH PROGRESSIVE CARCINOID TUMORS 
 
Eligibility Criteria 
Required Initial Laboratory Values 
Low- or intermediate-grade neuroendocrine carcinoma. (See §4.1.1)  
Granulocytes 
≥ 1,500/mcL 
Patients must have locally unresectable or metastatic carcinoid tumors arising in 
the foregut, midgut, hindgut, or other non-pancreatic site (See §4.1.2, 4.1.3) 
Platelets 
INR* 
≥ 100,000/mcL 
≤ 1.2 x ULN 
Radiological evidence for progressive disease (measureable or non-measurable) 
within 12 months prior to randomization. (See §4.1.4) 
No known endobronchial lesions and/or lesions infiltrating major pulmonary 
vessels that increase the risk of pulmonary hemorrhage. (See §4.1.5) 
QTc 
TSH 
Bilirubin 
AST/ALT 
≤ 480 msecs 
WNL 
≤ 1.5 x ULN 
≤ 2.5 x ULN  
Patients must have measurable disease 
Serum Creatinine 
≤ 1.5 x ULN 
No prior treatment with an inhibitor of VEGF or VEGFR 
UPC 
< 1 
Prior treatment must be completed at least 4 weeks prior to registration 
OR 
Concurrent use of somatostatin analogs is allowed 
Progression on octreotide required for patients with tumors arising in the midgut 
24-hour urine 
protein 
< 1 g 
Prior treatment with embolization or ablative therapies is allowed 
* Only needed if patient is on 
anticoagulant therapy 
No major surgeries < 4 weeks from registration 
No concurrent condition resulting in immune compromise 
No clinical evidence of brain metastases or carcinomatous meningitis  
No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to registration 
No clinically significant GI abnormalities that may increase the risk for GI bleeding < 28 days prior to registration 
No history of serious non-healing wound, ulcer, or bone fracture within 28 days prior to registration 
Patients with a history of hypertension must have blood pressure that is adequately controlled (< 140/90 mmHg). 
No symptomatic congestive heart failure, arterial thrombotic events including TIA, CVA, peripheral arterial thrombus, MI or 
unstable angina or angina requiring surgical or medical intervention within 6 months prior to registration 
Patients on therapeutic anticoagulation with low molecular weight heparins are allowed 
No ongoing cardiac dysrhythmias, atrial fibrillation, or prolongation of corrected QTc interval to > 480 msec. 
No evidence of active bleeding, bleeding diathesis, or hemoptysis within 8 weeks prior to registration. 
No currently unstable angina and/or uncontrolled cardiac arrhythmias 
No symptomatic peripheral vascular disease 
Ejection fraction on Echo or MUGA > 50% 
No chronic concomitant treatment with strong inhibitors of CYP3A4. Any such treatment must be discontinued 14 days prior 
to start of study treatment (See §4.5) 
Non-pregnant and non-nursing (See §4.6) 
Age ≥ 18; ECOG Performance Status: 0 – 1  
 
Schema 
1 cycle = 28 days 
 
R  
Double-Blinded  
 
 
 
 
 
A  
 
 
 
 
 
 
N  
Pazopanib 
800 mg p.o. daily 
 
 
 
 
 
D  
 
 
 
 
 
O  
 
 
 
Open Label 
 
M  
 
 
 
 
 
 
I 
 
Placebo  
p.o. daily 
PD* 
RE-
REGISTER 
 
Pazopanib 
800 mg p.o. 
daily 
 
Z  
 
 
 
E  
 
 
 
Treatment with pazopanib/placebo will continue until disease progression or unacceptable toxicity.  
* 
Upon progression as determined by central review, patients may be unblinded and those who were receiving placebo may 
elect to crossover to treatment with pazopanib. Patients who opt to cross over to active drug must be re-registered to the 
study; see Section 5.5. 
See Section 4.0 for eligibility criteria details and Section 8.0 for complete treatment information. 

ALLIANCE A021202 
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Update #12 
Table of Contents 
1.0 
INTRODUCTION .................................................................................................................... 8 
1.1 
Rationale for Selected Approach and Study Design ...................................................................... 8 
1.2 
Trial Importance ........................................................................................................................... 10 
1.3 
Registration Quality of Life (QOL) Measurements ..................................................................... 11 
1.4 
Inclusion of Women and Minorities ............................................................................................ 12 
2.0 
OBJECTIVES ......................................................................................................................... 12 
2.1 
Primary Objective ........................................................................................................................ 12 
2.2 
Secondary Objectives ................................................................................................................... 12 
2.3 
Exploratory Objectives ................................................................................................................ 13 
3.0 
ON-STUDY GUIDELINES ................................................................................................... 13 
4.0 
ELIGIBILITY CRITERIA.................................................................................................... 14 
4.1 
Documentation of Disease ........................................................................................................... 14 
4.2 
Measurable Disease ..................................................................................................................... 15 
4.3 
Prior Treatment ............................................................................................................................ 15 
4.4 
Patient History ............................................................................................................................. 16 
4.5 
Concomitant Treatment................................................................................................................ 17 
4.6 
Pregnancy/Nursing Status ............................................................................................................ 17 
4.7 
Age and Performance Status ........................................................................................................ 17 
4.8 
Required Initial Laboratory Values: ............................................................................................ 17 
5.0 
PATIENT REGISTRATION ................................................................................................ 18 
5.1 
CTEP Registration Procedures ..................................................................................................... 18 
5.2 
CTSU Registration Procedures .................................................................................................... 19 
5.3 
Patient Registration Requirements ............................................................................................... 20 
5.4 
Patient Registration/Randomization (Step 1) Procedures ............................................................ 21 
5.5 
Re-Registration (Step 2) at the Time of Progression ................................................................... 21 
5.6 
Registration to Correlative and Companion Studies .................................................................... 22 
5.7 
Stratification Factors .................................................................................................................... 22 
6.0 
DATA SUBMISSION, SPECIMEN SUBMISSION AND IMAGING .............................. 22 
6.1 
Data Submission .......................................................................................................................... 22 
6.2 
Imaging Submission ..................................................................................................................... 23 
6.3 
Submission of Quality of Life Questionnaires ............................................................................. 27 
6.4 
Specimen Submission for Banking .............................................................................................. 28 
7.0 
REQUIRED DATA ................................................................................................................ 30 
8.0 
TREATMENT PLAN ............................................................................................................ 31 
8.1 
Pazopanib/Placebo ....................................................................................................................... 31 
8.2 
Disease Progression/Crossover to Open Label Treatment ........................................................... 31 
9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY ................................ 32 
9.1 
Hematologic Toxicity .................................................................................................................. 32 
9.2 
Hepatic Toxicity ........................................................................................................................... 32 
9.3 
Proteinuria .................................................................................................................................... 32 
9.4 
Nephrotoxicity ............................................................................................................................. 33 
9.5 
Cardiac Toxicity ........................................................................................................................... 33 
9.6 
Thrombosis .................................................................................................................................. 33 
9.7 
Hypertension ................................................................................................................................ 33 

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9.8 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) (see CTCAE v.4: Nervous System 
Disorders) ................................................................................................................................. 34 
9.9 
Hemorrhage .................................................................................................................................. 34 
9.10 
Fistula, Perforations, Bowel Obstruction or Wound Dehiscence................................................. 34 
9.11 
Thyroid Dysfunction .................................................................................................................... 35 
9.12 
Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura (See CTCAE Blood and 
Lymphatic System Disorders) .................................................................................................. 35 
9.13 
Pneumonitis .................................................................................................................................. 35 
9.14 
Other Non-Hematologic Grade 3 or 4 Toxicity ........................................................................... 35 
10.0 
COMPANION STUDIES ...................................................................................................... 35 
10.1 
Imaging ........................................................................................................................................ 35 
10.2 
Quality of Life (A021202-HO1) .................................................................................................. 41 
10.3 
Banked Blood Plasma Specimens for Circulating Angiogenic and Inflammatory Markers 
(“Angiome”) ............................................................................................................................. 45 
10.4 
Banked Whole Blood Sample ...................................................................................................... 49 
11.0 
DRUG FORMULATION, AVAILABILITY, AND PREPARATION .............................. 53 
11.1 
Qualified Personnel ...................................................................................................................... 53 
11.2 
Pazopanib (GW786034) (NSC 737754) ...................................................................................... 53 
12.0 
ANCILLARY THERAPY ..................................................................................................... 59 
12.1 
Supportive Care ........................................................................................................................... 59 
12.2 
Treatment with Hormones or Other Chemotherapeutic Agents................................................... 59 
12.3 
Somatostatin Analog .................................................................................................................... 59 
12.4 
Growth Factors ............................................................................................................................. 59 
12.5 
Nausea/Vomiting ......................................................................................................................... 59 
12.6 
Management of Diarrhea ............................................................................................................. 60 
12.7 
Anticoagulants ............................................................................................................................. 60 
12.8 
Hypertension Guidelines .............................................................................................................. 60 
12.9 
CYP3A4 Inhibitors ...................................................................................................................... 61 
12.10 Surgery ......................................................................................................................................... 61 
12.11 Management of Pneumonitis ....................................................................................................... 61 
13.0 
CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE.................................. 61 
13.1 
Target Lesions .............................................................................................................................. 61 
13.2 
Non-target Lesions ....................................................................................................................... 62 
13.3 
Cytology and Histology ............................................................................................................... 63 
13.4 
Evaluation of Best Overall Response ........................................................................................... 63 
13.5 
Guidelines for Evaluation of Measurable Disease ....................................................................... 64 
13.6 
Confirmation Measurement/Duration of Response ..................................................................... 65 
14.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY ........................................ 66 
14.1 
Duration of Treatment .................................................................................................................. 66 
14.2 
Extraordinary Medical Circumstances ......................................................................................... 66 
15.0 
STATISTICAL CONSIDERATIONS .................................................................................. 66 
15.1 
Study Hypotheses ......................................................................................................................... 66 
15.2 
Primary Endpoint ......................................................................................................................... 66 
15.3 
Secondary Endpoints ................................................................................................................... 67 
15.4 
Interim Analysis ........................................................................................................................... 67 
15.5 
Exploratory Objectives ................................................................................................................ 68 
15.6 
Study Monitoring ......................................................................................................................... 68 

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16.0 
EXPEDITED ADVERSE EVENT REPORTING ............................................................... 68 
16.1 
Alliance A021202 Reporting Requirements ................................................................................ 69 
16.2 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Pazopanib (GW786034, 
NSC 737754) ............................................................................................................................ 71 
17.0 
REFERENCES ....................................................................................................................... 76 
APPENDIX I: 
COLLABORATIVE AGREEMENT PROVISIONS ............................................... 81 
APPENDIX II: DRUGS ASSOCIATED WITH QTC PROLONGATION ..................................... 83 
APPENDIX III: MEDICATION LOGS .............................................................................................. 85 
APPENDIX IV: REGISTRATION FATIGUE/UNISCALE ASSESSMENT .................................. 90 
APPENDIX V: QUALITY OF LIFE MEASURES ............................................................................ 92 
 
 

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Update #12 
1.0 
INTRODUCTION 
1.1 
Rationale for Selected Approach and Study Design 
Carcinoid tumors are relatively indolent, but treatment of advanced disease remains a challenge. 
Somatostatin analogs are routinely used to control hormone-mediated symptoms (carcinoid 
syndrome), but the identification of agents with anti-tumor efficacy has proven difficult.1, 2 Aside 
from octreotide for small bowel carcinoid, no treatment has proven anti-tumor activity.3 In the 
setting of liver-dominant disease, liver-directed treatment such as resection, ablation, and 
embolization are often employed. No standard chemotherapy exists, and the use of interferon is 
controversial. As such, additional therapeutic options are sorely needed. Advances in our 
understanding of the potential mechanisms underlying tumor progression have suggested several 
therapeutic targets (including the VEGF- and mTOR signaling pathways), but the precise role 
of targeted agents in carcinoid has not been established. (In contrast, everolimus and sunitinib 
are approved by the FDA for the treatment of patients with pancreatic NET). Progress in the 
field has been hampered by a number of factors, including the rarity of the disease, the 
heterogeneity that characterizes patients with the same diagnosis, and challenges related to 
interpreting the radiological response to treatment. 
Neuroendocrine tumors (NETs) are highly vascular and express VEGF as well as the VEGF 
receptor.4, 5 Yao et al. performed a randomized phase II study in which patients with advanced 
carcinoid received 18 weeks of bevacizumab or pegylated interferon alpha-2b. Up-front 
bevacizumab was associated with a higher response rate, reduction of tumor blood flow by 
functional CT, and improved progression-free survival at 18 wk compared to interferon.6 The 
results prompted initiation of an ongoing phase III trial in patients with high- risk/poor prognosis 
carcinoid (SWOG-0518) (accrual completed, results pending).   
Phase II studies with TKIs targeting the VEGF receptor, including sunitinib, sorafenib and 
pazopanib, have also suggested activity in NETs (pancreatic neuroendocrine tumors and 
carcinoid).7-9 Phase III data are lacking, however, with the exception of sunitinib, which 
improves PFS in patients with progressive pancreatic NET (median PFS 11.4 mo vs. 5.5 mo; 
HR 0.42, p<0.001).10 The activity of TKIs targeting the VEGFR in carcinoid is less convincing, 
perhaps because two studies evaluating these agents in metastatic carcinoid tumors have been 
terminated on interim analysis due to lack of objective radiographic response.9 In retrospect, 
while the likelihood of radiographic response is low with this class of agents in carcinoid, 
improved progression free survival appears very possible (based on 6 mo PFS data). 
Phase II trials with VEGFR TKIs: Carcinoid Population 
 
RR 
6 mo PFS 
Median PFS or TTP 
 
Sorafenib 
10% 
40% 
11.9 mo 
Hobday T et al. ASCO 2007 
Sunitinib 
2% 
73% 
10.2 mo 
Kulke M et al. JCO 2008 
Pazopanib 
0% 
68% 
12.0 mo 
Phan, et al. ASCO, 2010, 
Abstr#4001 
Pazopanib is an oral multitargeted receptor tyrosine kinase inhibitor with activity against 
VEGFR-2, and -3, PDGFR-alpha and beta, and stem cell factor receptor (c-KIT).11,12 It is a 
promising agent for treatment of metastatic carcinoid tumors because it’s spectrum of kinase 
inhibition matches receptor expression in carcinoid and other NETs.4,13,14 VEGF is upregulated 
in primary tumors, and in some studies expression correlates with angiogenesis and decreased 
progression-free survival.15 Terris et al reported that levels of VEGF are higher in midgut 
carcinoids compared to PNET.4 At least one group has shown that VEGF ligand/receptor 

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Update #12 
expression may be down-regulated in aggressive metastases.16 However, other groups have 
shown stable VEGF expression in metastatic disease. 17  
Over 5000 patients (in the context of >40 studies) have been treated with pazopanib since clinical 
development of the drug began in 2002. It has a relatively long half-life and is not extensively 
metabolized: unchanged pazopanib is the major circulating species in human plasma.  Pazopanib 
concentrations are affected by inducers and inhibitors of CYP3A4; renal clearance is minimal. 
Evidence for efficacy has been demonstrated in a phase III trial in renal cell carcinoma 
(VEGF10592, 435 pt, PFS 9.2 mo vs. 4.2 mo with placebo, HR 0.46, p<0.0000001). Pazopanib 
was generally well-tolerated. Most side effects were Gr 1/2, with the most common events (all 
grades) being diarrhea 52%, hypertension 40%, hair color changes 38%, nausea 26%, anorexia 
22%, and vomiting 21%. Grade 3/4 events occurred in 40% (vs. 20% in placebo) of patients 
(33% grade 3, 7% grade 4), with the most common events being ALT increase (7%), AST 
increase (5%), hypertension (4%) and diarrhea (4%). Of note, additional rare, but potentially 
clinically significant events have occurred in pazopanib trials, including: proteinuria, 
hypothyroidism, bleeding, GI perforation/fistula, arterial thromboembolic events, QT 
prolongation and Torsade de Pointe.  
Preliminary evidence for anti-tumor activity has been shown in several other solid tumors 
besides RCC.18-20 While pazopanib is capable of inducing tumor regression (e.g. 49% RR in 39 
patients with radioiodine-refractory metastatic differentiated thyroid cancers, 30% RR in the 
VEGF105192 randomized phase III trial in renal cell carcinoma), minor shrinkage is common, 
as is delayed tumor progression.18,20 Single arm phase II data suggest that pazopanib may slow 
disease progression without causing overt tumor regression in carcinoid.9 Recognizing that 
identification of agents that induce radiographic responses in carcinoid has proven exceedingly 
difficult, our hypothesis is that pazopanib will result in prolonged disease stability among 
patients with progressive advanced carcinoid tumors (and that this type of activity will be 
clinically meaningful).  Thus, in contrast to previous phase II studies with pazopanib and other 
VEGFR tyrosine kinase inhibitors, we will focus on progression-free survival as the primary 
trial endpoint (rather than response rate). Importantly, PFS is considered a valid endpoint in 
well-differentiated NET and was the basis for FDA approval of everolimus, as well as sunitinib, 
in PNET. 
Recent phase III data (see table below) from the RADIANT-2 study suggest a trend towards 
improved PFS in patients with progressive carcinoid treated with the mTOR pathway inhibitor, 
everolimus plus LAR.21 Importantly, while the RADIANT-2 data provide useful estimates of 
baseline progression-free survival for the patient population under study in this proposal, the 
results did not achieve statistical significance (according to pre-specified statistical plan for 
primary endpoint), thus the agent is not FDA approved for this indication. Consequently, there 
remain no proven agents for treatment of metastatic carcinoid tumors beyond somatostatin 
analogs, and the relative benefits of VEGFR TKIs compared to mTOR inhibitors in this patient 
population are not known. New treatments are desperately needed for patients with progressive 
disease.  
 
 

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Update #12 
RADIANT-2 phase III study in progressive carcinoid21 
 
Placebo 
Everolimus 
HR 
p-value 
Median PFS (central review) 1°Endpoint 
11.3 mo 
16.4 mo 
0.77 
0.026 
Estimated 12 mo PFS (central review) 
42% 
54% 
 
 
Median PFS (investigator-reported) 
8.6 mo 
12 mo 
0.78 
0.018 
Estimated 12 mo PFS (inv-reported) 
38% 
50% 
0.72 
 
1.2 
Trial Importance 
As noted above, there are no FDA-approved agents for treatment of metastatic carcinoid tumors 
beyond somatostatin analogs for the treatment of mid-gut carcinoids. New treatments are 
desperately needed for patients with progressive disease. Of note, the relative benefits of 
VEGFR TKIs compared to mTOR inhibitors in this patient population are not known. If SWOG-
0518 is negative, there will still be questions as to whether or not VEGF is a valid target for 
therapy, since bevacizumab is an antibody (not a small molecule) and the design (i.e. control 
arm interferon-treated) may confound the ability to see a true bevacizumab effect.  If SWOG-
0518 is positive, it will still be valuable to know if an oral, small molecule inhibitor of VEGFR 
has activity in this disease (and, if needed, our trial will be amended to stratify patients for prior 
exposure to bevacizumab). In short, whether or not SWOG-0518 is positive, evidence for 
activity in this study will provide strong support for a phase III study with pazopanib in carcinoid 
(e.g. bevacizumab vs. pazopanib, or pazopanib vs. placebo). If everolimus is used off-label for 
carcinoid, the optimal treatment of patients with everolimus-refractory disease will also be a 
valid question (and we can adjust for use of everolimus retrospectively). Thus the results of this 
study could lay the foundation for future trials in first line treatment of carcinoid. 
 
Table 1: Progression Free Survival Times in Selected Carcinoid Tumor Trials  
 
N 
Octreotide 
requirement 
Radiographic 
PD at entry? 
PFS (TTP) 
Reference 
Pazopanib 
Pazopanib + LAR 
20 
Stable dose x 2 mo 
required 
NO, but 85% 
had PD 
12.0 mo 
Phan et al. Proc ASCO, 
2010, abstr#4001 
Everolimus  
 
 
 
 
 
Ph II RAD001 
(Everolimus) 
+Octreotide LAR 
30 
63% (+) prior LAR 
NO 
14 mos. 
 
Yao JC, J Clin Oncol 
2008; 26: 4311-4318 
Ph III RAD+LAR 
vs. placebo +LAR 
(RADIANT-2) in 
patients with h/o 
carcinoid 
syndrome 
429 
80% prior SSTa; 
100% concurrent 
LAR 
YES (w/i 12 
mo) 
11.3 mo VS 16.4 mo 
(HR 0.77, p=0.0026) 
central rev (1°EP) 
8.6 mo VS 12 mo 
(HR 0.78, p=0.018); 
inv-reported 
o J, Yao, et al.  Journal of 
Clinical Oncology. 
2011;29 (Suppl 4; abstr 
159). 
 
Other VEGF pathway inhibitors 
Sorafenib 
42 
No 
No 
11.9 mos. 
Hobday T, Proc ASCO 
2007; A4504 (and personal 
commun.) 
Phase II 
Interferon/LAR VS 
Bevacizumab/LAR 
44 
 
Stable dose of  
LAR 
NO 
14 mo (63 wk) 
 
Yao, et al JCO, 2008 
Sunitinib (Phase II) 
 
41 
50% on Oct at 
entry 
NO 
10.2 mos. (TTP) 
Kulke et al. JCO 2008 

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Update #12 
 
Chemotherapy 
Phase II/III 
Strept/5-FU vs. 
Strept/DOX 
249 
 
? 
No 
5.3 mo vs. 
4.5 mo 
Sun, et al. J Clin Oncol, 2005 
Streptozocin/5-FU 
vs. 
Interferon 
64 
 
? 
Yes 
5.5 mos. vs. 
14.1 mos. 
Dahan, et al.  Endocr Relat 
Cancer, 2009 
Octreotide 
Phase III 
Octreotide vs. 
Placebo 
(PROMID) 
85 
 
Per protocol 
(OK if started <4 
wk) 
No 
14.3 mo vs. 
6.0 mo 
(by WHO) 
Rinke, et al.  2009. J Clin 
Onc 
 
Octreotide vs. 
Octreotide plus 
interferon (PNET 
plus carc) 
109 
 
Required on study 
YES (required 
for rand) 
(27% had SD at 6 mo 
in both groups) 
Arnold, et al. Clin Gast Hep, 
2005 
OTHER AGENTS 
Bortezomib 
(carc>PNET) 
? 
? 
NO 
3 mo 
Shah et al. Clin Can Res, 
2004 (CT q 12 wk) 
Endostatin 
22 
Allowed 
NO 
7.6 mo 
Kulke et al JCO, 2008 
Imatinib 
27 
? 
? 
5.9 mo 
Yao, et al Clin Cancer Res, 
2007 
Other pending carcinoid studies 
SWOG-0518 : 
BEV/OCT VS 
IFN/OCT 
 
283 
(to 
400) 
Prior OK; 20 mg q 
21d on study 
High risk 
(includes PD) 
Data 2012 
PFS 1°EP          (central 
review) 
Radiant-4 RAD001 
+ BSC vs. 
PLACEBO+BSC 
279 
Not Allowed 
YES (w/13mo) 
Non-functional 
NET of 
lung/GI origin 
OPEN 3/2012 
PFS 1°EP 
Other potentially relevant studies  (in PNET) 
Phase III in PNET: 
Sunitinib  VS 
Placebo 
(concurrent SSTa 
allowed—25% in 
both groups) 
171 
? 
Yes 
(w/i 12 mo) 
11.4 mo vs. 
5.5 mo; HR 0.42 (CI: 
0.26-0.66) 
( p<0.001) 
RR=9.3% sunit VS 
0% placebo 
6 mo PFS: 71.3% VS 
43.2% 
Raymond et al. NEJM, 
2011;364: 501-513. 
(1°EP-inv-reported PFS by 
RECIST) 
Phase III in PNET; 
RAD001/LAR VS 
Placebo/LAR 
(RADIANT-3) 
(about 50% prior 
SSta in both 
groups; concurrent 
SSta in about 40%) 
410 
Allowed w/i last 12 
mo IF prior PD on 
it 
YES 
(w/i 12 mo) 
11.0 mo 
4.6 mo 
(HR 0.35, CI=0.27-
0.45, p<0.001); 
PFS at 18 mo: 34% 
VS 9%;  RR 5% with 
rad, 2% placebo; 
11.4 vs. 5.4 mo, HR 
0.34 by central 
adjudicated review 
Yao et al. NEJM, 2011;364: 
514-23 
(1°EP inv-reported PFS by 
RECIST; excellent 
concordance with central and 
adjudicated central review) 
1.3 
Registration Quality of Life (QOL) Measurements 
QOL measurements of fatigue and overall perception of QOL are routinely included in Alliance 
studies and will be assessed upon registration in this study.  Evidence has arisen indicating that 
baseline single-item assessments of fatigue and overall QOL are strong prognostic indicators for 
survival in cancer patients, independent of performance status. This evidence was derived from 
two separate meta-analyses recently presented at ASCO, the first involving 23 NCCTG and 

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Update #12 
Mayo Clinic Cancer Center oncology clinical trials, the second involving 43 clinical trials. 
Routine inclusion of these measures should be considered similar to that of including 
performance status, either as stratification or prognostic covariates. 22  
1.4 
Inclusion of Women and Minorities 
This study will be available to all eligible patients, regardless of race, gender, or ethnic origin. 
There is no information currently available regarding differential effects of pazopanib treatment 
in subsets defined by race, gender, or ethnicity, and there is no reason to expect that such 
differences exist.  
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
1 
+ 
4 
= 
5 
Not Hispanic or Latino 
73 
+ 
87 
= 
160 
Ethnic Category: Total of all subjects 
74 
+ 
91 
= 
165 
Racial Category 
 
American Indian or Alaskan Native 
1 
+ 
0 
= 
1 
Asian 
0 
+ 
7 
= 
7 
Black or African American 
6 
+ 
8 
= 
14 
Native Hawaiian or other Pacific Islander 
0 
+ 
1 
= 
1 
White 
67 
+ 
75 
= 
142 
Racial Category: Total of all subjects 
74 
+ 
91 
= 
165 
2.0 
OBJECTIVES  
2.1 
Primary Objective 
For patients with progressive carcinoid tumors, progression-free survival (PFS defined by 
central review according to RECIST 1.1) will be compared between patients randomized to 
treatment with pazopanib versus placebo. 
2.2 
Secondary Objectives 
2.2.1 Overall Survival (OS) will be compared between treatment arms. 
2.2.2 Objective Response Rate duration of response, and time to treatment failure will be 
compared between treatment arms. 
2.2.3 Progression Free Survival (PFS) as assessed by central radiology review and local radiology 
review will be compared overall and within treatment arms. 
2.2.4 Safety and Tolerability of treatment with pazopanib/placebo will be evaluated within each 
treatment arm. 
2.2.5 PFS and other indicators of efficacy will be estimated in patients who crossover to pazopanib 
from placebo. 
2.2.6 To determine the turn-around time for timely adjudicated central review. 

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2.2.7 To characterize the nature of discordance between local and central radiology review in 
assessment of progression. 
2.2.8 To characterize the type and rate of progression in carcinoid (at study entry, on-study, and 
at progression). 
2.2.9 To develop new methods for modeling carcinoid growth and detecting treatment effects, 
and to perform simulations that advance new clinical trial designs to apply to future trials of 
carcinoid therapeutics. 
2.2.10 To assess for differences in QOL-related domains between the two treatment groups 
(pazopanib versus placebo) 
2.2.11 To determine if the more brief measures of QOL-related domains provide comparable 
information to that which is provided by the longer assessments (EORTC, NET21) 
2.2.12 To provide validation data for the EORTC NET21 module in terms of responsiveness over 
time and differences across arms. 
2.2.13 To determine whether components of the plasma Angiome panel that have been shown to 
be predictive previously (IL-6 and VEGF-D) are predictive of a therapeutic advantage for 
pazopanib treatment in baseline samples from the patients treated on A021202. 
2.2.14 To determine whether other components of the plasma Angiome panel tested (not IL-6 and 
VEGF-D) are predictive of a therapeutic advantage for pazopanib treatment in baseline 
samples from the patients treated on A021202. 
2.2.15 To evaluate the changes in the plasma Angiome markers after treatment with or without 
pazopanib over time. 
2.3 
Exploratory Objectives 
2.3.1 PFS at 6 months will be estimated within each treatment arm. 
2.3.2 Biochemical response (for chromogranin A, defined as a decrease of 50% or more in 
chromogranin A levels from baseline, and for 5-HIAA, defined as a decrease of 50% or 
more in urinary 5-HIAA levels from baseline) will be compared between treatment arms 
among patients with elevated baseline levels of CGA and 5-HIAA. 
3.0 
ON-STUDY GUIDELINES 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. All 
relevant medical and other considerations should be taken into account when deciding whether this 
protocol is appropriate for a particular patient. Physicians should consider the risks and benefits of 
any therapy, and therefore only enroll patients for whom this treatment is appropriate. Although they 
will not be considered formal eligibility (exclusion) criteria, physicians should recognize that the 
following may seriously increase the risk to the patient entering this protocol: 
• 
Psychiatric illness that impairs patient’s ability to give informed consent or comply with study 
procedures. 
• 
Medical condition such as uncontrolled infection (including HIV/AIDS/chronic hepatitis), or 
uncontrolled diabetes mellitus which, in the opinion of the treating physician, would make this 
protocol unreasonably hazardous for the patient and/or interfere with subject’s safety, provision 
of informed consent, or compliance to study procedures. 

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Update #12 
• 
Patients with a "currently active" second malignancy other than non-melanoma skin cancers. 
Patients are not considered to have a "currently active" malignancy if they have completed any 
necessary therapy and are considered by their physician to be at less than 30% risk of relapse. 
• 
Women and men of reproductive potential should agree to use an appropriate method of birth 
control throughout their participation in this study due to the teratogenic potential of the therapy 
utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, 
implantable hormonal contraceptives, or double barrier method (diaphragm plus condom).  
• 
Inability to swallow solid medications 
• 
Because pazopanib is metabolized by CYP3A4, inducers of CYP3A4 can decrease pazopanib 
exposure. The clinical significance of this, to date, is unknown. 
• 
Drugs that prolong the QTc interval should be avoided if possible. Pazopanib can prolong the 
QTc interval.  Drugs that are generally accepted to have a risk of causing Torsades de Pointes 
(See Appendix II) should be discontinued or replaced with drugs that do not carry this risk, if at 
all possible.  Patients who receive potential QTc-prolonging medications (See Appendix II) 
should be monitored closely. 
• 
For patients on anti-hypertensive medication at baseline: Concomitant use of pazopanib can alter 
exposure (increase or decrease) to anti-hypertensive medications. As such, investigators should 
consider replacing one medication with another in the same pharmacologic class that is less likely 
to interact with pazopanib.  If such a medication is discontinued and replaced, the transition 
period should occur no less than 7 days prior to the first dose of pazopanib. 
4.0 
ELIGIBILITY CRITERIA 
All questions regarding eligibility criteria should be directed to the Alliance Study Chair. Please note 
that the Study Chair cannot grant waivers to eligibility requirements. 
When calculating days of tests and measurements, the day a test or measurement is done is considered 
Day 0. Therefore, if a test were done on a Monday, the Monday four weeks later would be considered 
Day 28. 
4.1 
Documentation of Disease  
4.1.1 Histologic Documentation: Low- or intermediate-grade neuroendocrine carcinoma, 
including the following subtypes: carcinoid tumor, low- to intermediate-grade or well- to 
moderately-differentiated neuroendocrine carcinoma or tumor, atypical carcinoid tumor. 
Documentation from a primary tumor or metastatic site is sufficient. 
Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine 
carcinoma, adenocarcinoid tumor, or goblet cell carcinoid tumor are not eligible. 
4.1.2 Stage: Locally unresectable or metastatic carcinoid tumors. 
4.1.3 Tumor Site: Patients must have histologic documentation or clinical evidence of a carcinoid 
tumor of primary site (including foregut, midgut, hindgut or other non-pancreatic site). 
Tumors of unknown primary site are eligible provided the treating physician does not 
suspect medullary thyroid cancer, pancreatic neuroendocrine tumor, paraganglioma, or 
pheochromocytoma. 
Unknown primary tumors will be classified as small bowel tumors for the purpose of 
stratification.  
Functional (associated with a clinical syndrome) or nonfunctional tumors are allowed. 
Target lesions must have shown disease progression if therapy included peptide receptor 
radiotherapy (PRRT) and PRRT must be completed at least 8 weeks prior to registration. 

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4.1.4 Radiological Evidence: Radiological evidence for progressive disease (measureable or 
non-measurable) within 12 months prior to registration. Patients who have received anti-
tumor therapy during the past 12 months (including octreotide analogs) must have had 
radiological documentation of progression of disease while on or after receiving therapy. 
Baseline CT or MRI scan must meet imaging criteria in Section 6.2.2. 
4.1.5 No known endobronchial lesions and/or lesions infiltrating major pulmonary vessels 
that increase the risk of pulmonary hemorrhage. Patients with lesions infiltrating major 
pulmonary vessels (contiguous tumor and vessels) are excluded; however, the presence of a 
tumor that is touching, but not infiltrating (abutting) the vessels is acceptable (CT with 
contrast is strongly recommended to evaluate such lesions). 
Patients with large protruding endobronchial lesions in the main or lobar bronchi are 
excluded; however, endobronchial lesions in the segmented bronchi are allowed. 
4.2 
Measurable Disease 
Patients must have measurable Disease per RECIST 1.1 by computer tomography (CT) scan or 
MRI. Lesions must be accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 1 cm with CT or MRI (or ≥ 1.5 cm for lymph nodes). Index lesions for the purpose 
of RECIST 1.1 measurements will not be selected from within the radiation therapy treatment 
field. However, if there is evidence of disease progression within the radiation treatment field, 
measurement of the progressing lesions will be documented. 
4.3 
Prior Treatment 
4.3.1 No prior treatment with an inhibitor of VEGF or VEGFR. 
4.3.2 Prior treatment (somatostatin analogs excepted) must be completed at least 2 weeks prior 
to registration. In addition, prior treatment (somatostatin analogs excepted) must be 
completed at least 4 weeks prior to initiation of study drug. Treatment-related toxicities 
must have improved to ≤ grade 1 prior to registration, with the exception of alopecia. 
4.3.3 Concurrent use of somatostatin analogs (SSTa) is allowed, provided that the patient is 
on a stable dose for at least two months and progressive disease on somatostatin analog has 
been documented. 
Progression on octreotide is required for patients with tumors arising in the midgut. 
4.3.4 Prior treatment with embolization (including bland embolization, chemoembolization, 
and selective internal radiation therapy) or ablative therapies is allowed if measurable 
disease remains outside of the treated area or there is documented disease progression in a 
treated site. There is no limit on the prior number of procedures; prior liver-directed or other 
ablative treatment must be completed at least 8 weeks prior to registration. Index lesions for 
the purpose of RECIST 1.1 measurements will not be selected from within the radiation 
therapy treatment field. However, if there is evidence of disease progression within the 
radiation treatment field, measurement of the progressing lesions will be documented. 
4.3.5 Patients should have completed any major surgery ≥ 4 weeks prior to registration and 
must have completed any minor surgery ≥ 2 weeks prior to registration. Patients must 
have fully recovered from the procedure.  
• 
The following are examples of procedures considered to be minor: port placement, 
laparoscopy, thoracoscopy, bronchoscopy, mediastinoscopy, skin biopsies, incisional 

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Update #12 
biopsies, imaging-guided biopsy for diagnostic purposes, and dental extraction 
procedures. 
• 
Insertion of vascular access device, thoracentesis, paracentesis, and endoscopic 
ultrasonographic procedures are not considered to be major or minor surgeries. 
4.4 
Patient History 
4.4.1 No concurrent condition resulting in immune compromise, including chronic treatment 
with corticosteroids or other immunosuppressive agents. 
4.4.2 No clinical evidence of central nervous system (CNS) metastases (including 
carcinomatous meningitis) at baseline, with the exception of those patients who have 
previously-treated CNS metastases (surgery ± radiotherapy, radiosurgery, or gamma knife) 
and who meet both of the following criteria:  a) are asymptomatic and b) had no requirement 
for steroids or enzyme-inducing anticonvulsants within 6 months prior to registration. 
4.4.3 No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal 
abscess within 28 days prior to registration. 
4.4.4 No clinically significant gastrointestinal abnormalities that may increase the risk for 
gastrointestinal bleeding within 28 days prior to registration including, but not limited to:  
• 
Active peptic ulcer 
• 
Known endoluminal metastatic lesion(s) with history of bleeding. 
• 
Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s Disease), or other 
gastrointestinal conditions with increased risk of perforation. 
4.4.5 No history of serious (i.e., requiring active medical therapy with medication or medical 
device under the supervision of a physician) non-healing wound, ulcer, trauma, or bone 
fracture within 28 days prior to study entry. 
4.4.6 Patients with a history of hypertension must have blood pressure that is adequately 
controlled on antihypertensives. (< 140/90 mmHg).  
4.4.7 No symptomatic congestive heart failure (New York Heart Association Class II, III, or 
IV) within 6 months prior to registration. 
4.4.8 No arterial thrombotic events within 6 months of registration, including transient 
ischemic attack (TIA), cerebrovascular accident (CVA), peripheral arterial thrombus, 
myocardial infarction (MI), or unstable angina or angina requiring surgical or medical 
intervention in 6 months prior to registration. Patients with clinically significant peripheral 
artery disease (i.e., claudication on less than one block) are ineligible.  
Patients who have experienced a deep venous thrombosis or pulmonary embolus within 6 
months prior to registration must be on stable therapeutic anticoagulation for at least 6 weeks 
prior to enrollment of this study. 
4.4.9 Patients on therapeutic anticoagulation with low molecular weight heparins, 
fondaparinux, rivaroxaban or warfarin are eligible, provided that they are on a stable 
dose of anticoagulants.  
Patients who are currently receiving antiplatelet therapy of prasugrel or clopidogrel or 
antiaggregation agents (e.g., eptifibatide, epoprostenol, dipyridamole) or low doses of 
acetylsalicylic acid (up to 100 mg daily) are also eligible 

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Update #12 
4.4.10 No ongoing cardiac dysrhythmias, atrial fibrillation, or prolongation of corrected QTc 
interval to > 480 msec. 
4.4.11 No evidence of active bleeding, bleeding diathesis, or hemoptysis (≥ ½ teaspoon of red 
blood) within 8 weeks prior to registration. 
4.4.12 No currently unstable angina and/or uncontrolled cardiac arrhythmias. 
4.4.13 Patients with symptomatic peripheral vascular disease are ineligible. 
4.4.14 Ejection fraction on Echo or MUGA > 50%. 
4.5 
Concomitant Treatment 
Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this 
trial. Patients on strong CYP3A4 inhibitors must discontinue the drug 14 days prior to the start 
of study treatment. See Section 12.9 for more information. 
4.6 
Pregnancy/Nursing Status 
Women must not be pregnant or nursing. Women of child bearing potential must have a 
negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of 
HCG) within 72 hours prior to registration.  
Women of child-bearing potential include any female who has experienced menarche and who 
has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral 
oophorectomy) or is not postmenopausal [defined as amenorrhea ≥ 12 consecutive months; or 
women on hormone replacement therapy (HRT) with documented serum follicle stimulating 
hormone (FSH) level > 35 mIU/mL]. 
4.7 
Age and Performance Status 
4.7.1 Age ≥ 18 years of age 
4.7.2 ECOG Performance Status 0 – 1 
4.8 
Required Initial Laboratory Values: 
Granulocytes 
≥ 1,500/mcL  
Platelets 
≥ 100,000/mcL 
International normalized ratio (INR)* 
≤ 1.2 X ULN 
QTc 
≤ 480 msecs 
TSH**** 
WNL 
Bilirubin 
≤ 1.5 x ULN 
AST (SGOT) & ALT (SGPT) 
≤ 2.5 x ULN ** 
Serum Creatinine 
≤ 1.5 x ULN 
Urine Protein to Creatinine Ratio < 1, or, 24-hour urine protein < 1g*** 
* 
Only required for patients receiving anticoagulant therapy. Patients are eligible if their INR is stable 
and within the recommended range for the desired level of anticoagulation 
** 
Concomitant elevations in bilirubin and AST/ALT above 1.0 X ULN are NOT permitted. Also, if 
liver metastases are present, AST & ALT ≤ 5 x ULN is allowed 
*** 
If UPC ≥ 1, then a 24-hour urine protein must be assessed. Patients must have a 24-hour urine 
protein value < 1 g to be eligible. Use of urine dipstick for renal function assessment is not 
acceptable. 

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Update #12 
**** Medications for thyroid dysfunction are allowed as long as TSH is normal at registration. In 
patients with abnormal TSH, if the Free Thyroxine (Free T4) and Free Thyroxine Index (FTI) are 
normal and patient is clinically euthyroid, patient is eligible. 
5.0 
PATIENT REGISTRATION 
5.1 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e. clinical site staff 
requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). Documentation requirements per 
registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<https://ctep.cancer.gov/investigatorResources/default.htm>. For questions, please contact the 
RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 

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Update #12 
5.2 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory 
Office before they can be approved to enroll patients. Assignment of site registration status in 
the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRB Manager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office. In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
5.2.1 Downloading Site Registration Documents 
Site registration forms may be downloaded from the A021202 protocol page located on the 
CTSU members’ website. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS.  
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the NCTN - Alliance link to expand, then select trial protocol #A021202 
• 
Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided 
5.2.2 Requirements for A021202 Site Registration 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 

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Update #12 
5.2.3 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS.  
Regulatory Submission Portal: www.ctsu.org (members’ area) → Regulatory Tab                  
→ Regulatory Submission 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
     
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
5.2.4 Checking Your Site’s Registration Status 
You can verify your site registration status on the members’ section of the CTSU website.   
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol 
or the enrolling investigator’s status with the NCI or their affiliated networks. 
5.2.5 Credentialing 
See Section 6.2.1 for Institutional credentialing requirements for imaging.   
5.3 
Patient Registration Requirements 
• 
Informed consent: the patient must be aware of the neoplastic nature of his/her disease and 
willingly consent after being informed of the procedure to be followed, the experimental 
nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. 
Current human protection committee approval of this protocol and a consent form is 
required prior to patient consent and registration. 
• 
Patient completed booklets: Patient questionnaire booklets are to be ordered prior to the 
registration of any patients. Patient completed booklets can be ordered by downloading and 
completing the CTSU supply request form (located under the site registration documents 
section of the A021202 website) and faxing the form to the CTSU data operations center at 
1-888-691-8039. Samples of the booklets are found in Appendix V, which are to be used 
for reference and IRB submission only. They are not to be used for patient completion. 
 
 

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Update #12 
5.4 
Patient Registration/Randomization (Step 1) Procedures  
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available on a 24/7 basis. To access OPEN, the site 
user must have an active CTEP-IAM account (check at < https://ctepcore.nci.nih.gov/iam >) and 
a 'Registrar' role on either the LPO or participating organization roster. Registrars must hold a 
minimum of an AP registration type. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data, and, upon enrollment, initializes the patient in 
the Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the 
CTSU members’ side of the website at https://www.ctsu.org. To assign an IVR or NPIVR as the 
treating, crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer in 
OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used on 
the site’s IRB approval. 
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ side of 
the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional 
questions contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
Once the patient has been registered and randomized, the initial shipment of blinded 
pazopanib/placebo will arrive within 7-10 days. 
5.5 
Re-Registration (Step 2) at the Time of Progression  
Upon confirmation of progression by the Imaging Core Lab, patients may elect to be unblinded 
to their treatment assignment; see Section 11.2.5. Patients who were initially assigned to placebo 
will have the option to receive open-label pazopanib. 
Note: As of 03/14/2019, patients who were initially assigned to placebo were given the option 
to receive open-label pazopanib due to the release of study results.  
Re-registration should occur within 14 days of the CT or MRI scan documenting progression. 
• 
Women of child-bearing potential must have a negative pregnancy test within 72 hours 
prior to re-registration. 
 
Re-registration Procedures: 
OPEN may be accessed at https://open.ctsu.org, from the OPEN tab on the CTSU website at 
https://www.ctsu.org.  
To enroll a patient within OPEN, institution staff must have: 
1. A valid and active CTEP-IAM account (check at <https://ctepcore.nci.nih.gov/iam>). This 
is the same user ID and password used for CTSU’s website (for more information see 
https://www.ctsu.org/public/CTEP-IAM_Factsheet.pdf).  
2. Enrollment of patients on Alliance coordinated protocols requires a ‘Registrar’ role on either 
the LPO or participating organization roster. Registrars must hold a minimum of an AP 
registration type. Assignment of the ‘Registrar’ role for Alliance member sites is managed 

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Update #12 
through the Alliance Central Office via submission of a roster update form signed by the 
Principal Investigator of the member network. 
The OPEN system will provide the registering site with a printable confirmation of re-
registration. Please print the confirmation for your records. Further instructional information is 
provided on the CTSU members’ website 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.  
Once the patient has been re-registered and crossed over to the open-label portion of the study, 
the initial shipment of pazopanib will arrive within 7-10 days. 
5.6 
Registration to Correlative and Companion Studies 
5.6.1 Registration to Substudies Described in Section 10.0  
There is one substudy within Alliance A021202. This study must be offered to all patients 
enrolled on Alliance A021202 (although patients may opt not to participate). This substudy 
does not require separate IRB approval. The substudy included within Alliance A021202 is: 
• 
A021202-HO1: “Quality of Life Studies in Alliance A021202” 
If a patient answers “yes” to “I choose to take part in the Quality of Life Study.  I agree to 
fill out the Quality of Life Questionnaires,” (Question #1) in the Model Consent, s/he has 
consented to participate in the quality of life study described in Section 10.2. The patient 
should be registered to Alliance A021202-HO1 at the same time that s/he is registered to the 
treatment trial (A021202) Questionnaires should be submitted per Section 6.3.  
When ordering the booklets, the type of Patient Questionnaire must be specified:  
• 
Patient Questionnaire-Baseline, Prior to Cycle 4, and 12 months  
or  
• 
Patient Questionnaire-Cycle 1 (Weeks 1, 2, 3, and 4). 
5.7 
Stratification Factors 
5.7.1 Site of Primary 
a) Small Bowel (defined as tumors arising in the small bowel, cecum, appendix, or 
unknown primary site) 
b) Other 
5.7.2 Concurrent Somatostatin Analog 
a) Yes  
b) No 
6.0 
DATA SUBMISSION, SPECIMEN SUBMISSION AND IMAGING 
6.1 
Data Submission 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application to 
all persons with the appropriate roles assigned in Regulatory Support System (RSS). To access 
Rave via iMedidata, the site user must have an active CTEP-IAM account (check at < 
https://ctepcore.nci.nih.gov/iam >) and the appropriate Rave role (Rave CRA, Read-Only, CRA 
(Lab Admin, SLA or Site Investigator) on either the LPO or the participating organization roster 
at the enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a 

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minimum of an AP registration type. To hold the Rave Site Investigator role, the individual must 
be registered as an NPIVR or IVR. Associates can hold Read-Only roles in Rave. 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page. Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed. Trainings will be 
in the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in 
the upper right pane of the iMedidata screen.  
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 
1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
6.1.1 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 the trial using Medidata Rave. Additionally, certain adverse events 
must be reported in an expedited manner for more timely monitoring of patient safety and 
care. Section 16.0 provides information about expedited reporting. 
Common Terminology Criteria for Adverse Events: This study will utilize the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 for toxicity and adverse event 
reporting. However, CTCAE version 5.0 must be used for serious AE reporting through 
CTEP-AERS as of April 1, 2018; see Section 16.0. 
6.1.2 Routine Adverse Event Reporting 
Solicited Adverse Events: The following adverse events are considered “expected” and their 
presence/absence should be solicited, and severity graded, at baseline and for each cycle of 
treatment. 
• 
Alanine aminotransferase increased  
• 
Aspartate aminotransferase increased  
• 
Blood bilirubin increased  
• 
Diarrhea 
• 
Fatigue 
• 
Hair color change/hair depigmentation 
• 
Hypertension  
• 
Nausea  
• 
Neutrophil count decreased 
6.2 
Imaging Submission 
6.2.1 Institutional Credentialing Procedures for Imaging 
Prior to the enrollment of the first patient, the Alliance Imaging Core Laboratory (ICL) at 
the Ohio State University Medical Center must approve institutions to participate in the trial. 
For this purpose, participating sites need to submit the baseline CT (and/or MRI) imaging 

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Update #12 
data of the first subject to be enrolled to the ICL for a quality check. The ICL will provide 
a brief A021202 protocol refresher if needed, and if necessary followed with a virtual site 
visit, to the site to complete the protocol specific site credentialing process. Once sites are 
credentialed by the ICL, the first patient and future patients can be enrolled into this trial. 
The ICL does perform a quality review of the images, identifies any non-compliant exams 
that have protocol deviations and notifies sites of the results within 72 hours upon data 
receipt. 
6.2.2 Requirements for Participation 
CT Scan Requirements 
Optimal Technique: The requirements listed below are to be used for the multiphase CT 
scan of chest/abdomen/pelvis whenever possible. 
• 
Scanning mode: Helical 
• 
Patient position: Supine, arms up 
• 
Scan extent: Thoracic inlet through pubic symphysis 
• 
Scan time: Single breath-holding period, in full inspiration 
• 
Section thickness: 2.5 mm or less 
• 
Enhancement: Intravenous contrast unless contraindicated by allergy. 
• 
Reconstruction: Contiguous or overlapping sections; no gaps 
• 
Consistency: Same technique to be used between baseline and follow-up scans 
Minimum CT requirements are listed below. Note that a CT scan made as part of a PET-CT 
is acceptable if it meets these requirements. Any CT scan that does not meet these minimal 
requirements must be repeated. 
• 
Scanning mode: Helical 
• 
Patient position: Supine, arms up if possible 
• 
Scan extent: Thoracic inlet through pubic symphysis 
• 
Scan time: Single breath-holding period, in full inspiration 
• 
Section thickness: 5 mm or less 
• 
Enhancement: Required if not clinically contraindicated. 
• 
Reconstruction: Contiguous or overlapping sections; no gaps 
• 
Consistency: Same technique to be used between baseline and follow-up scans 
Note: For both optimal and minimum CT requirements, if contrast used at baseline 
scans but contraindicated at a restaging time point while on protocol therapy, scans 
obtained at all future restaging time points should be obtained with both contrast and 
non-contrast to maintain consistency. 
MRI Scan Requirements 
MRI may be performed instead of CT. It is of utmost importance that the same imaging 
modality be used at baseline and all subsequent follow up visits if clinically able. 
MRI should be performed with routine slice thickness generally not to exceed 5 mm. T1-
weighted, T2-weighted as well as pre- and post-dynamic contrast enhanced T1-weighted 
images should be obtained. The precise TR and TE values as well as other pulse sequence 
parameters can be determined based upon local site preferences. At subsequent time points, 
the same imaging technique and sequences should be consistently used unless the patient 

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Update #12 
can no longer receive IV contrast. Optimally, MRI should be performed of the abdomen and 
pelvis and if the chest needs to be scanned this should be done with non-contrast CT. 
If there is a need to switch imaging modalities, for example, from CT to MRI, then a best 
attempt should be made to account for differences in imaging techniques and care should be 
taken not to progress a patient because of a potentially more sensitive imaging test. 
6.2.3 Imaging Sub-study Data Submission 
The primary endpoint of progression-free survival will be based on the timely central review 
of local imaging. Sites will be asked to transfer imaging data sets, as well as the results of 
“local radiologic review” to the Alliance Imaging Core Lab (ICL) within 3 business days 
(See Imaging Correlative Study Section 10.1 below). Central review of these scans will be 
performed as described in Section 6.2.6 and adjudication will occur in the event that there 
is discordance between the central review and the local review. The adjudicated central 
review will be available to the treating physician within one week of submission to the ICL. 
The central review interpretation will determine whether or not progression has occurred. 
(In the case of discordance, patients will be treated on study until progression by adjudicated 
central review). Refer to Section 6.2.6 for specifics on real-time central review of submitted 
images. 
Adjudicated central review will be available to the treating site in RAVE within one week 
of submission. 
Average time to submission of scans to the ICL and average ICL “turn-around” times will 
be determined. Baseline scans will be submitted for timely review to confirm adequate 
quality (refer to Section 6.2.5); inadequate baseline scans (e.g. non-contrast CT scan) will 
require a repeat scan prior to enrollment.  
Scans that are deemed by the local interpretation to show stable disease, partial response or 
complete response may be batch shipped to the ICL, as these scans will not be read in real 
time. Batch shipment of these non-progression scans and their reports are to be submitted to 
the ICL within 6 months of their image acquisition. 
6.2.4 Images to be Submitted 
The following images will be collected digitally for centralized, real-time re-review: 
• 
Baseline (28 days prior to patient registration) 
• 
Time of Restaging (every 3 cycles after Cycle 1 Day 1) 
In addition, submission of scans taken within 12 months prior to study enrollment will 
be collected for central review (not necessarily in real time) to assess the type and rate of 
progression at study entry. These scans should be submitted within 60 days after registration 
of the patient. 
Patients that are crossed over to open label treatment should continue to submit restaging 
images to the ICL, with the same time frames for submission as blinded treatment patients 
(within 3 business days for a progression scan documenting progression or within 6 months 
for a non-progression scan). 
6.2.5 CT/MR Scan Submission Instructions  
All CT/MRI images will be collected digitally for archival purposes.  
The complete re-staging CT/MRI scans in digital DICOM format will be submitted to 
Alliance Imaging Core Laboratory within 3 business days once the image acquisition is 
completed at site. BMP files, JPG files, or hard copies (films) are not acceptable. The raw 

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Update #12 
data of the entire study should be saved until the scan is accepted by the Imaging Core 
Laboratory. The Imaging Core Lab will notify site and Alliance A021202 imaging 
committee within 2 business days of the data receipt as well as within 3 business days of 
the quality check report upon data receipt.  
Sites need to de-identify the patient data using institutional procedures to remove patient 
name and medical record number while preserving the Alliance patient ID number (e.g. 
112136) and protocol number (e.g., A021202), respectively.  
For baseline staging and pre-surgical restaging CT/MR scans, imaging data must be 
submitted to the Imaging Core Lab electronically via either Web-based data transfer or FTP 
data transfer approaches for timely central review purposes. For CT and/or MR scans at 
other time points, CD/DVD Shipment is acceptable. 
Web-based Data Transfer: 
Any PCs with Internet access can be used to upload images to the Imaging Core Lab via this 
approach. The standard Web access information will be provided separately through the 
specific trial e-mail Alliance021202@imagingcorelab.com, per the request by participating 
sites before their first data submission. 
FTP Transfer:  
Any FTP software can be used to upload images to the secure FTP Server of the Imaging 
Core Laboratory. The standard FTP access information will be provided separately through 
the specific trial e-mail Alliance021202@imagingcorelab.com, per the request by 
participating sites before their first data submission. 
Shipment/Mail Transfer: 
If the electronic data transfer approaches cannot be achieved at sites, the de-identified digital 
images in DICOM format can be burned to CDs, labeled with Alliance A021202 patient ID 
(e.g., 112136), date of study and study period (e.g., baseline, D22-28), and mailed to the 
Imaging Core Lab at: 
Alliance Imaging Core Lab 
Attn: Alliance A021202 
Wright Center of Innovation 
The Ohio State University 
Rm#414, 395 W. 12th Ave 
Columbus, Ohio, 43210 
Direct: (614) 293-2929 Office: (614) 293-2788  
Fax: (614) 293-9275 
Send 
an 
e-mail 
notification 
to 
inform 
the 
Imaging 
Core 
Lab 
at 
Alliance021202@imagingcorelab.com of the imaging data submission once the data 
transfer is completed. Any questions or problems about the data transfer to the Imaging Core 
Lab, call the Core Lab IT group at 614-293-2630 or 614-366-4932 for help. 
6.2.6 Real-time Imaging Central Review 
A real-time imaging central review will be performed by the A021202 imaging central 
review panel, if either one of the following events happen: 
1. Site determines the patient based upon local completion of the imaging 
endpoint CRF to be PD.  
Participating site needs to notify the ICL of local radiology assessment at the time 
of site determination of PD, and all imaging studies will be centrally reviewed to 
evaluate for efficacy on a per time point basis and to confirm the presence of PD. 

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Update #12 
2. Local site PI and/or local radiologist has questions about the appropriate 
interpretation of the scan. 
The Imaging Core Laboratory will contact the A021202 central review panel, within 24 
hours (except weekends and holidays) after images being received, for scheduling a real-
time remote review. The ICL notifies both the participating site and Alliance of the central 
review results within 24 hours after receiving the results from the central review panel. 
The overall turn-around time between imaging data receipt and central review results 
notification is within 24-72 hours after the imaging data receipt (except weekends and 
holidays). 
Central review results will be reported back to the site PI for further evaluation and 
determination of patient status. Under whichever events above, if participating site 
disagrees with the central review results, an adjudicator organized through the Imaging 
Core Lab will be involved, blindly review images, and determine with which interpretation 
(local or central) they agree. This process may take additional 24-72 hours turn-around 
time, and the adjudicator’s decision will be used as the final central review decision from 
the Imaging Committee through the Imaging Core Laboratory for the interpretation and 
response determinations.  
The final treatment decision is determined by the central review. If progressive disease is 
the final determination by the central review adjudication of the results, blinded treatment 
will be discontinued and the patient will be unblinded. If patient is found to be on placebo, 
patient will be offered to crossover to open-label pazopanib. 
Scans for patients on open-label pazopanib should be submitted to the ICL with the same 
submission schedule as with blinded therapy. If patient on open-label pazopanib is deemed 
to have progressive disease, the scan should be submitted to the ICL for real time central 
review of the scan. The process will follow the same procedure as described above for the 
double blinded portion of the study, including the adjudication process. Sites should also 
indicate to the ICL that the patient is on the open-label pazopanib treatment arm.  
For any such related questions, participating sites may directly contact the ICL instead of 
the central reviewer(s), via either the trial email at Alliance021202@ImagingCoreLab.com 
or call at (614) 293-2929. 
6.3 
Submission of Quality of Life Questionnaires 
 
Prior to 
treatment 
Weekly during 
cycle 1 
Prior to cycle 4 
At 1 year 
EORTC-QLQ 
X 
X 
X 
X 
NET21 
X 
X 
X 
X 
LASA 
X 
X 
X 
X 
 
 
 
 
 

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Update #12 
6.4 
Specimen Submission for Banking 
All participating institutions must ask patients for their consent to participate in the banking of 
their specimens for future correlative studies, although patient participation is optional. Potential 
uses for these samples are outlined in Sections 10.3 and 10.4 
 
 
During Blinded Therapy 
During Open Label Therapy 
 
 
 
Prior to 
Treatment 
Prior to  
Day 1 of 
Cycle 2 
At 
Progression* 
Prior to  
Day 1 of 
Cycle 2 
At 
Progression* 
At the End 
of Protocol 
Therapy* 
Ship to: 
EDTA Plasma1 
(lavender top) 
1 x 10 mL 
1 x 10 mL 
1 x 10 mL 
1 x 10 mL 
1 x 10 mL 
1 x 10 mL 
OSU 
Citrate 
Plasma1  (light 
blue top)  
3 x 2.7 mL 
or  
2 x 4.5 mL 
3 x 2.7 mL 
or 
2 x 4.5 mL 
3 x 2.7 mL  
or  
2 x 4.5 mL 
3 x 2.7 mL 
or 
2 x 4.5 mL 
3 x 2.7 mL  
or  
2 x 4.5 mL 
3 x 2.7 mL  
or  
2 x 4.5 mL 
OSU 
Whole Blood1,2 
(lavender top) 
1 x 10mL 
 
 
 
 
 
OSU 
* 
Patients for whom the end of treatment occurs within 28 days of documented progression do not 
need to have samples submitted twice at this time point. 
1 
To be banked for potential correlative science studies as noted in Sections 10.3 and 10.4. 
2 
Sample may be drawn at any time, although baseline (prior to treatment) is preferred 
6.4.1 
Specimen Registration and Tracking 
Use of the alliance biospecimen management system (BioMS) is mandatory and all 
specimens must be logged and shipped via this system.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials.  Authorized individuals may access BioMS at the following URL:  
http://bioms.allianceforclinicaltrialsinoncology.org using most standard web browsers 
(Safari, Firefox, Internet Explorer).  For information on using the BioMS system, please 
refer to the ‘Help’ links on the BioMS web page to access the on-line user manual, FAQs, 
and training videos.  To report technical problems, such as login issues or application errors, 
or for assistance in using the application, or questions or problems related to specific 
specimen logging, please contact: 855-55BIOMS. 
After logging collected specimens in BioMS, the system will create a shipping manifest.  
This shipping manifest must be printed and placed in the shipment container with the 
specimens. Instructions for the collection of samples are included below.  
6.4.2 Plasma Collection Procedures 
For EDTA plasma, collect 10 mL of peripheral venous blood in one lavender top tube 
(K2EDTA anti-coagulant) at baseline, after one cycle of treatment, and at the end of protocol 
therapy. Draw 1 x 10 mL of blood into lavender top vacutainer. Invert several times and 
centrifuge for 15 minutes at 2500 x g. Remove plasma and transfer to clean 10 mL tube. 
Repeat centrifuge at 2500 x g for 15 minutes. Aliquot 0.5 mL plasma into each cryovial. 
Label and freeze cryovials at –80°C. (If –80°C is not available, temporary storage at -20°C 
prior to shipment is acceptable.) Ship on dry ice to the Alliance Biorepository at Ohio State 
University (OSU) per Section 6.4.3. 
For citrate plasma, collect 10 mL of peripheral venous blood in 3 x 2.7 mL or 2 x 4.5 mL 
light blue top tubes (3.2% sodium citrate anti-coagulant) at baseline, after one cycle of 
treatment, and at the end of protocol therapy. Draw 3 x 2.7 mL or 2 x 4.5 mL of blood into 

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Update #12 
light blue top vacutainer. Invert several times and centrifuge for 15 minutes at 2500 x g. 
Remove plasma and transfer to clean 10 mL tube. Repeat centrifuge at 2500 x g for 15 
minutes. Aliquot 0.5 mL plasma into each cryovial. 
Label and freeze cryovials at –80°C. (If –80°C is not available, temporary storage at –20°C 
prior to shipment is acceptable.) Ship on dry ice to the Alliance Biorepository at Ohio State 
University (OSU). 
Label samples with the following identification: 
1) Procurement date 
2) Alliance patient number 
3) Alliance study number (i.e. A021202) 
4) EDTA plasma, citrated plasma or urine (as applicable). 
6.4.3 Whole Blood Collection Procedures 
For patients who consent to participate (on the addendum to the consent added with Update 
#05 to the protocol), whole blood samples will be used for future pharmacogenomic studies 
as noted in Section 10.4.  
Collect 10 mL of peripheral venous blood into EDTA (lavender) tube. The tubes should be 
inverted several times to mix the EDTA and refrigerated until shipped on cool pack by 
overnight mail to the Alliance PCO. The samples should be shipped the same day that the 
blood is drawn. 
6.4.4 Plasma and Whole Blood Labeling and Shipping Procedures 
Many of the biomarker assays are time-sensitive. Please process the samples as quickly as 
possible. For each plasma sample processed, please log the following information in the 
Specimen Tracking System: time sample was obtained (i.e. 9:04 am), time sample was 
frozen (i.e. 9:45 am). 
Plasma tubes and whole blood-containing tubes are to be labeled with the following 
information: 
1. Protocol number 
2. Alliance Patient ID 
3. Patient initials  
4. Sample Collection Date 
5. Sample Type (i.e. EDTA plasma, citrate plasma, whole blood) 
Plasma samples are to be delivered on dry ice by overnight delivery Monday through 
Thursday to the Alliance Biorepository at Ohio State University (see address below). The 
whole blood sample should be shipped to OSU the same day that it is drawn.  
Do not ship specimens on Friday or Saturday. Please be sure to use a method of shipping 
that is secure and traceable. Extreme heat precautions should be taken when necessary. All 
samples should be sent to the following address: 
Alliance Biorepository at Ohio State University 
The Ohio State University 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073 
Fax: 614-293-7967 

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Update #12 
7.0 
REQUIRED DATA 
Pre-Study Testing Intervals 
To be completed within 16 DAYS before registration: history and physical and all blood work, urine tests, ECG, and MUGA 
(with the exception of pregnancy testing, which is to be completed within 72 hours prior to protocol treatment). 
To be completed within 28 DAYS before registration: any X-ray, scan of any type, or ultrasound that is utilized for tumor 
measurements 
NOTE: Requirements for tests, observations, labs, and staging are the same during either the blinded or 
unblinded portions of the study. 
 
Prior to 
Registration 
Day 1 of 
Cycle 1* 
Day 1 every cycle 
after Cycle 1* 
Post Treatment 
Follow up** 
Tests & Observations 
 
 
 
 
Physical Examination (MD, PA or NP visit) 
X 
XA 
X 
X 
Pulse, Blood pressure 
X 
XA 
X 
 
Performance status 
X 
XA 
X 
X 
12-lead ECG 
B 
 
B 
 
Echo or MUGA 
X 
 
 
 
Medication Diary 
 
X 
X 
 
Fatigue/Uniscale Assessment 
G 
 
 
 
Drug Toxicity Assessment 
 
XA 
X 
 
Laboratory Studies 
 
 
 
 
CBC, Differential, Platelets 
X 
X 
X 
 
Creatinine, Mg, Phos 
X 
 
X 
 
Albumin, alk. phos. ALT, AST, bili, total protein 
X 
H 
H 
 
TSH 
X 
 
D 
 
UPC 
X 
X 
D 
 
Pregnancy test (Urine HCG) 
C 
 
 
 
PT/INR 
E 
E 
 
 
Chromogranin A^ 
X 
 
F 
 
24 hour urine 5HIAA (and additional tumor markers***) 
X 
 
F 
X 
Staging † 
 
 
 
 
CT abd/pelvis (with and w/o contrast) or MRI abdomen 
with contrast 
X 
 
F 
X 
CXR or CT chest 
X 
 
F 
X 
Correlative Studies‡ 
 
QOL measures 
See Section 6.3 
Citrate and EDTA Plasma, Whole Blood 
See Section 6.4 
* 
C1D1 of blinded and unblinded treatment. Pre-registration labs may be used for Day 1 of Cycle 1 tests if obtained within 
7 days prior to Day 1 of Cycle 1. For subsequent cycles, Day 1 required tests, observations and laboratory studies may 
be obtained within 72 hours prior to day of treatment. 
** 
For patients who discontinue study treatment prior to tumor progression, physical examination, performance status, and 
radiologic imaging studies should be performed every 12 weeks until tumor progression; radiologic imaging may be 
obtained +/- 10 days of the scheduled assessment date. After disease progression regardless of whether or not the patient 
is on open-label pazopanib, patients should be followed every 6 months for survival until 5 years after registration. 
*** Additional tumor markers are optional. If elevated at baseline, repeat at each disease reevaluation 
^ 
Plasma or serum chromogranin may be collected. Sample type must be maintained consistent throughout study 
† 
Multiphase CT scan (chest/abdomen/pelvis) is the preferred modality for imaging. Equivalent modalities (e.g. CXR and 
MRI scan of abdomen) may be used at the discretion of the investigator. Octreotide scan cannot be used for tumor 
measurements. See Section 6.2 for imaging requirements, including the requirement for submission of all disease 
assessment scans (i.e. PD and non-PD scans) to the ICL. Scan modalities must be kept consistent throughout study. 
‡ 
For those patients who have consented to these studies. 
A 
Also to be completed on Day 15 of the first cycle of blinded treatment as well as Day 15 of open label treatment. 
 
B 
Prior to initiation of protocol treatment then every 8 weeks. 
C 
For women of childbearing potential. To be completed within 72 hours prior to the initiation of protocol therapy. NOTE: 
Pregnancy test must be repeated prior to re-registration. 
D 
Every other cycle (C3, C5, C7, etc.). 
E 
Required only for patients on warfarin: PT/INR is required at baseline, then as clinically indicated. 
F 
Every 12 weeks +/- 10 days from the initiation of treatment regardless of treatment interruptions or holds. 24 hour urine 
5HIAA (and additional tumor markers) do not need to be repeated prior to initiation of unblinded treatment. 
G 
Within 21 days prior to registration. 
H 
Also to be completed on Day 15 of Cycle 1 and 2 of blinded and open label treatment 

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8.0 
TREATMENT PLAN 
This is a randomized, double-blind trial. Blinded, patient-specific clinical supplies of 
pazopanib/placebo will be requested by the Alliance Statistical Center at the time of randomization 
and should arrive at the clinical site within 7 to 10 days of randomization (see Section 11.2). Protocol 
treatment is to begin within 14 days of registration. Questions regarding treatment should be directed 
to the Alliance Study Chair. 
8.1 
Pazopanib/Placebo 
Patients will be instructed to take pazopanib/placebo 800 mg orally every day until disease 
progression or unacceptable toxicity. 
Pazopanib/placebo should be taken orally without food at least two hours after or one hour 
before a meal. The tablets should be swallowed whole and must not be crushed or broken. The 
time of day the tablets are taken should be relatively constant. 
CYP3A4 inducers may decrease plasma pazopanib concentrations. Please refer to the drug 
section for more information. 
For patients receiving concurrent somatostatin analog, the somatostatin analog should be 
continued at the current dose and schedule according to institutional practice. 
For patients receiving a medically necessary H2-receptor antagonist, pazopanib should be 
taken without food at least 2 hours before or at least 10 hours after a dose of the H2-receptor 
antagonist.  Pazopanib should be administered at least 1 hour before or 2 hours after 
administration of short-acting antacids. 
Central review of scans: After every staging scan, patients should continue protocol therapy 
until the results of the adjudicated central review are available. The results of the adjudicated 
review must be used by the treating physician if the patient is to remain on protocol treatment 
(see Section 10.1).  
8.2 
Disease Progression/Crossover to Open Label Treatment 
At the time of documented radiographic progression as determined by central review, patients 
may be unblinded (see Section 11.2). Patients who were receiving placebo may elect to 
crossover to treatment with pazopanib 800 mg orally every day. Patients must be re-registered 
to the crossover portion of the study per Section 5.5.  
Once the patient has been re-registered and crossed over to the open-label portion of the study, 
the initial shipment of pazopanib will arrive within 7-10 days. Patients should initiate open-label 
treatment within 28 days of the most recent CT or MRI scan documenting progression. Dose 
modifications for open-label therapy will proceed according to Section 9.0. 
Patients who discontinue protocol treatment for reasons other than progressive disease by central 
review (e.g. toxicity or progression by local read only) will not be eligible for crossover. 
Required tests should be collected per Section 7.0. Abnormal labs found on Cycle 1 Day 1 of 
open-label treatment are to be managed according to the dose modifications found in Section 
9.0. 
Central Review of Scans: Scans should continue to be submitted to the ICL as outlined in 
Section 6.2. Determination of progression will be done in real-time using the same procedures 
as the double-blinded portion of the study. After every staging scan, patients should continue 
protocol therapy until the results of the adjudicated central review are available. Once the patient 
has deemed to have progressive disease by the central review, protocol treatment will be 
discontinued and further treatment is at the discretion of the treating physician. See Section 6.2.6 
for further details. 

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Update #12 
9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
General rules for dose modifications: 
• 
Pazopanib/placebo will not be re-escalated once reduced. 
• 
If dose reduction below 400 mg/day is required or pazopanib/placebo is held > 3 weeks, 
pazopanib/placebo will be discontinued. 
• 
If more than one of these apply, use the most stringent (i.e. the greatest dose reduction). 
Dose level table for pazopanib 
Dose level 
Pazopanib/placebo 
0 
800 mg daily 
-1 
600 mg daily 
-2 
400 mg daily 
9.1 
Hematologic Toxicity 
For grade 3 ANC on Day 1 of a cycle: Delay pazopanib/placebo until toxicity resolves to ≤ 
grade 2, then resume pazopanib/placebo at the previous dose level. 
For grade 4 ANC on Day 1 of a cycle: Delay pazopanib/placebo until toxicity resolves to ≤ 
grade 2, then resume pazopanib/placebo with one dose level reduction. 
For grade 3 or 4 ANC decreased during a cycle interrupt pazopanib/placebo until ANC 
improves to ≤ grade 2, then resume pazopanib/placebo with one dose level reduction. 
Febrile neutropenia: Delay pazopanib/placebo until toxicity resolves and ANC ≤ grade 2, then 
resume pazopanib/placebo with one dose level reduction. 
For grade 3 or 4 thrombocytopenia: Delay pazopanib/placebo until platelets ≥ 100,000, then 
resume pazopanib/placebo with one dose level reduction. 
For grade 3 or 4 anemia: Delay pazopanib/placebo until toxicity resolves to ≤ grade 2, then 
resume pazopanib/placebo at the previous dose level. 
9.2 
Hepatic Toxicity 
For grade 2 ALT, AST, or bilirubin, continue pazopanib/placebo, but monitor weekly until 
ALT, AST, and bilirubin return to ≤ grade 1. 
For grade 3 or 4 ALT or AST or Bilirubin, delay pazopanib/placebo. Restart treatment with 
one dose level reduction of pazopanib/placebo when AST, ALT and bilirubin improve to ≤ grade 
1.  
For grade ≥ 2 ALT/AST AND concurrent grade ≥ 2 bilirubin, discontinue protocol therapy. 
For ≥ grade 3 hepatic failure, discontinue protocol therapy. 
For any AST/ALT elevation occurring in a patient receiving simvastatin, discontinue 
simvastatin and follow the appropriate dose modification for pazopanib. 
9.3 
Proteinuria 
For UPC Ratio < 2.0 or urine protein < 2 g/24 hours, continue same dose of 
pazopanib/placebo.  
For UPC Ratio ≥ 2.0 and < 3.0 or urine protein  2.0 g/24 hours and < 3.0, hold 
pazopanib/placebo until proteinuria resolves to UPC < 2.0 or urine protein < 2.0 g/24 hours. 
Once resolved, continue treatment at current dose level.  

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For UPC Ratio ≥ 3.0 and < 4.0 or urine protein ≥ 3.0 g/24 hours and < 4.0, hold 
pazopanib/placebo until proteinuria resolves to UPC < 2.0 or urine protein <2.0 g/24 hours. 
Once resolved, resume treatment with one dose level reduction.  
For UPC Ratio ≥ 4.0 or Nephrotic Syndrome: Discontinue pazopanib/placebo. 
9.4 
Nephrotoxicity 
For grade 2 creatinine increased, delay pazopanib/placebo until toxicity resolves to ≤ grade 
1, then resume pazopanib/placebo with one dose level reduction. 
For grade 3 or 4 creatinine increased, discontinue pazopanib/placebo. 
9.5 
Cardiac Toxicity 
For QTc interval > 500 msecs, check calcium, potassium, and magnesium levels and correct 
any abnormalities interrupt pazopanib and if possible, stop any medications that may prolong 
the QTc interval. Once QTc returns to ≤ 500 msecs, electrolyte abnormalities have been 
corrected, and any symptoms have resolved, resume pazopanib/placebo with one dose level 
reduction for all subsequent cycles. Remove patient from study if repeat ECG shows QTc 
interval >500 msec. 
9.6 
Thrombosis  
For grade 2 or 3 venous thrombosis requiring anticoagulation, interrupt pazopanib/placebo. If 
the planned duration of full dose anticoagulation is ≤ 2 weeks, omit pazopanib/placebo until 
anticoagulation is completed. If the planned duration of full dose anticoagulation is > 2 weeks, 
pazopanib/placebo may be restarted during anticoagulation if all of the following are met: 
• 
The patient must have an in-range INR (usually between 2 and 3) on a stable dose of 
warfarin or be on a stable dose of LMWH prior to restarting pazopanib/placebo. 
• 
The patient must not have any pathological condition that carries a high risk of bleeding. 
• 
The patient must not have had any hemorrhagic events while on study.  
For 
recurrent/worsening 
venous 
thromboembolic 
events 
after 
resumption 
of 
pazopanib/placebo, discontinue pazopanib/placebo. 
For grade 4 venous thromboembolic events, discontinue pazopanib/placebo.  
For arterial thromboembolic events (any grade) including cerebrovascular ischemia, cardiac 
ischemia/infarction, peripheral or visceral arterial ischemia, discontinue pazopanib/placebo.  
9.7 
Hypertension  
• 
If patients require a delay of greater than 3 weeks for management of hypertension, 
discontinue protocol therapy. 
• 
24 to 48 hours should elapse between modifications of anti-hypertensive therapy. 
• 
Treating physicians should avoid adding antihypertensive medications that are strong 
inducers or inhibitors of CYP3A4. 
9.7.1 Persistent Grade 2 Hypertension (Systolic 140-159, Diastolic 90-99) 
Recommend maximal medical management as described in Section 12.8. If BP is still not 
controlled after maximal medical management (see guidelines under Section 12.8), proceed 
with 1 dose level reduction. 

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Update #12 
NOTE: Stopping or reducing the dose of pazopanib/placebo is expected to cause a decrease 
in BP. The treating physician should monitor the patient for hypotension and adjust the 
number and dose of antihypertensive medication(s) accordingly. 
9.7.2 Persistent Grade 3 Hypertension (Systolic ≥ 160 Diastolic ≥ 100)  
Hold pazopanib/placebo until systolic BP ≤ 159 and diastolic BP ≤ 99. Once BP is controlled 
to this level, resume pazopanib/placebo at1 dose level reduction. HOWEVER, if the patient 
requires hospitalization for management of symptomatic systolic BP > 180 or diastolic BP 
> 110, permanently discontinue pazopanib/placebo. 
NOTE: Stopping or reducing the dose of pazopanib/placebo is expected to cause a decrease 
in BP. The treating physician should monitor the patient for hypotension and adjust the 
number and dose of antihypertensive medication(s) accordingly 
9.7.3 Grade 4 Hypertension (Life-threatening Consequences of Hypertension) 
Permanently discontinue pazopanib/placebo. Recommend optimal management with 
intensive IV support in ICU 
NOTE: Stopping or reducing the dose of pazopanib/placebo is expected to cause a decrease 
in BP. The treating physician should monitor the patient for hypotension and adjust the 
number and dose of antihypertensive medication(s) accordingly 
9.8 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) (see CTCAE v.4: Nervous 
System Disorders) 
For signs and symptoms suggestive of RPLS (e.g., confusion, headache, seizures, cortical 
blindness) interrupt pazopanib. Suspected RPLS should be investigated with MRI. If RPLS is 
confirmed, discontinue pazopanib/placebo.  
• 
If RPLS is ruled out via MRI, the decision to resume pazopanib/placebo should be based on 
the signs and symptoms: for grade 2 to 4 RPLS considered at least possibly related to 
pazopanib/placebo, discontinue pazopanib/placebo.   
9.9 
Hemorrhage 
For grade 2 CNS or pulmonary hemorrhage, discontinue pazopanib/placebo. For other 
grade 2 bleeding, hold pazopanib/placebo until resolved to ≤ grade 1; reduce dose to next lower 
dose level, and continue treatment. If grade 2 or greater hemorrhage/bleeding recurs following 
dose reduction, discontinue pazopanib/placebo.  
For any grade 3 or 4 hemorrhage, discontinue pazopanib/placebo.  
9.10 
Fistula, Perforations, Bowel Obstruction or Wound Dehiscence 
For any grade perforation of any organ, GI leak, or any fistula, discontinue pazopanib/placebo.  
For 
any 
grade 
bowel 
obstruction 
requiring 
medical 
intervention, 
interrupt 
pazopanib/placebo until obstruction resolves completely, then resume pazopanib/placebo at the 
previous dose. For obstruction requiring surgery interrupt pazopanib/placebo until full recovery 
from surgery, then resume pazopanib/placebo at the previous dose. If pazopanib/placebo is 
interrupted for > 21 days for bowel obstruction, discontinue pazopanib/placebo.  
For 
wound 
dehiscence 
requiring 
medical 
or 
surgical 
intervention 
discontinue 
pazopanib/placebo.  

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Update #12 
9.11 
Thyroid Dysfunction  
For grade 3 or 4 hyper-or hypothyroidism, discontinue pazopanib/placebo. 
9.12 
Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura (See CTCAE 
Blood and Lymphatic System Disorders) 
For any grade of hemolytic uremic syndrome (thrombotic microangiopathy) or thrombotic 
thrombocytopenic purpura, discontinue pazopanib/placebo. 
9.13 
Pneumonitis 
For grade 2 or 3 pneumonitis, interrupt pazopanib/placebo until ≤ grade 1. Resume 
pazopanib/placebo at one dose level reduction. 
For grade 4 pneumonitis, discontinue pazopanib/placebo. 
9.14 
Other Non-Hematologic Grade 3 or 4 Toxicity  
For other grade 3 or 4 non-hematologic toxicity not described above, (excluding nausea, 
vomiting, and diarrhea; unless refractory to anti-emetics and/or anti-diarrheals) and considered 
at least possibly related to treatment, interrupt pazopanib/placebo treatment until toxicity 
improves to ≤ grade 1, then resume treatment with one dose level reduction.  
For recurrent other non-hematologic grade 3 or 4 toxicity regardless of attribution, discontinue 
pazopanib/placebo. 
10.0 COMPANION STUDIES  
There is one mandatory substudy and one optional companion study for Alliance A021202. The 
mandatory substudy is comprised of the imaging study and is described in Section 10.1. Section 10.2 
describes the optional Quality of Life companion study (A021202-HO1). Section 10.3 and Section 
10.4 describe the potential uses of the optional banked biospecimens.  
10.1 
Imaging 
10.1.1 Study Design 
Turn-around Time for Central Review 
Radiographic studies will be performed 7-10 days before the next cycle of therapy begins 
and will be electronically transmitted to the Alliance ICL for expert, timely central review 
(PD images should be submitted within 3 business days, and, as of 03/15/2015 [i.e. the 
issuance of Update #05], at which time 112 patients had been accrued, non-PD images 
should be submitted in batches within 6 months; see Section 6.2.3). Dr. Nathan Hall will 
coordinate this effort given the ICL’s experience with timely central review (the logistics 
are already in place).  Baseline scans will be submitted for timely review to confirm adequate 
quality. The type of follow-up scan required will be specified in the imaging submission 
section of the protocol (see Section 6.2). The central review interpretation will determine 
whether or not progression has occurred. Results of the central radiology review (after 
adjudication, if necessary) will be provided to the local investigators. The central radiology 
review will determine progression and is the basis of the primary analysis. Average times to 
submission (and variability) of scans to the ICL and average ICL “turn-around” times will 
be determined. 
Assessment of Discordance between Local and Central Radiology Determination of 
Progression 
Discordance between the local radiology and central radiology reviews (PD; no PD) will be 
assessed at the time of the final analysis for the primary endpoint. Discordance will be 

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assessed at the time the first progression is determined by either local or central radiology 
review. Patients will continue to be followed on study until progression has been determined 
by (if necessary, adjudicated) central review. Once progression is determined by adjudicated 
central review, changes in therapy (including crossover from placebo to pazopanib) will be 
made at the discretion of the treating physician.   
Rate and Quality of Progression 
The definition of rate of progression is fully articulated in Section 10.1.5, and effectively it 
is the slope of the sum of the longest dimensions of RECIST target lesions over time. Scans 
up to 12 months prior to enrollment will also be reviewed centrally (not necessarily in real-
time) to assess type of progression at entry (RECIST or not), time period over which the 
progression occurred (< 3 mo, 3-6 mo, 6-9 mo, 9-12 mo, 12 mo or greater) and rate of 
progression at study entry. In addition, the nature of the progression will also be tracked 
(existing lesions vs. new lesions, single site vs. multiple sites, liver-only vs. extrahepatic).  
Analyses will be descriptive. 
10.1.2 Specific Hypothesis 
A) Timely expert central review can be performed within seven days in an Alliance-
sponsored clinical trial. 
B) Discordance between the local and central review interpretations is likely in a subgroup 
of carcinoid patients enrolled on this study.  
Carcinoid tumors are historically difficult to image radiographically.23 This characteristic, 
coupled with an inherent insensitivity to treatment, and the indolent nature of the disease 
profoundly limits our ability to develop new treatments for carcinoid. While targeted 
therapies hold much promise, recent data suggest that our inability to reliably assess 
response may limit our capacity to identify active agents (particularly those which are 
cytostatic in nature). RADIANT-2 was a randomized phase III trial of everolimus vs. 
placebo in carcinoid. 21 The primary endpoint of the study was PFS by central review, which 
was not performed in real time. Crossover at the time of progression was allowed in patients 
initially assigned to placebo. Discordance between investigator-reported response and that 
of the central review occurred in approximately 30% of cases. Adjudication was performed 
by an expert panel in the setting of discordance, however, the study design ultimately 
required the censoring of many patients in whom progression was declared prematurely by 
the investigator (relative to central review). This led to a loss of power for the primary 
endpoint (PFS by central review).  In the end, the study just missed meeting its primary 
endpoint and everolimus was not approved for the treatment of carcinoid. Several additional 
observations are worth noting: 1) consistent with the refractory nature of carcinoid, 
everolimus is less active in carcinoid than in PNET (HR 0.77 vs. HR 0.4 respectively), 2) 
discordance between investigator-reported response and central review may be a much 
bigger problem in the carcinoid than the PNET (discordance was minimal in the everolimus 
and sunitinib phase III studies in PNET).10, 24 In short, historically, carcinoid tumors have 
proven to be relatively refractory to chemotherapy, as well as targeted agents. As such, 
stability is a much more likely indicator of efficacy than shrinkage. Our ability to identify 
active agents, however, is limited by our ability to reliable assess these tumor 
radiographically, a problem which seems to be more of an issue in carcinoid, than in PNET.  
To date, no one has undertaken a careful analysis of the radiographic features of carcinoid, 
explored the causes underlying our inability to reliably image the disease, or made a serious 
attempt to identify potentially superior radiographic endpoints for assessing treatment 
activity. We plan to examine cases in which discordance occurs between central and 

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investigator-reported response in an effort to define the areas of disagreement (i.e., new sites 
of disease versus extent of progression at existing sites) and inform future trial design. 
C) The rate of progression is not constant in carcinoid.  
We anticipate that rate or type of progression may be a valuable endpoint in carcinoid. We 
also hypothesize that the type/rate of progression may vary between patients at the time of 
enrollment and that this may have an impact on response to therapy. As a result, we plan to 
characterize the type of progression at baseline (by RECIST or not, new sites of metastases 
and/or growth of existing lesions, progression in liver metastases vs. other sites). In addition, 
the rate of progression at baseline will be calculated; scans up to 12 months prior to 
enrollment will be reviewed centrally in order to assess the time period over which the 
progression occurred (< 3 mo, 3-6 mo, 6-9 mo, 9-12 mo, 12 mo or greater). This information 
will inform future trial design/eligibility criteria. Given the presence of preclinical data 
suggesting that VEGF inhibitors may change the biology of well-differentiated 
neuroendocrine tumors in the setting of evasive resistance, the type and rate of progression 
will also be assessed in pazopanib-treated patients and compared to controls.25, 26 Changes 
in rate of progression over time will be explored as a potentially novel endpoint (at study 
entry, after 3 months on study, and at study termination). The type of progression (growth 
of existing lesions vs. new lesions, liver vs. other sites) will also be characterized, and then 
treatment arms will be compared adjusting for the type of progression. Interestingly, similar 
issues have been identified in glioblastoma, in which the exact nature of bevacizumab effects 
has proven extremely difficult to define radiographically.27 In short, a critical review of the 
radiological effects of pazopanib in carcinoid is warranted. Note that the proposed imaging 
endpoints complement the correlative studies focused on pharmacogenetics and angiome 
profiling (both of which have the potential to lend insight into primary, as well as, evasive 
resistance). 
D) Novel metrics based on technical advancements in image analysis (tumor burden change 
and radiomic feature analysis at baseline and change analysis) and computational 
modeling of disease should improve evaluation of therapeutics for carcinoid.  
To categorize a continuous outcome (quantitative change in tumor burden) discards useful 
quantitative information and reduces statistical power to detect true differences in treatment 
effects.28, 29 One limitation on improving clinical trials with all solid tumors, but especially 
in carcinoid, is reliance on RECIST-based categorical assessment (CR, PR, PD, and SD). 
The use of continuous tumor measurements (CRF-captured RECIST) collected at multiple 
time points from each subject by means of quantitative disease-drug-trial modeling 
framework would be an efficient way to assess treatment effects in this indolent form of 
cancer.30 This placebo-controlled trial provides a unique opportunity to enhance the 
understanding of carcinoid growth trajectory with placebo and with pazopanib. We expect 
that pooling all available continuous tumor measurements from different subjects and using 
a quantitative modeling framework will help to develop a new biomarker that predicts 
overall survival and effect of treatment on overall survival accounting for subject-specific 
prognostic factors in a basic disease progression model. The biomarker-overall survival 
model, thus established, could be used to evaluate and inform efficient trial designs in the 
future for carcinoid by clinical trial simulations. Recently, there has been several published 
reports of continuous tumor progression modeling in non-small cell lung cancer, colorectal 
cancer, and renal cell carcinoma with demonstrated benefit of quantitative modeling for 
early decision making in drug development.31-33 
Tumor volume measurements have been especially informative of treatment effects in 
slower growing tumors such as tuberous sclerosis.34, 35 Alliance member investigators have 
been instrumental in developing new image analysis technology for semi-automated volume 

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Update #12 
measurement of liver lesions.36, 37 This provides an opportunity to fully investigate the 
potential for these quantitative measurements to augment detection of treatment effects in a 
slower progressing disease like carcinoid.38 To date, there are no reports of quantitative 
modeling of tumor volume measurements to assess disease progression and treatment effects 
specifically in carcinoid. In addition to quantitative modeling of CRF-captured RECIST 
tumor measurements, we also plan to develop a quantitative disease-drug framework for 
tumor volume measurements which could potentially lead to capturing slow progressive 
cancer in a more efficient manner with far-reaching implications for future carcinoid trial 
designs. 
10.1.3 Objectives 
10.1.3.1 To determine the turn-around time for timely adjudicated central review 
10.1.3.2 To characterize the nature of discordance between local and central radiology review 
in assessment of progression  
10.1.3.3 To characterize the type and rate of progression in carcinoid (at study entry, on-study, 
and at progression) 
10.1.3.4 To develop new methods for modeling carcinoid growth and detecting treatment 
effects, and to perform simulations that advance new clinical trial designs to apply to 
future trials of carcinoid therapeutics. 
10.1.4 Methods 
Radiographic studies (CT scans or MRIs) will be transmitted to the ICL in real-time (within 
3 business days of scan acquisition) via FTP (electronic) transfer. Pretreatment images 
should be available on up to 165 patients (Minimum 150 pt). There are two types of 
characterizations which are described as follows: 
1) Progression associated with study treatment: Although the study was originally 
designed to perform central reviews of disease status using RECIST v1.1 and in real 
time for all enrolled patients, it was later amended in Update #04 to focus the real-time 
review on only those suspected of having progression by local determination. 
Regardless, the remainder of the images (e.g. non-PD cases) will be reviewed 
throughout the course of the trial. Statistical analyses will take into account this trial 
modification. Progression associated with study treatment will be characterized in detail 
by the Expert Readers coordinated through the ICL and entered into the Rave database. 
Patients having PD based on deterioration of global health status (see Section 13.4) will 
be described separately, as clinical PD in the absence of radiographic PD cannot be 
assessed by the central reviewers. 
2) Rate of progression for up to 12 months prior to enrollment: The central reviewers will 
determine if the baseline scan is adequate and will characterize the type and rate of 
progression at baseline (reviewing scans up to 12 months prior to enrollment). The type 
of scans allowed for follow-up are defined in the protocol, as are the definition of 
progression (according to RECIST v1.1 for radiographic measures and new lesions). 
Submitted scans that indicate progressive disease will be reviewed centrally at the time 
of submission and the results of the central review will be documented. Progression at 
the time of enrollment will be characterized in detail by the Expert Readers coordinated 
through the ICL (rate and type of progression).  
The images received at the ICL have been coded with subject identifiers, but with all PHI 
removed, per the process described above in #1. They will then be transferred via secure 
FTP to Dr. Lawrence Schwartz, the Alliance Imaging Committee Chair, and designated 

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research radiologists at the Columbia University Image Analysis Lab. Designated research 
radiologists will identify target lesions and perform the semi-automated volumetric 
measures of carcinoid by a well standardized procedure.36 Measurements for each lesion for 
each subject ID on each CT/MRI study will be entered by ICL staff directly into the 
Medidata Rave® database. The Alliance Statistics and Data Center (SDC) A021202 
Statistician will prepare analysis datasets in conjunction with clinical/outcome data. The 
A021202 Statistician will then coordinate the analyses of the images specified in Section 
10.1 with the Alliance ICL and the A021202 Population Pharmacology and 
Pharmacogenomics Co-Chair, Dr. Michael Maitland, and designated computational analysis 
teams at the Inova Schar Cancer Institute and the University of Maryland. Analyses will be 
conducted using the analysis datasets used for the analysis of the clinical endpoints to ensure 
consistent data is reported for the primary and secondary endpoints (e.g. data associated 
with censoring, proper inclusion of crossover data, and data to be excluded in cases of 
consent withdrawals for follow-up and correlative studies). 
10.1.5 Statistical Considerations 
Turn-around Time for Central Review (Assessments Required for Registration and 
Treatment) 
Assessment of timely central review of scans for confirmation of progressive disease 
associated with study treatment (including the baseline scan taken within the 28 days prior 
to enrollment) will be based on the scan submission times and ICL turn-around times for 
results. The unit of analysis will be the scan. Average times from date of a scan to 
submission of the scan to the ICL (expected to be < 3 business days) and average time in 
the ICL (“turn-around” times; date of scan receipt at ICL to date scan results are returned; 
expected to be 7 days) will be computed. Average submission and turn-around times will be 
estimated among patients for whom scans indicating progression are submitted. Analyses 
will take into account the timing of the protocol modification requiring real-time reviews on 
patients having reported progression by the local site and subsequently not in real time (e.g. 
covariate for pre- versus post-Update #04 changing expectations of which reads were real-
time versus not real-time). One hundred fourteen (n=114) patients with progression are 
expected at the time of the final analysis. With 114 scans a difference between mean turn-
around times of 7 days (null hypothesis) and 9 days (alternative hypothesis) can be detected 
with 85% power (1-sided test of single exponential parameter, α=0.05). Differences in 
average turn-around times among the first group of 38 scans, second group of 38 scans, and 
third group of 38 scans will be explored.  
Discordance 
At the time of the final analysis, the proportion of images reporting progression by the local 
radiology and not confirmed by the central radiology review as PD will be estimated among 
all patients with progression based on the local radiology review. In each case, discordance 
will be assessed at the time the first progression is determined. One hundred fourteen 
patients (d=114) are expected to have progressed at the time of the final analysis. The 95% 
CI estimate will be computed for the discordant proportion. With progression data on 114 
patients the discordant proportion can be estimated to within at most +/- 0.092 with 95% 
confidence.  
Rate of Tumor Progression (Prior to Registration) 
The sum of the longest diameters of the target lesions (and new lesions, if observed) will be 
computed for each patient at each radiologic assessment (central radiology review). Rate of 
tumor progression will be measured by the slopes associated with the recorded tumor 
measurements at three time points: pre-study (prior to study enrollment based on scans from 

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the 12 month prior to study entry), on-study (baseline to 3 months after enrollment), time of 
progression (measurements at the time of progression and nearest prior). Pre-study scans up 
to 12 months prior to enrollment will be obtained and reviewed centrally to determine the 
pre-study rate.  Differences in the average rates of tumor progression between two treatment 
groups and across three time points will be explored using a two-way, fixed effects analysis 
of variance. No preliminary data are available for this study. The test of ‘no interaction’ 
between time point and treatment will be considered. Let the effect size for interaction be 
denoted by f=σx/σ, where σ denotes the common, within-population standard deviation and 
σx denotes the square root of the mean of the squared interaction effect values (xij=mij-mi.-
m.j+m, where i=2, j=3 and mij, mi., mj, and m denote the cell mean, the main effect means 
and the total population mean, respectively) for the 2 x 3 cells.  We expect at least 40 patients 
with data in each treatment group at all three time points (approximately 70% of 114 patients 
with progression at the final analysis). With this sample size at least 80% power is achieved 
to detect an effect size of f=0.20 (α=0.05).  Equal sample sizes within cells and independence 
across cells are assumed. Power will be greater due to repeated measures on the same patient 
at each time point. If no significant interaction is detected differences in mean tumor 
progression rates will be compared across the three time points and between the two 
treatment groups, respectively. Let the main effect size be denoted by f=σm/σ, where σ 
denotes the common, within-population standard deviation and σm denotes the standard 
deviation of the population means. Assuming that no interaction is observed, with data on 
at least 40 patients in each treatment group at all three time points:  for the comparison across 
time points (k=3), an effect size of f=0.20 can be detected with at least 80% power (α=0.05) 
and for the comparison between treatment arms (k=2), an effect size of f=0.20 can be 
detected with at least 88% power (α=0.05). Assuming maximum variability in the means, 
these effect sizes translate to ranges of standardized means of d=0.42 and d=0.53, 
respectively, considered to be “medium” effect sizes. The range of standardized means is 
defined as d=mmax-mmin/σ. Assuming maximum variability f=0.471d.39  
Tests of binomial proportions will be used to characterize the types of progression by 
treatment arm (e.g. existing lesions vs. new lesions, single site vs. multiple sites, liver-only 
vs. extrahepatic). With data on approximately 80 patients, 40 patients per treatment arm, 
differences in the proportions of patients with a given characteristic of 0.35 and 0.65, for 
treatment with and without pazopanib, can be detected with 0.86 power (2-sided α=0.1). 
Since only large differences are detectable these analyses will be considered exploratory. 
Disease-drug Modeling in Carcinoid 
The disease-drug modeling in carcinoid will be performed in two steps: 1) development and 
evaluation of the tumor measurement model, and 2) tumor – overall survival model 
development and evaluation. 
Tumor Model: The sum of the longest diameter of the target lesions obtained from CRF-
captured RECIST measurements and the tumor volume measurements available at pre-
study, on-study and time of progression for all subjects will be utilized to develop the tumor 
(size/volume) progression model. Disease-drug models will be developed separately for 
longitudinal tumor size or tumor volume measurements as dependent variables. The 
longitudinal tumor measurements will be analyzed by the non-linear mixed effects modeling 
technique using Phoenix NLME 1.3 software (Certara USA, Inc., Princeton, NJ, USA).  
Extensive graphical analysis and descriptive statistics of the tumor (size/volume) 
measurements will be used as a guide for the quantitative model building exercise and will 
be performed using R (R Foundation for Statistical Computing, Vienna, Austria) running 
under the R Studio interface (Free Software Foundation, Inc., Boston, MA, USA).  Different 
reported structural models, but not limited to, describing the tumor progression and tumor 

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shrinkage pertinent to carcinoid will be evaluated.40 The tumor shrinkage/drug effect 
parameter will reflect the effect of the treatment (placebo/pazopanib).  Since multiple tumor 
measurements will be available from each subject, both random between subject variability 
in tumor shrinkage and progression parameters and residual variability in tumor 
measurements will be estimated. The structural model describing the tumor progression will 
be chosen based on the standard goodness of fit plots (observed vs. predicted, conditional 
weighted residual vs. time and conditional weighted residual vs. predicted) and difference 
in Akaike information criteria (AIC). Subject-specific prognostic factors (covariates) that 
may influence the tumor (size/volume) model parameters will be investigated and the 
significance of prognostic factors will be determined by comparison of the AIC values. The 
independently developed final tumor (size/volume) model will be assessed by a set of 
diagnostics such as goodness of fit plots (described above), shrinkage in the parameter 
estimates, the precision of the parameter estimates and by comparing the precision of the 
estimates obtained by non-parametric bootstrap with the model based estimates. 
Since, to our knowledge, there has not been a quantitative analysis of the tumor size or 
volume in carcinoid, it is expected that the tumor measurement progression model might 
offer new insights in to the understanding of the disease progression in carcinoid.  Additional 
thorough explorations of relationship between tumor size and tumor volume in carcinoid 
will be performed as needed. 
Overall Survival Model: To determine the relationship between the tumor measurement 
(size/volume) and the time of death, the individual tumor model will be used to predict 
tumor measurements at relevant time points considered mechanistically plausible to be a 
predictor for overall survival in carcinoid. A parametric survival model (accelerated failure 
time model) will be considered to establish a quantitative link between different metrics of 
the tumor measurements (for ex: change from baseline at a given time [t], percent change 
from baseline at a given time [t]) and overall survival. Several widely used survival 
functions such as exponential, weibull, log-normal, etc. will be considered and model 
selection will be based on AIC differences and diagnostic plots.  The tumor-overall survival 
model will be adjusted for subject specific covariates. The final tumor-survival model will 
be thoroughly evaluated by means of simulations and comparing the simulated data with 
observed overall survival data. 
Finally, we will utilize the developed and evaluated tumor (size/volume) model and tumor-
overall survival model to explore scenarios pertaining to different treatment effects and trial 
design considerations that can be applied to inform future trials of carcinoid therapeutics. 
10.2 
Quality of Life (A021202-HO1) 
10.2.1 Study Design 
The aim of the correlative study is to assess the effects of pazopanib 800 mg p.o. daily on 
quality of life, sexual function, bowel function and recovery parameters. Measures of quality 
of life are relevant here because patients with carcinoid/neuroendocrine tumours are 
relatively young, making family, social and financial issues important, including sexual 
function.41 Much attention has been paid to the flushing and diarrhea symptom expression 
among NET patients, but data on the impact of the disease, these symptoms, and the 
treatment on overall QOL and other specific aspects is lacking. While some work has been 
done in this area42 (Froid, 2007), there are challenges remaining with the assessment of QOL 
in this patient population (carcinoid tumors). 
There is not a measure to assess QOL-related domains specifically for carcinoid tumors: 
The recent literature reviews indicate that the most common approach has been to use 
generic measures such as the EORTC-QLQ-C30, with some supplementation for specific 

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domains. The evidence to date indicates that while QOL issues in this population are 
considerable42, the assessment of these disease-specific issues has suffered by a lack of 
specificity among the measures.43 In a 2010 presentation at ASCO, Beaumont indicated that 
NET patients did express deficits in various QOL domains that could be detected by general 
measures but was in need of supplementary specific domain assessment.44 A further 
example of this lack of sensitivity to NET-specific issues was evident in a study of 
sunitinib45 wherein a generic multi-item measure of fatigue (the FACIT-fatigue scale) failed 
to detect any change in fatigue despite differences in adverse event reporting. This is 
consistent with our own previous work within the NCCTG that demonstrated how a multi-
item measure was less sensitive in detecting fatigue than a single item measure, which we 
now use in all Alliance trials due to its prognostic implications for survival. In choosing 
measures for this study then, we have taken particular care to combine measures validated 
in previous work that can be used alongside developing measures specific for the key issues 
relevant to patients with carcinoid tumors. 
In particular, while extensively validated, the EORTC-QLQ-C30 does not contain issues 
specific to carcinoid disease. This has led the EORTC to develop a neuro-endocrine-specific 
QOL module. The EORTC has followed its usual careful and methodic approach to the 
development of the NET 21 over a period of close to a decade. The measure remains to be 
fully validated however and so we believe that the platform of this modest study is perfectly 
suited to provide key validation data to inform the design of future studies. We have been 
in contact with the EORTC (personal correspondence with Andrew Bottomley and Neil 
Aaronson) and they wholeheartedly support the application of their NET measure for this 
trial. Quality of life in this study hence will be evaluated using the EORTC-QLQ-C30 and 
NET12 questionnaires, the Linear Analog Self-Assessment items for general QOL and 
protocol-specific issues. 
The impact of the disease on patient function and quality of life (QOL) will be evaluated at 
registration. These data will serve as our baseline data. Subsequent assessments will be 
collected weekly for the first month, and thereafter at the three month and one year visits. 
This schedule of assessments is consistent with the sunitinib trial, although measures were 
collected weekly through the first four cycles of treatment, which we believe is excessive. 
These assessment time-points have been chosen to gather information on short and long-
term QOL-related deficits so that future interventions may be planned. The weekly 
assessments in the first month will capture acute QOL deficits, which may point us to 
interventions that could be incorporated into future procedures. The 3-month and 12-month 
time points are included to gain information about long term impact on QOL. Not only will 
we be able to compare these different impacts on QOL between these two treatments, we 
will be able to gain knowledge about potential interventions to improve QOL for patients in 
this population. 
A cross-comparison of instruments will be conducted, specifically to compare the single-
item indicators to the more lengthy and detailed multi-item instrumentation (the EORTC-
QLQ C30, NET21 and the LASA single-items). This is a core line of research that will allow 
the Alliance to plan efficient QOL assessments for future Alliance trials. Dr. Sloan has done 
considerable research in this area; demonstrating that in general cancer patient populations, 
there is merit to the use of simple, single-item assessments. Limited work has been done, 
however, in NET trials and assessment of quality of life is thought to be critical when using 
agents like pazopanib, which are considered to be cytostatic/palliative in nature. 
Regardless of whether the study is positive, in terms of observing impacts on QOL by the 
disease/treatment processes involved, valuable information will be obtained just as is the 
case for biologic endpoints, which are often little more than exploratory investigations. The 

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QOL science here, however, is based on a long and substantiated line of research within the 
NCCTG and now the Alliance cooperative group. If the study is positive, we expect the 
individual items in the EORTC measures to indicate differences over time and across 
treatment. We will not only be using the overall scale measures produced, we will also look 
at individual items. We expect that we will observe a subset of items that will be most useful 
to detecting the specific QOL-related impacts of treatment and disease, instead of an overall 
aggregated score as was used in the sunitinib study. Were the study to be negative, we would 
still be able to obtain comparative data on the relative amount of information that is to be 
gained from the general EORTC QLQ-C30, versus the NET21, versus the simple LASA 
items. Irrespective of the results, the study will provide vital validation data for the EORTC 
NET21 measure, as expressed by the EORTC leadership (personal communication: Andrew 
Bottomley). 
NOTE: QOL may be completed at any time during the day in the clinic, or they may be 
taken home by the patient for completion and then returned. 
10.2.2 Measures 
The European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 (EORTC QLQ-C30) is a 30-item questionnaire about patient 
ability to function (measured via five functional scales), symptoms related to the cancer and 
its treatment (via eight symptom scales/items), overall health and quality of life, and 
perceived financial impact of the cancer and its treatment.46 Each item is measured on a 1-4 
scale (1=not at all; 4=very much). Seven of nine scales had Cronbach’s alpha greater than 
0.70 and the test-retest reliability for all scales and one single item was 0.78 or higher.47 
These instruments are available in other languages upon request. 
The NET21 module is intended for use among patients with gastrointestinal-related 
neuroendocrine tumors, who vary in disease stage and treatments. The module comprises 
21 questions assessing disease symptoms, side effects of treatment, body image, disease-
related worries, social functioning, communication and sexuality. The measure is presently 
in phase IV validation testing as set out in the EORTC module development process, 
indicative that initial content and construct validity has been achieved, but that further data 
are needed to demonstrate responsiveness and discriminant validity. 
The Linear Analogue Self-Assessment (LASA) consists of 6 single-item numeric 
analogue scales. One item measures overall QOL while the five remaining items address the 
major domains of QOL (mental, physical, emotional, social, and spiritual well-being) on a 
scale of 0-10. LASA items such as these have been validated as general measures of global 
QOL dimensional constructs in numerous settings.48-52 The six items have been validated at 
the Mayo Clinic for use in cancer patients and have been successfully used in numerous 
clinical trials.53 Normative data for the LASA have recently been published so that the 
results of this trial can be compared relative to other patient populations.54, 55 
This instrument is available in English only. It may be administered to non-English speaking 
patients via an interpreter. 
10.2.3 Hypotheses 
A. There will be differences in QOL-related domains between the two treatment groups 
(pazopanib 800 mg p.o. daily versus placebo) in terms of the patients’ overall experience 
during the trial. 
B. The more brief measures of QOL-related domains will provide comparable information 
to what is provided by the longer assessments. 

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C. The NET21 module will demonstrate sensitivity across treatment arms for NET-specific 
domains 
10.2.4 Objectives 
10.2.4.1 To assess for differences in QOL-related domains between the two treatment groups 
(pazopanib versus placebo) 
10.2.4.2 To determine if the more brief measures of QOL-related domains provide comparable 
information to that which is provided by the longer assessments (EORTC, NET21) 
10.2.4.3 To provide validation data for the EORTC NET21 module in terms of responsiveness 
over time and differences across arms. 
10.2.5 Statistical Considerations 
For Objective 10.2.4.1 and 10.2.4.3, the AUC summary statistic will be calculated for each 
patient using the baseline and weeks 1-4 and at three months, and first year (12 month) data. 
AUC will be applied to all QOL endpoints. If a patient only provides baseline data, they will 
be excluded from the analysis. All QOL endpoints will be translated where appropriate onto 
a 0 – 100 point scale for comparability and ease of interpretability in the analysis phase.56-59 
Parametric procedures (e.g. t-tests) will be used unless there is evidence of non-normality 
via Shapiro Wilk testing 65, in which case non-parametric procedures (e.g. Wilcoxon tests) 
will be applied. 
Analysis of the AUC scores for the QOL endpoints will compare the average AUC for the 
Pazopanib 800 mg p.o. daily arm to the average AUC for the placebo arm using a single 
two-sample independent samples t-test. Confidence intervals will be constructed for mean 
reduction in total AUC score for the two arms. With the minimum expected sample size of 
150 (75 per treatment arm), this study will provide 86% power to detect a difference in the 
two groups in QOL endpoints of 0.5 standard deviations, a moderate effect size, using two-
sided test at level 0.05.  
For Objective 10.2.4.2, the EORTC-QLQ C30 and the LASA single-items will be compared 
via Bland-Altman procedures, which have been established as the preferred methodology to 
compare assessments intended to measure the same concept.60 Dr. Sloan’s QOL team has 
experience in applying these procedures in cancer clinical trials.61 
Supplementary analysis of QOL scores will involve t-tests and Wilcoxon procedures at each 
time point as well as a repeated measures analysis of variance (ANOVA) and general 
estimating equations (GEE) modeling using data from all time points.62 Models will include 
covariates of patient characteristics as well as treatment arm to perform a conditional 
analysis of treatment comparison in the presence of potentially confounding variables. 
Further analysis will involve an examination of the clinical significance for changes over 
time by calculating the percentage of patients on each arm that report an improvement of 
more than 10 points on the 0-100 point scale for any QOL endpoint. These percentages will 
be compared via chi-square testing. 
Correlative analyses will be done on QOL endpoints to determine the relationships between 
various QOL endpoints. Such correlations will be done at single data points such as baseline 
or months 3, 12, or 24. The extent of missing data will be explored for non-random 
influences.63 Sensitivity analysis will be performed using various simple imputation 
techniques for which Dr. Sloan’s QOL team has developed specific computer algorithms, 
to ensure results are not unduly influenced by the presence of missing data.64, 65 The impact 
of imputing will be examined using such methods as last-value-carried forward, nearest-
neighbor imputation, zero-value imputation, minimum-value imputation, maximum-value 

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imputation on the result of the primary analysis. The degree of variability in the results will 
allow for a calibration of the impact of the best and worst case scenarios in terms of patterns 
in the missing data on the stability of the analytical results. 
Analyses will be coordinated by the Alliance SDC A021202 Statistician using the analysis 
datasets used for the analysis of the clinical endpoints to ensure consistent data is reported 
for the primary and secondary endpoints (e.g. data associated with censoring, proper 
inclusion of crossover data, and data to be excluded in cases of consent withdrawals for 
follow-up and correlative studies).  
10.3 
Banked Blood Plasma Specimens for Circulating Angiogenic and Inflammatory Markers 
(“Angiome”) 
10.3.1 Background 
There is an urgent need to develop biomarkers that can guide the use of novel agents in 
patients and to better understand and overcome the mechanisms of resistance to these 
therapies. Previously, we developed a novel protein multiplex array (“Angiome”) to assess 
tumor inflammation and angiogenesis (see Table 1 below). We identified several biomarkers 
that were shown to be prognostic and/or predictive of benefit from anti-VEGF therapies in 
patients with colorectal, pancreatic, ovarian, and renal cancers. Potential predictive markers 
for bevacizumab include IL-6, SDF-1, VEGF-D, ANG-2, and HGF. 
Table 1: Plasma-based Marker Identification 
Soluble Angiogenic Factors 
Matrix-derived 
Factors 
Markers of 
Vascular 
Activation and 
Inflammation 
ANG-2 
VEGF-A 
BMP-9 
CD73 
bFGF 
VEGF-C 
OPN 
ICAM-1 
HGF 
VEGF-D 
TGFβ1 
IL-6 
PDGF-AA 
sVERGFR1 
TGFβ2 
IL-6R 
PDGF-BB 
sVEGFR2 
TGFβR3 
IL-6ST (GP130) 
PlGF 
sVEGFR3 
TIMP1 
SDF-1 
 
 
TSP2 
VCAM-1 
Previous multiplex analyses have identified IL-6 as a potential predictive biomarker 
of benefit from bevacizumab. IL-6 has been identified by our group as a strong candidate 
predictive biomarker for bevacizumab in CALGB 90206, a phase III study of IFN +/- 
bevacizumab in advanced renal cell cancer.66 Interestingly, high IL-6 was a negative 
prognostic factor but a strongly favorable predictive marker. Importantly, nearly identical 
prognostic and predictive effects for IL-6 were noted in the phase III study of pazopanib 
versus best supportive care in refractory renal cancer.67 Interestingly, this group employed 
the same multiplex technology (Aushon Biosystems) that we employed in our analysis of 
CALGB 90206. The CALGB 90206 study also found a predictive role for HGF that was IL-
6 dependent (i.e. a 3-way treatment interaction).66 The role of the IL-6-Jak-Stat axis is 
particularly intriguing given its role in tumor associated inflammation and anti-tumor 
immunity.68  

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We recently presented new data supporting IL-6 as a candidate predictor for bevacizumab 
in patients enrolled on the GOG-218 study.69 GOG-218 was a phase III, 3-arm, placebo-
controlled, randomized clinical trial evaluating the efficacy of concurrent and maintenance 
bevacizumab in women with advanced ovarian cancer. Our results demonstrate that IL-6 
levels are predictive for benefit from bevacizumab for both progression-free survival (PFS) 
and overall survival (OS) in ovarian cancer patients.69 For PFS: Q1 hazard ratio (HR) 0.87 
[95% CI 0.70-1.08]; Q2 HR 0.77 [95% CI 0.58–1.006]; Q3 HR 0.67 [95% CI 0.48–0.94]; 
and interaction p = 0.009. For OS: Q1 HR 1.07 [95% CI 0.84–1.37]; Q2 HR 0.92 [95% CI 
0.67–1.26]; Q3 HR 0.79 [95% CI 0.54–1.16]; and interaction p = 0.005. Additionally, IL-6 
was found to be highly prognostic for PFS (p = 1.97-4) and OS (p = 7.85-6). The data across 
all three studies are highly congruent and strongly suggest that IL-6 levels can predict for 
benefit or lack of benefit from bevacizumab in these patient populations. 
Previous multiplex analyses have identified VEGF-D, and markers of inflammation, 
as potential predictive biomarkers of benefit from bevacizumab. In addition to these 
studies in which IL-6 has been identified as a potential predictive biomarker, we have 
analyzed two other phase III studies of bevacizumab. CALGB 80303 was a randomized, 
double-blind, placebo-controlled study of standard of care gemcitabine +/- bevacizumab in 
patients with advanced or metastatic pancreatic cancer.70 Three statistically significant 
predictive markers were identified using Cox proportional hazards modeling: VEGF-D, 
ANG2, and SDF1.71 With respect to VEGF-D levels, we observed benefit from 
bevacizumab in the patients with low VEGF-D, while lack of benefit was observed in 
patients with high VEGF-D. Relatedly, our initial analysis of VEGF-related biomarkers for 
CALGB 80405 was just presented at ASCO 2016.72 Of the markers evaluated, we observed 
that low VEGF-D protein levels were predictive of PFS benefit. Patients with low baseline 
VEGF-D levels received greater benefit from bevacizumab (HR=1.70) than cetuximab 
(HR=0.92), uncorrected interaction p = 0.0097. This data in colon cancer is consistent with 
our biomarker analyses in pancreatic cancer (CALGB 80303). Finally, the ability of VEGF-
D to predict for benefit from bevacizumab is supported by the independent findings of the 
Australian 
GI 
Cancer 
Trials 
Group, 
who 
analyzed 
tissue 
VEGF-D 
by 
immunohistochemistry using archived FFPE tumor samples from the MAX trial.73 For many 
reasons, testing plasma VEGF-D by ELISA is likely to be far more convenient and 
reproducible than analysis of IHC in legacy FFPE samples, and analysis in blood also allows 
for serial monitoring during the course of treatment. Regardless, across all three trials, 
VEGF-D levels in the bottom quartile had the strongest predictive effect for benefit from 
bevacizumab. These consistent results support the role of VEGF-D as an alternate ligand for 
VEGFR2, a finding well described in preclinical systems.74, 75 Taken together, these data 
serve as proof of principle for the ability of multiplex protein arrays in general, and the 
Nixon Lab in particular, to identify profiles that can reliably select patients for targeted 
therapies. 
10.3.2 Objectives 
10.3.2.1 To determine whether components of the plasma Angiome panel that have been 
shown to be predictive previously (IL-6 and VEGF-D) are predictive of a therapeutic 
advantage for pazopanib treatment in baseline samples from the patients treated on 
A021202. 
10.3.2.2 To determine whether other components of the plasma Angiome panel tested (not IL-
6 and VEGF-D) are predictive of a therapeutic advantage for pazopanib treatment in 
baseline samples from the patients treated on A021202. 

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10.3.2.3 To evaluate the changes in the plasma Angiome markers after treatment with or 
without pazopanib over time. 
10.3.3 Methods 
Our laboratory serves as the Molecular Reference Laboratory for multiplex ELISAs within 
the NCTN cooperative group system. The laboratory is an SOP-driven, HIPAA-compliant 
laboratory, and it has quality control procedures in place for all aspects of sample handling, 
inventory management, assay conduct, and data storage. We also have extensive experience 
working with cooperative group sample repositories and statistical centers, having 
conducted similar analyses on several large, randomized phase III studies. All assays, 
whether custom ordered from a commercial vendor or developed internally, are quality 
assured for issues related to performance in cancer patient plasma, type of sample (EDTA 
plasma, citrate plasma, serum), and interference from related soluble receptors or ligands or 
any relevant antibody therapeutics.  
Blood samples (1 x 10 mL = 10 mL) will be obtained at various time points coinciding with 
patient visits for clinical assessments (both study arms: baseline, on-treatment, end of 
treatment, progression, withdrawal, or removal from study) from all patients enrolled in the 
clinical trial who consent for participation in correlative analyses. One 10 mL sample will 
be used for the analysis of plasma inflammatory factors.  
Plasma Protein Analyses: Double-spun platelet-poor plasma will be isolated from 10 mL 
of blood collected into lavender-topped (K2EDTA) tubes (BD Vacutainer, Catalog no. 
366643). Within one hour of the time the blood is drawn each sample will be spun at 2500 
x g for 15 min at 4°C, and the resulting plasma layer will be removed to a fresh 
polypropylene tube and respun in the same manner. The final double-spun plasma will be 
aliquoted into 1 mL volumes in screw-capped cryotubes, frozen, and stored at -80°C. Prior 
to analysis, all samples will be shipped frozen to the Phase I Biomarker Laboratory at Duke 
University, an Alliance Molecular Reference Laboratory directed by Andrew Nixon, PhD. 
The laboratory has quality control procedures in place to address many of the issues involved 
in clinical trials research including sample quantity, sample integrity, and sample 
heterogeneity and expertise in the utilizing ELISA technologies with clinical trials samples. 
Samples will be analyzed using multiplex ELISAs for the plasma angiome. 
10.3.4 Statistical Analyses 
The data collected from the samples, as described above, will be sent using encrypted secure 
spreadsheets to the Alliance SDC A021202 Statistician to prepare analysis datasets in 
conjunction with the clinical/outcome data. The A021202 Statistician will then coordinate 
the analyses with the A021202 Correlative Science Co-Chair, Dr. Andrew Nixon. Analyses 
will be conducted using the analysis dataset used for the analysis of the clinical endpoints 
to ensure consistent data is reported for the primary and secondary endpoints (e.g. data 
associated with censoring, proper inclusion of crossover data, and data to be excluded in 
cases of consent withdrawals for follow-up and correlative studies). 
Predictive and Prognostic Biomarker Analysis (See Section 10.3.2.1): Baseline protein 
levels of candidate biomarkers will be correlated with OS and PFS using multiplicative Cox 
proportional hazards models to test for interaction between marker expression level and 
treatment.76 Expression levels will be log-transformed and analyzed as continuous measures, 
ensuring normal distribution of the covariates used in the modeling. Model assumptions will 
be verified to assess the validity of the models and statistical tests.  
Prediction of Treatment Benefit: The two biomarkers of interest are IL-6 and VEGF-D, 
for the analysis of the interaction between each marker and treatment. We will assume that 

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approximately 150 of 171 (57% pazopanib, 43% pazopanib) cases will have viable samples 
and test results for this analysis. We will test the hypothesis of no interaction with treatment 
and for one marker, using a multivariate Cox Proportional Hazards model including 
covariates of treatment, marker level (dichotomous), and an interaction term. We may adjust 
each model further to account for other known prognostic factors. The significance level of 
each of these two statistical tests for the significance of a single marker (IL-6, VEGF-D) by 
treatment interaction will be adjusted using appropriate multiple testing methods. Interaction 
terms will be visualized using forest plots. As an additional visual tool, optimal cut points 
for expression levels will be determined and used to generate Kaplan-Meier plots for the 
dichotomized expression levels.77 We will conduct sensitivity analyses to assess the 
potential effects of outliers and influential data points on the results. 
The following tables represent the estimated power of each test of interaction between 
treatment and each marker (Table 1 IL-6 or Table 2 VEGF-D), individually, and assuming 
that we observe the targeted clinical hypotheses of observing a 14 month median PFS with 
pazopanib and 9 month median PFS in the placebo treated patients. Low versus High IL-6 
will be classified based on the median value observed IL-6 result from our sample.   
Similarly, Low versus High VEGF-D will be classified based on the VEGF-D value 
associated with the 1st quartile of our sample and the remaining 75% of patients will be 
classified as having high VEGF-D. 
As of March 31, 2018, we have observed a minimum follow-up of 75.5 months on all 
enrolled patients and assume that any of the estimated 150 patients having viable samples 
were possibly enrolled in the last few months of enrollment (i.e. we could observe 75.5 
months of follow-up). We further assumed 57% of 150 cases were enrolled to pazopanib, 
43% of 150 cases were enrolled to placebo, 50% of patients will have Low IL-6 (vs. High) 
and which is associated with improved PFS compared to patients having High IL-6, and that 
25% of patients will have Low VEGF-D (vs. High) and which is associated with improved 
PFS compared to High (75% of patients). 
 
Table 1. Estimated Power a of a Statistical Test for Interaction (IL-6 & Treatment) 
Lack of benefit,  
within HIGH IL-6 
Benefit,  
within LOW IL-6 
Estimated Power (%), when alpha =  
Median PFS 
Pazopanib 
Median 
PFS 
Placebo 
Median PFS 
Pazopanib 
Median 
PFS 
Placebo 
 
0.05c 
 
0.10 
 
0.15 
 
0.20 
 
0.25 
 
0.30 
9b 
5 
19 
13 
9 
16 
21 
26 
30 
34 
9 
4.5 
19 
13.5 
18 
28 
35 
41 
46 
51 
9 
4 
19 
14 
33 
46 
54 
60 
65 
69 
9 
3.5 
19 
14.5 
53 
66 
73 
78 
82 
84 
9 
3 
19 
15 
70 
80 
85 
89 
91 
93 
8 
4 
20 
14 
17 
27 
34 
40 
45 
49 
9 
4 
19 
14 
33 
45 
54 
60 
65 
69 
10 
4 
18 
14 
52 
64 
72 
77 
81 
84 
11 
4 
17 
14 
70 
80 
85 
88 
91 
93 
a) Using application located at https://stattools.crab.org/Calculators/interactionSurvivalColored.html 
b) In months, assuming no interaction (i.e. pazopanib median PFS=14 months, placebo median PFS=9 months) 
c) 2-sided test 
 

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Table 2. Estimated Power a of a Statistical Test for Interaction (VEGF-D & Treatment) 
Lack of benefit, 
within HIGH VEGF-D 
Benefit,  
within LOW  VEGF-D 
Estimated Power (%), when alpha =  
Median PFS 
Pazopanib 
Median 
PFS 
Placebo 
Median PFS 
Pazopanib 
Median 
PFS 
Placebo 
 
0.05c 
 
0.10 
 
0.15 
 
0.20 
 
0.25 
 
0.30 
9b 
5 
29 
21 
10 
17 
23 
28 
33 
37 
9 
4 
29 
24 
37 
49 
57 
64 
68 
72 
9 
3.5 
29 
25.5 
57 
69 
76 
80 
84 
86 
9 
3 
29 
27 
77 
85 
89 
92 
94 
95 
10 
8 
26 
12 
30 
42 
50 
56 
61 
66 
9 
8 
29 
12 
52 
64 
71 
76 
80 
83 
8 
8 
32 
12 
73 
82 
87 
90 
92 
94 
7 
8 
35 
12 
96 
98 
99 
99 
99 
100 
6 
8 
38 
12 
99 
100 
100 
100 
100 
100 
a) Using application located at https://stattools.crab.org/Calculators/interactionSurvivalColored.html 
b) In months, assuming no interaction (i.e. pazopanib median PFS=14 months, placebo median PFS=9 months) 
c) 2-sided test 
 
Biomarker Predictive (Not IL-6 & VEGF-D) (See Section 10.3.2.2): We will repeat the 
analysis described above for Objective 10.3.2.1 for the remaining biomarkers. 
Analysis of Changes in Markers Over Time (See Section 10.3.2.3): The characteristics of 
blood analytes will be investigated using a variety of measures. Baseline and on-treatment 
samples will be assessed. Coefficients of variation will be used to assess the dispersion of 
each marker. Pair-wise correlations among the analytes will be estimated using Kendall’s 
Tau. For additional visualization of these analytes, plots of dendrograms and/or heat maps 
with clustering relationships among the analytes will be presented. Descriptive statistics will 
also be presented. Summary statistics, including mean, standard deviation, and %CV, will 
be calculated for each marker for each time point. Linear mixed effect models will be used 
to examine inter- and intra-patient variability and trends.78 We will conduct sensitivity 
analyses to assess the potential effects of outliers and influential data points on the results. 
Box plots will be used to illustrate the variability of the markers over time.  
10.4 
Banked Whole Blood Sample 
Due to insufficient sample collection, the potential pharmacogenomic studies described below 
will not be performed as of Update #11. The whole blood samples collected for potential 
correlative science studies will remain in the Alliance Biorepository at The Ohio State 
University until a separate correlative science protocol has been reviewed and approved in 
accordance with National Clinical Trials Network (NCTN) policies. 
The current trial offers an excellent opportunity for pharmacogenetic research. The presence of 
a placebo arm ensures that the toxicity profile and overall efficacy is likely to be different in the 
individual arms. All patients enrolled in the accompanying randomized phase II study will be 
given the option to provide written informed consent for germline DNA analysis. A single blood 
sample (10 ml in a lavender top) will be collected at baseline (or any follow-up visit) for 
pharmacogenetic analysis. Germline DNA will be extracted using standard techniques and 
genetic testing appropriate to specific study questions will be performed. The concentration and 
quality of DNA will be quantified by ultraviolet spectroscopy.  

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All DNA samples and unprocessed blood will be frozen and will be banked at the Alliance 
Biorepository at Ohio State University until they are distributed to the appropriate laboratory for 
analysis. The typical yield of DNA from a 10ml blood sample is 100 ug (range of 80-150 ug).  
For the potential studies described below we will need up to 5 ug for both the candidate gene 
analysis as well as the whole genome analysis, leaving the majority of the sample stored at the 
Alliance Biorepository at Ohio State University and available for additional future genotyping 
projects.  In addition, plasma samples will be collected at baseline (prior to starting therapy), 
and after one cycle of treatment (cycle 2 day 1) according to standard protocol. 
All samples are being banked for future use. Below are description of potential studies using the 
banked specimens and the possible hypotheses, objectives and statistical considerations that 
would be involved in future studies. Once more information is available from the parent study, 
a separate and full pharmacogenomics study proposal providing more details of the background 
scientific hypothesis, research plan, assay methods for use of the biospecimens, and a complete 
statistical section will be submitted for review by the Correlative Science Committee at CTEP 
in accordance with the NCI policies for banked tissue specimens.  
10.4.1 Potential Hypothesis 
A. Germline variants in angiogenesis/tumor microenvironment- related genes may predict 
response to pazopanib in carcinoid patients  
Response to pazopanib monotherapy varies between patients, and up-front or secondary 
resistance is the rule. In carcinoid, the treatment effect is expected to be cytostatic rather 
than cytotoxic.  Thus, radiographic responses are likely to be rare, with transient disease 
stabilization the more likely indicator of “response”. To date, no predictive biomarkers have 
been validated.  A recent limited scope candidate functional polymorphism analysis 
identified several polymorphisms nominally associated with pazopanib treatment outcomes 
in a cohort of 397 patients with renal cell carcinoma.79  The SNP with the strongest 
association was rs1126647, encoding an A/T change in the 3’UTR of the gene encoding 
Interleukin-8, IL8.79  The same authors also reported an inferior PFS for the homozygous 
carriers of the minor allele TT (median PFS 27 weeks) compared with the homozygous 
carriers of the common allele AA (median PFS, 48 weeks, P = 0.009).  Notably, a proximal 
region of the 3’UTR has been demonstrated to regulate IL-8 expression via the micro RNA 
mir17/20.  The down-regulation of IL-8 expression in stromal cells via this mechanism is 
associated with reduced breast cancer cell migration and invasiveness.80 That this SNP has 
a putative functional mechanism by which the germline variant could affect response to 
therapy and that this SNP had the strongest association with PFS among many candidate 
SNPs and genes supports further study. 
B. Genotype/endophenotype associations are relevant to pazopanib therapy 
A challenge for use of genetic markers in predicting treatment outcomes in oncology is the 
myriad environmental, patient-specific, and tumor-specific factors that modify the 
genotype/ultimate clinical phenotype relationship.  In other fields of complex medical 
genetics, notably the heritability of schizophrenia-spectrum diseases, the concept of 
endophenotyping has been adopted to advance investigation and understanding of the 
complex relationships.81, 82 For developing predictors of tumor response to kinase inhibitors, 
the circulating protein sVEGFR2 has features consistent with an endophenotype worth 
intensive study.  Among cancer patients, those with greater declines in sVEGFR2 with 
exposure to the VEGFR2 inhibitor motesanib in thyroid cancer and pazopanib in non-small 
cell lung cancer were more likely to have tumor response to therapy.83, 84 The PET 
Committee Co-Chair for the study (in collaboration with the Genetics team from Glaxo 
SmithKline and collaborators within the Pharmacogenomics Research Network), Dr. 

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Maitland, has completed an investigation of the circulating protein, sVEGFR2 as an 
endophenotype for genome-wide study in non-cancer patient populations.  Those studies 
identified the missense polymorphism rs34231037 within the gene for VEGFR2, KDR, as 
a functional polymorphism affecting circulating concentrations of this marker.  Further 
study has revealed that carriers of the uncommon allele have greater declines with pazopanib 
exposure than non-carriers.  We expect to replicate this finding in this carcinoid study in the 
future proposal. Similarly, we plan to determine the association between the IL-8 
polymorphism associated with PFS in renal cell carcinoma patients with the pre-treatment 
and end-of-cycle-1 measurements of IL-8 in the carcinoid patients. 
C. Genome-wide association studies 
As a randomized trial with uniform assessment and follow-up especially for an uncommon 
disease like carcinoid this represents an important opportunity to better understand the 
relationships among germline genetic variation, disease, and treatment-response 
phenotypes.  In unusual and useful fashion, the therapeutic intervention in this trial is under 
evaluation in renal cell carcinoma patients with an accompanying genome-wide association 
study. A similar evaluation in this trial will provide the opportunity to detect disease-
independent effects of germline genetic variants of modest effect size through meta-analysis 
strategies on both disease response and adverse effect phenotypes.  At this time, the 
Population Pharmacology and Pharmacogenomics Committee of Alliance is conducting 
genome-wide analyses of previously completed CALGB trials using The Illumina 1M 
platform in collaboration with the RIKEN Center for Genomic Medicine. More than 
1,000,000 SNPs are simultaneously genotyped. In addition, there are 4,300 SNPs in regions 
of copy number variations (CNVs), thus allowing for the detection of CNVs as well. In 
addition, the Pharmacogenomics Research Network of NIGMS has begun to conduct 
genome-wide meta-analyses.  
10.4.2 Potential Objectives 
10.4.2.1 To determine whether biomarker associations discovered in other diseases 
treated with pazopanib have a consistent effect in carcinoid  
10.4.2.2 To investigate the association between the genotypes of rs1126647 and baseline 
IL-8 levels 
10.4.2.3 To investigate the association between the IL-8 SNP (rs1126647) and 
progression-free survival (PFS) 
10.4.2.4 To investigate the potential for a SNP by drug, and SNP by IL8 level interactions 
with respect to PFS  
10.4.2.5 To identify specific SNPs and/or copy number variations that are associated with 
the response to and toxicity associated with pazopanib therapy 
10.4.3 Potential Statistical Considerations 
Germline DNA will be extracted from peripheral blood using standard techniques. The 
primary objective for the proposed pharmacogenomic companion is to investigate the 
association between the genotypes of rs1126647 and baseline IL-8 levels. The primary 
analyses will be restricted to the European population. Evidence from a series of GWAS 
completed by the CALGB suggests that using a combination of self-reported race (white) 
and ethnicity (non-Hispanic) serves as a reasonable surrogate filter to identify a genetic 
European population.  The patient population selection can of course be refined using 
genome-wide SNP data. 

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This companion will be designed under the assumption that 150 patients will be randomized 
to the two arms of the clinical study.  It is expected that 85% of the patients will provide 
usable DNA along with consent to the pharmacogenomic analyses and that 85% will self-
report as non-Hispanic whites.  Thus, the expected sample size for the pharmacogenomic 
analyses will be n=108 (54 patients from each arm).  
The Jonkheere Terpstra test, at the two-sided, will be employed to the test the baseline IL-8 
level and genotype association. The analysis will be powered for an additive trend with T as 
the risk allele. The reported relative allele frequency by Xu et al (JCO 2011) for this SNP is 
0.43. The relative genotypic frequencies are assumed to follow Hardy-Weinberg based on 
this relative minor allele frequency.  The estimated mean and standard deviation of baseline 
IL-8 plasma levels in 10 patients provided data set by Maitland et al are 46 and 23 pg/ul 
respectively. We will assume that the mean level in the population is 46 pg/ul and is 
expressible as a mixture of normally distributed components with means m0, m0*R and 
m0*R^2 respectively. The mixture probabilities are 0.57^2, 2*0.43*0.57 and 0.43^2 
respectively. The standard deviation for each component is assumed to be 23 pg/ul. Under 
these assumptions, the minimum effect size detectable with a power of 0.8, at the two-sided 
0.05 level, is R=1.25 
As secondary objectives we will investigate the association between this SNP and 
progression-free survival (PFS), to validate the results reported by Xu et al (JCO 2011), and 
the association between baseline IL-8 level and PFS. The Cox score test will be employed 
to test the PFS by SNP association while the association between PFS and IL8 levels will 
be investigated using the Cox rank score test. We will also investigate if the change in IL-8 
levels from baseline is associated with this. 
As an exploratory objective, we will investigate the potential for a SNP by drug, and SNP 
by IL8 level interactions with respect to PFS within the framework of two-way 
multiplicative Cox models. 
In addition, we may use the DNA collected to consider other candidate SNPs or to conduct 
a GWAS to validate other or identify novel candidates, or, as next generation sequencing 
platforms become more cost effective, consider exome or whole-genome sequencing. 
All SNPs will be evaluated for deviation from Hardy-Weinberg.  In the absence of a 
hypothesized effect, the association analyses will be powered for allele dosing (i.e., additive) 
effects. To this end, the Cochran-Armitage test (for binary endpoints), Jonkheere-Terpstra 
test (for quantitative traits including biomarker or gene expressions in serum or tumor RNA) 
and the Cox score test (for censored time-to-event outcomes) will be used to quantify 
marginal associations.  Multivariable models, with molecular, clinical and demographic 
variables, will be constructed using conditional inference trees and random forests.  
As stated above, when sufficient information is available from this treatment study, a 
separate pharmacogenomics study proposal providing more details of the scientific 
hypothesis, research plan, assay methods for use of the biospecimens, and a complete 
statistical section will be submitted and reviewed by CTEP in accordance with the NCI 
policies for banked tissue specimens. 
 
 

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11.0 DRUG FORMULATION, AVAILABILITY, AND PREPARATION 
11.1 
Qualified Personnel 
Qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe disposal 
of chemotherapeutic agents in a self-contained, protective environment. 
11.2 
Pazopanib (GW786034) (NSC 737754)   
For more information, please refer to the Investigational Brochure for pazopanib. 
11.2.1 Availability 
Pazopanib (NSC 737754) and matching placebo will be provided free of charge by Novartis 
and distributed by the Pharmaceutical Management Branch (PMB), Cancer Therapy 
Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), 
National Cancer Institute (NCI). 
Pazopanib monohydrochloride (GW786034) (NSC 737754) and placebo will be supplied in 
induction-sealed bottles made of high-density polyethylene, have a white, plastic child-
resistant closures, and contain 34 tablets. Each tablet has an aqueous film-coating and 
contains either 200 mg or 0 mg of the pazopanib free base or placebo for pazopanib. The 
tablets are oval-shaped and white in color. Refer to the pazopanib IB for information 
regarding the physical and chemical properties of pazopanib. Tablet excipients include 
microcrystalline cellulose, povidone, sodium starch glycolate, and magnesium stearate. The 
film-coat consists of titanium dioxide, hypromellose, macrogol/polyethylene glycol 400, 
and polysorbate 80. 
Pazopanib open-label supplies will be provided in commercially labeled bottles. The 
commercial tablets are gray and debossed with “GS JT” on one side. In addition to the 
excipients listed above, the film-coat for commercially-labeled 200 mg tablets contains iron 
oxide black. 
Each blinded or open-label, patient-specific bottle will be labeled with: 
• 
Protocol Number (i.e., A021202) 
• 
Bottle Number (i.e., “Bottle 1 of 2”, “Bottle 2 of 2”, etc.) 
• 
Number of Tablets (i.e., “34 tablets” or “120 tablets”) 
• 
Patient ID Number (e.g., "999999") 
• 
Patient Initials (i.e., Last initial, First initial, Middle initial [e.g., “L, FM”]) 
• 
Agent Identification (i.e., “Pazopanib 200 mg or Placebo” or “Pazopanib 200 mg”) 
• 
A blank line for the pharmacist to enter the patient’s name 
• 
Administration Instructions (i.e., “Take __ tablets every day for 28 days.”) 
• 
Storage Instructions (i.e., “Store at Controlled Room Temperature between 20° 
and 25° C.”) 
• 
Emergency Contact Instructions 
• 
Julian Date 
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., 2009 = 09, 2010 = 10) and a day count (e.g., January 
1 = 001, December 31 = 365). For example, a bottle labeled and shipped on January 1, 2009 
would have a Julian date of ‘09001’ and a bottle labeled and shipped on December 31, 2010 
would have a Julian date of ‘10365’. The Julian Date – Order Number (e.g., 2014352-0003) 

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from the patient-specific label must be used as the “Lot No.” field on the NCI Agent 
Accountability Form (DARF), as it 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 pazopanib 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 240-276-6575 Monday through Friday between 8:30AM and 4:30PM 
Eastern Time or by emailing PMBAfterHours@mail.nih.gov anytime. 
11.2.2 Drug Orders, Transfers, Returns, and Accountability 
Drug Orders: 
BLINDED PHASE 
No blinded starter supplies will be available for this study. Blinded, patient-specific 
clinical supplies will be sent to the registering investigator at the time of randomization and 
should arrive within approximately 7 to 10 days. This randomization will be performed by 
the Alliance Statistics and Data Center. The assigned Alliance patient ID number must be 
recorded by the registering institution for proper bottle dispersion. Once a patient has been 
registered, the Alliance Statistics and Data Center will electronically transmit a clinical drug 
request for that patient to the PMB. This request will be entered and transmitted by the 
Alliance Statistics and Data Center the day the patient is registered and will be processed by 
the PMB the next business day and shipped the following business day. Shipments within 
the United States will be sent by FedEx Ground; shipments to Canada will be sent by FedEx 
(generally one to two day delivery). Shipments to United States sites can be expedited (i.e., 
receipt on Thursday in example above) by the provision of an express courier account name 
and number to the Alliance Statistics and Data Center at the time the patient is randomized. 
The initial request will be for 8 bottles - 34 tablets per bottle - [a 2 cycle (8 week) supply at 
a dose of 4 tablets given once daily] of pazopanib 200 mg or matching placebo. After 6 
weeks (two weeks before needed), sites may reorder an additional 8 bottles- 34 tablets per 
bottle - [a 2 cycle (8 week) supply at a dose of 4 tablets given once daily] of pazopanib 200 
mg or matching placebo using 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. The assigned patient ID number (e.g., "999999") and the patient initials (e.g., "L, 
FM") must be entered in the "Patient or Special Code" field. A separate order is required for 
each patient ID number (e.g., "999999") being ordered. All drug orders will be shipped 
directly to the physician responsible for treating the patient. 
UNBLINDED CROSSOVER PHASE (OPEN-LABEL) 
NOTE: Patients will not be able to obtain unblinded supplies until the patient has been 
unblinded (at progression) by following the unblinding procedures in Section 11.2.5 
AND a clinical drug request has been transmitted to the PMB. The patient ID number 
will NOT change for the crossover portion of the study. 
No open-label starter supplies will be available for this study. Open-label, patient-
specific clinical supplies will be sent to the registering investigator at the time of re-
registration and should arrive within approximately 7 to 10 days. This re-registration will 
be performed by the Alliance Statistics and Data Center. Once a patient has been re-
registered, the Alliance Statistics and Data Center will electronically transmit a clinical drug 
request for that patient to the PMB. This request will be entered and transmitted by the 

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Alliance Statistics and Data Center the day the patient is re-registered and will be processed 
by the PMB the next business day and shipped the following business day. Shipments within 
the United States will be sent by FedEx Ground, and shipments to Canada will be sent by 
FedEx (generally one to two day delivery). Shipments to United States sites can be expedited 
(i.e. receipt on Thursday in example above) by the provision of an express courier account 
name and number to the Alliance Statistics and Data Center at the time the patient is re-
registered. 
The initial request will be for 2 bottles – 120 tablets per bottle - [a 2 cycle (8 week) supply 
at a dose of 4 tablets given once daily] of pazopanib 200 mg. After 6 weeks (two weeks 
before needed), sites may reorder an additional 2 bottles – 120 tablets per bottle - [a 2 cycle 
(8 week) supply at a dose of 4 tablets given once daily] of pazopanib 200 mg using 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. The assigned patient ID number (e.g. "999999") and the patient initials (e.g. "L, 
FM") must be entered in the "Patient or Special Code" field. A separate order is required for 
each patient ID number (e.g. "999999") being ordered. All drug orders will be shipped 
directly to the physician responsible for treating the patient. 
Drug Transfers: Tablets 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 principal investigator at a 
given clinical site 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 240-276-
7893) a Transfer Investigational Agent Form available on the CTEP home page 
(http://ctep.cancer.gov) or by calling the PMB at 240-276-6575. The patient ID number (e.g. 
"99999"') and the patient initials (e.g. "L, FM") 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. "A021202"). 
Drug Returns: When it is necessary to return undispensed 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) or by calling 
the PMB at 240-276-6575. The patient ID number (e.g., "99999") and the patient initials 
(e.g., "L, FM") should be entered in the "Lot Number" field. 
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 Oral Investigational Agent Accountability Record available 
on the CTEP home page (http://ctep.cancer.gov) or by calling the PMB at 240-276-6575. A 
separate NCI Investigational Agent Accountability Record must be maintained for each 
patient ID number (e.g., "99999") and each Phase (Blinded and Unblinded Crossover) on 
this protocol. Please note that a new Oral Agent Accountability Record must be started when 
patients transition from the 34 count bottle of blinded supplies to the 120 count bottle. The 
Julian Date – Order Number (e.g., 2014352-0003) from the patient-specific label must be 
used as the Lot number on the NCI DARF. 
Investigator Brochure Availability: The current versions of the IBs for the agents will be 
accessible to site investigators and research staff through the PMB Online Agent Order 
Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP 
Identity and Access Management (IAM) account, and the maintenance of an “active” 

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account status and a “current” password. Questions about IB access may be directed to the 
PMB IB coordinator via email. 
Useful Links and Contacts: 
• 
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration: PMBRegPend@ctep.nci.nih.gov 
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
• 
PMB Online Agent Order Processing (OAOP) application: 
https://eappsctep.nci.nih.gov/OAOP/pages/login.jspx 
• 
CTEP Identity and Access Management (IAM) account: 
https://eappsctep.nci.nih.gov/iam/ 
• 
CTEP Associate Registration and IAM account help: 
ctepreghelp@ctep.nci.nih.gov 
• 
PMB email: PMBAfterHours@mail.nih.gov 
• 
PMB phone and hours of service: 240-276-6575 Monday through Friday between 
8:30AM and 4:30PM Eastern Time 
• 
IB Coordinator: IBCoordinator@mail.nih.gov 
11.2.3 Storage and Stability 
Store tablets at USP controlled room temperature (20° to 25° C or 68° to 77° F). 
Stability studies are ongoing. An opened original container of tablets is stable for 3 months. 
If exact quantity must be dispensed, then extra tablets must be removed, documented and 
destroyed immediately. Alternatively, if exact quantity is dispensed in a pharmacy bottle, 
the supply should be assigned a 30-day expiration. If tablets of a patient-specific/blinded 
supply are dispensed in a pharmacy bottle, all of the information on the CTEP applied 
label (including the Julian Date) MUST be on the bottle dispensed to the patient. 
11.2.4 Administration 
Oral pazopanib/placebo should be taken on an empty stomach either 1 hour before or 2 hours 
after meals. The tablets should be swallowed whole and cannot be crushed or broken. 
Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-
fold increase in area under the plasma drug concentration curve (AUC) and maximum 
observed plasma drug concentration (Cmax). 
If a dose is missed, the patient should take the dose as soon as possible, but only if there are 
12 or more hours remaining before the next dose is due.  If the next dose is due in less than 
12 hours, the patient should skip the missed dose and take the next dose as scheduled. 
If vomiting occurs after taking pazopanib/placebo, the patient should not take a replacement 
dose on that day.  The patient should resume taking pazopanib/placebo at the next scheduled 
dose on the following day.  If vomiting persists, the patient should be instructed to notify 
the investigator. 
11.2.5 Unblinding Procedures  
Emergency unblinding will be available 24 hours a day, every day, according to the criteria 
below. 

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Unblinding can be done in the event of an emergency or at progression. Please note that, if 
treatment is unblinded due to an emergency, the patient must permanently discontinue all 
protocol therapy. 
Emergency Unblinding Procedures: 
Examples of emergencies include 1) a life-threatening unexpected adverse event that is at 
least possibly related to the investigational agent and for which unblinding would influence 
treatment decisions; or 2) medication error, such as accidental overdose. Expected adverse 
events are listed in the “Toxicities” section below.  
 
Contact the Alliance Executive Office on call by calling 773-702-6800, pressing 1 to speak 
with an operator, and then asking for pager ID 8625 to return the call.  
The institution must provide the following information to the Alliance Executive Officer: 
• 
Alliance study ID (i.e., “A021202”) 
• 
Alliance patient ID number (e.g., “999999”) 
• 
Patient initials (e.g., “L, FM”) 
• 
Institution name 
• 
Name and telephone number of treating physician 
• 
Name and contact information of person requesting the unblinding procedure 
• 
Name and contact information of person to inform of treatment assignment 
• 
Reason for emergency unblinding 
Please remember that emergency unblinding request may be authorized only by an Alliance 
Executive Officer, and emergency unblinding applies only if unblinding would influence 
management of the medical situation. 
After the Executive Officer deems unblinding is warranted, the treatment assignment will 
be provided to the contact person at the treating site. 
Unblinding Procedures upon Progression: 
Study participants can be unblinded upon progression. To receive patient treatment 
assignment, contact the Mayo Registration Office at 507-284-0661 during regular business 
hours and provide the e-mail confirmation from the Imaging Core Lab to 
random01@mayo.edu that the patient has progressed radiographically. If the patient was 
assigned to the placebo arm of the study, s/he has the option to receive open label pazopanib. 
See Section 5.5 for instructions regarding re-registration and Section 11.2.2 regarding drug 
ordering. 
11.2.6 Toxicities and Potential Drug Interactions 
In vitro data indicate that pazopanib is primarily metabolized by the human CYP3A4 
isoenzyme. Potent CYP3A4 inhibitors are prohibited, and potent CYP3A4 inducers should 
be used with caution. Pazopanib is also a substrate for p-glycoprotein and breast cancer 
resistance protein (BCRP) transporters and concomitant administration of inhibitors such as 
lapatinib will result in increased plasma pazopanib concentrations. 
Medications that strongly inhibit CYP3A4 include (but are not limited to): 
• 
Antibiotics: clarithromycin, telithromycin, troleandomycin 
• 
HIV: protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, 
lopinavir) 

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• 
Antifungals: itraconazole, ketoconazole, voriconazole   
• 
Antidepressants: nefazodone 
Clinical studies indicate that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and 
CYP2D6.  Drugs that have narrow therapeutic windows and are substrates for these enzymes 
should be administered with extreme caution.  Because of pazopanib’s long half-life, caution 
should continue to be exercised for at least 7 days and up to 15 days after the last dose of 
pazopanib when administering these medications. 
Medications that are substrates for these enzymes and have narrow therapeutic windows 
medications include (but are not limited to): 
• 
Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine 
(potential increased risk for developing ergot toxicity that includes severe vasospasm 
leading to peripheral as well as cerebral ischemia) 
• 
Neuroleptics: pimozide (potential increased risk for QT interval prolongation, 
ventricular arrhythmia, and sudden death) 
• 
Antiarrhythmics: bepridil, flecainide, lidocaine, mexiletine, amiodarone, quinidine, 
propafenone (potential increased risk for QT interval prolongation and Torsade de 
Pointes) 
• 
Immune modulators: cyclosporine, tacrolimus, sirolimus (potential increased risk for 
nephrotoxicity and neurotoxicity) 
• 
Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine. 
Co-administration of pazopanib with medicines that increase gastric pH should be avoided. 
If the concomitant use of a proton pump inhibitor (PPI) is medically necessary, 
pazopanib/placebo should be taken without food once daily in the evening with the PPI. If 
the concomitant administration of an H2-receptor antagonist is medically necessary, 
pazopanib/placebo should be taken without food at least 2 hours before or at least 10 hours 
after a dose of an H2-receptor antagonist. Administer pazopanib/placebo at least 1 hour 
before or 2 hours after administration of short-acting antacids. See also Section 8.1. 
In vitro studies also showed that pazopanib is a potent inhibitor of UGT1A1 and OATP1B1 
with IC50 of 1.2 and 0.79 M respectively. Pazopanib may increase concentrations of drugs 
primarily eliminated through UGT1A1 and OATP1B1. 
Pazopanib can prolong the QTc interval.  Drugs that are generally accepted to have a risk of 
causing Torsades de Pointes (See Appendix 1) should be discontinued or replaced with 
drugs that do not carry this risk, if at all possible.  Patients who receive potential QTc-
prolonging medications (See Appendix 1) should be monitored closely. 
Pazopanib may increase bleeding.  Patients receiving pazopanib and anticoagulation agents 
should be monitored for bleeding. 
Pazopanib may cause decreased glucose.  Patients receiving pazopanib and hypoglycemia 
agents should be monitored for hypoglycemia. 
Thrombotic microangiopathy (hemolytic uremic syndrome) has been reported in clinical 
trials with pazopanib as monotherapy, in combination with bevacizumab, and in 
combination with topotecan. Reversal of the manifestations of thrombotic microangiopathy 
has been observed following discontinuation of pazopanib. 
Avoid co-administration of pazopanib/placebo with simvastatin. Concomitant use of 
pazopanib and simvastatin increases the risk of ALT elevation. Data are not sufficient to 
assess the risk of concomitant administration of other statins and pazopanib. 

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Recent reports describe hepatotoxicity occurring in patients receiving pazopanib. Elevations 
in ALT and AST, including grade 3/4 elevation in approximately 9.4% and 6.9% of patients, 
respectively, have been reported. Less common are grade 3/4 elevations in bilirubin, and 
fatal hepatotoxicity has been reported to occur in < 1% of patients. Most elevations in liver 
function tests have been seen within the first two months of beginning pazopanib. 
For patients who develop hepatic impairment, refer to the protocol document for appropriate 
dose modification or dose delay. 
Pazopanib/placebo should be used with caution in patients with a history of QT interval 
prolongation, in patients taking antiarrhythmics or other medications that may prolong QT 
interval, and those with relevant pre-existing cardiac disease. Monitor ECGs and serum 
electrolytes (e.g., calcium, magnesium, potassium) at baseline and periodically and maintain 
within the normal range. 
12.0 ANCILLARY THERAPY 
12.1 
Supportive Care 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, etc., when appropriate. 
12.2 
Treatment with Hormones or Other Chemotherapeutic Agents 
Treatment with hormones (besides somatostatin analogs) or other chemotherapeutic agents may 
not be administered except for steroids given for adrenal failure; hormones administered for 
non-disease-related conditions (e.g., insulin for diabetes); and intermittent use of 
dexamethasone. 
12.3 
Somatostatin Analog 
Patients already receiving a somatostatin analog (e.g. octreotide LAR) with or without 
subcutaneous octreotide for breakthrough at the time of study initiation may continue at their 
current dose level and schedule (according to institutional practice) throughout the course of 
study treatment. 
12.4 
Growth Factors 
Treatment with filgrastim (G-CSF), pegfilgrastim, and sargramostim (GM-CSF) are not allowed 
on this protocol. The use of epoetin (EPO) is permitted at the discretion of the treating physician, 
but is discouraged. 
12.5 
Nausea/Vomiting 
Every attempt should be made to control nausea and vomiting in patients who have emesis and 
are unable to retain pazopanib/placebo. Routine pre-medication for nausea is not necessary, but 
symptomatic patients should be treated with standard anti-nausea/anti-emetic therapy as 
necessary. 
If a patient vomits after taking study medication, the patient should be instructed not to take a 
replacement dose on that same day. The patient should resume taking pazopanib/placebo at the 
next scheduled dose on the following day. If vomiting persists, then the patient should contact 
their physician. 
To prevent or treat nausea and vomiting standard medications are recommended.  Depending 
upon approved medications in your region, these may include: 5-HT3 receptor antagonist 
(granisetron, ondansetron, dolasetron mesylate); NK-1 receptor antagonists such as aprepitant, 
metoclopramide, 
phenothiazines 
(prochlorperazine); 
corticosteroids, 
(dexamethasones, 

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prednisone); and cannabinoids (dronabinol). If ondansetron is used, the dose should be no more 
than 16mg/day due to concerns related to possible prolongation of QTc interval. 
12.6 
Management of Diarrhea 
Hydration: have patient drink 8 to 10 large glasses (approximately 2 liters) of clear 
non-caffeinated liquids a day (e.g., broth or electrolyte-containing sports drinks).  
Dietary Modifications: have patient stop all lactose-containing products and eat frequent, small 
meals 
Pharmacologic Intervention Using Loperamide: Begin loperamide at initial dose of 4 mg 
followed by 2 mg every 4 hours or after every unformed stool. The recommended maximum 
daily dose of loperamide is 16 mg/day. Continuation of loperamide is suggested until diarrhea-
free for 12 hours. If mild to moderate diarrhea persists for more than 24 hours, administer 
loperamide 2 mg every 2 hours and pursue evaluation for other treatable causes. If mild to 
moderate diarrhea persists after 48 hours total treatment with loperamide, discontinue study 
drug(s) and consider initiation of second-line agents (lomotil, octreotide). 
12.7 
Anticoagulants 
Results from drug-drug interaction studies conducted in patients with cancer suggest that 
pazopanib has no effect on the metabolism of S-warfarin. Hemorrhagic events, however, have 
been reported in clinical studies with pazopanib; therefore, pazopanib should be used with 
caution in patients with increased risk of severe bleeding or who are receiving concomitant 
anticoagulant therapy (e.g. warfarin or its derivatives, low molecular weight heparin, 
unfractionated heparin). Patients taking concomitant anticoagulant therapy should be monitored 
regularly for changes in relevant coagulation parameters as clinically indicated, as well as for 
any clinical bleeding episodes. 
12.8 
Hypertension Guidelines 
Antihypertensive Therapy: 
Step 1) Consider initiating beta blocker treatment and if needed, after 24-48 hours of 
treatment, increase dose in stepwise fashion every 24-48 hours until BP is 
controlled or at the maximum dose of therapy. 
Step 2) If BP still not controlled, consider adding another antihypertensive agent, a long 
acting dihydropyridine calcium channel blockers, angiotensin converting enzyme 
inhibitors, angiotensin II receptor blockers, alpha beta blocker; increase dose of 
this drug as described in Step 1.   
Step 3) If BP is still not controlled, consider adding 3rd drug 
For systolic BP >180 or diastolic BP > 110 
If the patient is symptomatic: Recommend optimal management with intensive IV support 
in ICU; note that stopping pazopanib may result in a decrease in BP 
If the patient is asymptomatic, consider adding 2 new anti-hypertensives given together 
from Step 1 (and dose escalated appropriately as in Step 1). 
NOTE: Stopping or reducing the dose of pazopanib/placebo is expected to cause a decrease in 
BP The treating physician should monitor the patient for hypotension and adjust the number and 
dose of antihypertensive medication(s) accordingly 

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12.9 
CYP3A4 Inhibitors 
Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this trial. 
The follow drugs are EXAMPLES of strong inhibitors of CYP3A4 and are not allowed during 
treatment with pazopanib: 
• 
Indinavir 
• 
Clarithromycin 
• 
Ketoconazole 
Because lists of these agents are constantly changing, please consult and review any drugs for 
their potential to inhibit CYP3A4. Examples of resources that may be utilized include the 
product information for the individual concomitant drug in question, medical reference texts 
such as the Physicians’ Desk Reference, the FDA and/or IUPUI websites, or your local 
institution’s pharmacist. 
CYP3A4 inducers should also be used with caution. 
12.10 Surgery 
If a patient requires surgery while on study treatment, pazopanib/placebo may be held up to a 
maximum of 28 days. If study drug must be held greater than 28 days, patient must be taken off 
study. Patients should continue to follow the required test schedule per Section 7.0 of the 
protocol. 
12.11 Management of Pneumonitis 
The following are recommendations for toxicity management and are not required: 
Grade 1:  Recommend performing CT scans with lung windows and pulmonary function testing 
including: spirometry, DLCO, and room air O2 saturation at rest. Repeat chest x-ray/CT scan 
every 2 Cycles until return to baseline. 
Grade 2: Recommend CT scan with lung windows and pulmonary function testing including: 
spirometry, DLCO, and room air O2 saturation at rest. Repeat each subsequent Cycle until return 
to baseline. Consider bronchoscopy. Consider corticosteroids for symptomatic disease  
Grade 3 or 4: Recommend CT scan with lung windows and pulmonary function testing 
including: spirometry, DLCO, and room air O2 saturation at rest. Repeat each subsequent Cycle 
until return to baseline. Bronchoscopy is recommended. Treat with corticosteroids if infection 
is ruled out.  
13.0 CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE 
For the purposes of this study, patients should be reevaluated every 3 cycles (12 weeks). In addition 
to a baseline scan, confirmatory scans should also be obtained no less than 4 weeks following initial 
documentation of objective response. 
13.1 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and will be recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, and should be chosen based 
on their suitability for accurate repetitive measurements. It may be the case that, on occasion, 
the largest lesion does not lend itself to reproducible repeated measurements in which case the 
next largest lesion which can be measured reproducibly should be selected. A sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will 

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be calculated and reported as the baseline sum diameters.  If lymph nodes are to be included in 
the sum, then only the short axis is added into the sum. The baseline sum LD will be used as 
reference to further characterize the objective tumor response of the measurable dimension of 
the disease. 
13.1.1 Complete Response: Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
13.1.2 Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.  
13.1.3 Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progression). 
13.1.4 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD taking as references the smallest sum diameters while on study. 
13.2 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
13.2.1 Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for 
a patient to be considered in complete clinical response. 
13.2.2 Non-complete Response (non-CR)/Non-progression (non-PD): Persistence of one or 
more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. 
13.2.3 Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 
Although a clear progression of non-target lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed later on by the review panel (or study chair). 
13.2.4 FDG-PET: The use of FDG-PET in response assessments needs additional study.  Alliance 
A021202 does not require or recommend FDG-PET for response assessment. If an FDG-
PET is obtained at the discretion of the treating physician, the following algorithm may be 
used: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
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occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
13.3 
Cytology and Histology 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
These techniques can be used to differentiate between PR and CR in rare cases (for example, 
residual lesions in tumor types such as germ cell tumors, where known residual benign tumors 
can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
13.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e. Target Disease) 
Target Lesions 
Non-target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required 
CR 
CR 
No 
CR 
≥ 4 wks confirmation* 
CR 
Non-CR/Non-PD 
No 
PR 
≥ 4 wks confirmation* 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least 
once ≥ 4 wks from 
baseline* 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 

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* 
Only for non-randomized trials with response as the primary endpoint. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration” on the Off Treatment Form in Rave and are considered to have had 
“clinical progression.” Every effort should be made to document the objective “radiographic” 
progression even after discontinuation of treatment. 
 
For Patients with Non-measurable Disease (i.e. Non-target Disease) 
Non-Target 
Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised. 
13.5 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
13.5.1 Clinical Lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes) and ≥ 10 mm diameter as assessed using calipers (e.g., skin 
nodules). For the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
13.5.2 Chest X-ray: Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
13.5.3 Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body 
scans). CT and MRI scan requirements can be found in Section 6.2.2. 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 

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specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type 
of scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans. Body scans should be performed with breath-hold scanning 
techniques, if possible.  
13.5.4 PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time. Note, however, that the 
PET portion of the CT introduces additional data, which may bias an investigator if it is not 
routinely or serially performed.   
13.5.5 Ultrasound (US): Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, 
MRI may be used instead of CT in selected instances. 
13.5.6 Endoscopy and Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
13.5.7 Tumor Markers alone cannot be used to assess response. If markers are initially above the 
upper normal limit, they must normalize for a patient to be considered in complete clinical 
response.  
13.6 
Confirmation Measurement/Duration of Response 
13.6.1 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat studies that should be performed no less than 4 weeks after the criteria for response 
are first met. In the case of SD, follow-up measurements must have met the SD criteria at 
least once after study entry at a minimum interval of no less than 6 weeks. 
13.6.2 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall complete response is measured from the time measurement criteria 
are first met for CR until the first date that progressive disease is objectively documented. 

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13.6.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment started, 
including the baseline measurements. 
14.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
14.1 
Duration of Treatment 
14.1.1 CR, PR, or SD (as determined by central radiology review) 
Continue treatment at the highest tolerable dose until the appearance of disease progression 
or unacceptable toxicity per Section 9.0. 
14.1.2 Disease Progression (as determined by central radiology review) 
Patients who progress on blinded therapy, may be unblinded and if randomized to placebo, 
they will be allowed to cross over to open label pazopanib. After progression, follow the 
patient for survival and second malignancy every 6 months until death or 5 years after 
registration. 
14.2 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Notify the Study Chair. 
• 
Document the reason(s) for discontinuation of therapy on the Off-Treatment Form. 
• 
Follow the patient for protocol endpoints per the Required Data section. 
15.0 STATISTICAL CONSIDERATIONS 
15.1 
Study Hypotheses 
The primary endpoint for this trial is progression-free survival (PFS) based on central review.  
For determining the target HR we noted that everolimus (mTOR inhibitor) and sunitinib 
(VEGFR inhibitor like pazopanib) yielded similar HRs in the PNET population (0.35-0.42). The 
HR for everolimus in the RADIANT-2 study was around 0.78 in a patient population similar to 
the one proposed for this study (with the exception that concurrent octreotide was required and 
20-25% patients had not received prior SSTa).  We believe that targeting a larger difference, 
HR=0.64, is realistic in the proposed study with pazopanib for two main reasons: 1) concurrent 
octreotide will not be required and 2) previous progression on octreotide will be required in 
patients receiving concurrent octreotide. Both of these elements should reduce the potential for 
a confounding anti-tumor effect of octreotide in this study.  Also, achieving a HR of 0.7 or lower 
is likely to reflect clinically meaningful drug activity. Since the primary endpoint of the study is 
PFS by central review, we believe a hypothesized median PFS of 9 months in the placebo group 
is reasonable based on the RADIANT-2 data. 
15.2 
Primary Endpoint 
PFS will be measured from date of patient entry until documented progression of disease as 
determined by central review or death from any cause. If a patient does not have a documented 
date of progression or death, then PFS will be censored at the date of last adequate assessment. 
PFS will be estimated within treatment arm using the Kaplan-Meier method. 

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Patients will be randomized with equal probability to treatment with pazopanib or placebo. With 
150 patients enrolled over 25 months (6 patients per month) and a follow-up period of 12 
months, 85% power is achieved to detect the difference between a median PFS of 14 months 
with pazopanib and 9 months for placebo (logrank test, 1-sided α =0.1; hazard ratio 0.6429).  
One hundred and fourteen PFS events (d=114) are expected at the time of the final analysis.  
Accounting for 10% drop out, we estimate that we will need to enroll approximately 165 patients 
in order to meet the targeted sample size (N=150). This dropout rate includes patients who may 
withdraw from treatment due to lack of consensus between the local and central determination 
of progression. 
The primary efficacy analysis will be conducted as intent-to-treat (ITT) and the ITT population 
will comprise all randomized patients by assigned treatment arm regardless of whether or not 
treatment was administered.  
15.3 
Secondary Endpoints 
The objective response rate (ORR) will be defined as the percentage of patients with a confirmed 
CR or PR per RECIST 1.1 criteria.  A patient with unknown or missing response will be omitted 
from the analysis. The exact binomial confidence interval will be used to estimate ORR. 
Overall survival (OS) will be measured from randomization until death from any cause.  A 
patient who is alive at the time of the statistical analysis will be considered censored at the last 
date of known contact. OS will be estimated by the Kaplan-Meier method within each treatment 
arm. 
Duration of response (DR) will be defined, for the subset of patients with a confirmed CR or 
PR, as the time from first documented evidence of CR or PR until first documented disease 
progression or death from any cause. If sample size permits, DR will be summarized 
descriptively using Kaplan-Meier medians and quartiles. Only the subset of patients with 
confirmed complete or partial tumor responses will be included in this analysis. 
Time to treatment failure (TTF) will be measured from randomization until termination of 
protocol therapy for any reason including progression of disease, adverse events, and death.  
Patients will be censored at the last known follow-up date during therapy. 
Patients who crossover from placebo to active therapy at the time of progression will be followed 
for a second progression unless they withdraw from treatment for other reasons; in that case they 
will be followed for toxicity and survival only. Any data analysis in this subset of patients will 
be considered exploratory. 
15.4 
Interim Analysis 
Interim analyses for futility (PFS comparison between treatment arms) will be conducted when 
38% and 75% of the expected number of events (d = 114) have been observed. The first interim 
analysis is expected to occur during the accrual period at approximately 18 months from trial 
activation (n=108 patients enrolled); the second interim analysis is expected during the follow-
up period at approximately 28 months from activation. Study enrollment will not be suspended 
for interim analyses. The overall significance level of 0.10 will be maintained by employing the 
Lan-DeMets boundaries (O’Brien-Fleming analogue; one-sided α = 0.10). Futility will be 
assessed at these time points using a confidence interval approach. The adjusted 95% upper 
confidence bound (UCB) for the PFS log hazard ratio (placebo versus pazopanib) will be 
determined at each interim analysis. If the targeted log hazard ratio of log (1.55) = 0.4418 lies 
above the estimated 95% UCB, consideration will be given to declaring lack of efficacy for 
pazopanib. 

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15.5 
Exploratory Objectives 
Estimate PFS at 6 months within each arm. Kaplan-Meier methods will be used including 
calculations of 95% confidence intervals for 6 month PFS. 
Biochemical response (for chromogranin A, defined as a decrease of 50% or more in 
chromogranin A levels from baseline, and for 5-HIAA, defined as a decrease of 50% or more in 
urinary 5-HIAA levels from baseline) will be compared between treatment arms among patients 
with elevated baseline levels of CGA and 5-HIAA. 
15.6 
Study Monitoring 
15.6.1 CDUS 
The Alliance Statistical Data Center will submit quarterly reports to CTEP by electronic 
means using the Clinical Data Update System (CDUS). 
15.6.2 Data and Safety Monitoring 
The principal investigator and the study statistician will review the study at least twice a 
year to identify accrual, adverse event/safety, and any endpoint problems that might be 
developing. The Alliance Data Safety Monitoring Board (DSMB) is responsible for 
reviewing accrual and safety data for this trial at least twice a year, based on reports provided 
by the study statistician. 
16.0 EXPEDITED ADVERSE EVENT REPORTING 
Investigators are required by Federal Regulations to report serious adverse events as defined below. 
Investigators are required to notify the Investigational Drug Branch, the Alliance Protocol Operations 
Office, the Study Chair, and their Institutional Review Board if a patient has an adverse event 
requiring expedited reporting. All such events must be reported in an expedited manner using the 
NCI CTEP Adverse Event Reporting System (CTEP-AERS). The descriptions and grading scales 
found in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for expedited AE reporting beginning April 1, 2018. All treatment areas should have access 
to a copy of the CTCAE version 5.0. It can be downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
In the rare event when Internet connectivity is disrupted, a 24-hour notification should be made to 
the NCI by telephone at 301-897-7497. An electronic report must be submitted upon re-establishment 
of Internet connection. 
The Alliance requires investigators to route all CTEP-AERS reports through the Alliance Protocol 
Operations Office for Alliance-coordinated studies 
Be sure to read this entire section, as requirements are described in both the table and the bullet 
points following the table. Note that the table and the Additional Instructions or Exclusions may 
conflict. The Additional Instructions or Exclusions are protocol-specific, and in the case of a conflict, 
the Additional Instructions or Exclusions supersede the table. Most exclusions cover “expected” 
events that a sponsor would not be required to report to the FDA in an expedited manner.  
 
 

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16.1 
Alliance A021202 Reporting Requirements 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under an IND within 30 Days of the Last Administration of the Investigational 
Agent1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS 
within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar Days 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” – The AE must initially be reported via CTEP-AERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar days of learning 
of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational agent require reporting 
as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs that are at least possibly related to treatment 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization, and that are at least possibly 
related to treatment 
• Grade 3 adverse events that are at least possibly related to treatment 
Effective Date:  May 5, 2011 
 
 
 

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Additional Instructions or Exclusion to CTEP-AERS Expedited Reporting Requirements 
for A021202: 
• 
Alliance A021202 uses a drug under a CTEP IND. The reporting requirements for 
investigational agents under a CTEP IND should be followed for all treatment arms in this 
trial. 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB, according to local IRB policies. 
• 
Treatment expected adverse events include those listed in the package insert and in the 
CAEPR for pazopanib. Note that the ASAEL column of the CAEPR has been replaced with 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) column. The SPEER 
includes “expected” severity grades in addition to event terms. Events listed in the SPEER 
only require expedited reporting if the severity grade is above the grade noted in SPEER. 
• 
When evaluating hypertension, consider the description of severity (especially for grade 3) 
relative to the last AE reporting period/CTEP-AERS report. That is, for “more than one drug 
or more intensive therapy than previously used,” “previously” should be considered the last 
reporting period. A regimen more intensive than that used in a previous reporting period 
need only prompt expedited reporting the first time that it us used. If blood pressure is stable 
on the more intensive regimen, do not continue to report the same grade hypertension via 
CTEP-AERS. 
• 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying disease (e.g. radiological changes 
suggesting tumor growth or progression: clinical deterioration associated with a disease 
process) should be submitted. 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours. 
• 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, 
probably, or definitely related to the investigational agent/intervention. 
• 
All new malignancies should be reported through CTEP-AERS independent of attribution 
to treatment. This includes solid tumors (including non-melanoma skin malignancies), 
hematologic malignancies, myelodysplastic syndrome (MDS)/acute myelogenous leukemia 
(AML), and in situ tumors. In CTCAE version 5.0, new malignancies (second and 
secondary) may be reported as one of the following: 1) leukemia secondary to oncology 
chemotherapy, 2) myelodysplastic syndrome, or 3) treatment-related secondary malignancy. 
Whenever possible, CTEP-AERS reports for new malignancies should include tumor 
pathology, history of prior tumors, prior treatment/current treatment including duration, any 
associated risk factors or evidence regarding how long the new malignancy may have been 
present, when and how it was detected, molecular characterization or cytogenetics of the 
original and new malignancy (if available), and treatment and outcome of the new 
malignancy, if available. All new malignancies should also be reported on routine forms as 
required. 
• 
All pregnancies and suspected pregnancies occurring in female patients during therapy or 
within 28 days after completion of treatment must be reported via CTEP-AERS. 
• 
CTEP-AERS reports should be amended upon completion of the pregnancy to 
report pregnancy outcome (e.g. normal, spontaneous abortion, therapeutic 
abortion, fetal death, congenital abnormalities). In CTCAE v5.0, pregnancy loss is 
defined as “Death in utero,” and any pregnancy loss should be reported 

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expeditiously as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium and 
perinatal conditions SOC. A pregnancy should NOT be reported as a Grade 5 event 
under the Pregnancy, puerperium and perinatal conditions SOC as currently 
CTEP-AERS recognizes this event as a patient death. 
• 
Neonatal death occurring within 28 days of birth that is considered at least possibly 
related to in utero exposure to treatment on A021202 should be reported via CTEP-
AERS. A neonatal death should be reported expeditiously as Grade 4 “Death 
neonatal” under the General disorders and administration SOC. 
• 
> Grade 2 ALT and > grade 2 bilirubin should be reported via CTEP-AERS within 10 
calendar days. 
16.2 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Pazopanib 
(GW786034, NSC 737754) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that 
are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer 
to 
the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 2383 patients. Below is the CAEPR for 
Pazopanib (GW786034). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next 
to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
Version 2.8, January 31, 20191 
 
 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 5.0 Term) 
[n= 2383] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
 
Hemolytic uremic 
syndrome2 
  
 
 
Thrombotic 
thrombocytopenic purpura 
  
CARDIAC DISORDERS 
  
 
 
Cardiac disorders - Other 
(Torsades de Pointes) 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction 
  
 
Sinus bradycardia 
 
  
ENDOCRINE DISORDERS 
  
 
Hypothyroidism 
 
  
EYE DISORDERS 
  

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 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 5.0 Term) 
[n= 2383] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
 
Eye disorders - Other (eye 
hemorrhage, retinal 
hemorrhage) 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
  
 
 
Gastrointestinal fistula3 
 Gastrointestinal fistula3 (Gr 2) 
 
 
Gastrointestinal 
hemorrhage4 
  
 
 
Gastrointestinal perforation5  Gastrointestinal perforation5 (Gr 
2) 
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
 
Infection6 
  
INVESTIGATIONS 
  
 
Activated partial 
thromboplastin time prolonged 
 
  
Alanine aminotransferase 
increased 
 
 
 Alanine aminotransferase 
increased (Gr 4) 
 
Alkaline phosphatase 
increased 
 
 Alkaline phosphatase increased 
(Gr 3) 
Aspartate aminotransferase 
increased 
 
 
 Aspartate aminotransferase 
increased (Gr 3) 
Blood bilirubin increased 
 
 
 Blood bilirubin increased 
(Gr 3) 
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 
 
 
Ejection fraction decreased   
 
 
Electrocardiogram QT 
corrected interval prolonged 
  
Lymphocyte count decreased  
 
 Lymphocyte count decreased 
(Gr 4) 
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr 
4) 
Platelet count decreased 
 
 
 Platelet count decreased  
(Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 2) 
White blood cell decreased 
 
 
 White blood cell decreased (Gr 
3) 
METABOLISM AND NUTRITION DISORDERS 
  

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 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 5.0 Term) 
[n= 2383] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypercalcemia 
 
  
Hyperglycemia 
 
 
 Hyperglycemia (Gr 2) 
 
Hyperkalemia 
 
 Hyperkalemia (Gr 2) 
 
Hypermagnesemia 
 
  
 
Hypernatremia 
 
  
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 2) 
 
Hypocalcemia 
 
 Hypocalcemia (Gr 3) 
 
Hypoglycemia 
 
 Hypoglycemia (Gr 2) 
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
Hyponatremia 
 
 
 Hyponatremia (Gr 3) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS 
AND POLYPS) 
  
 
Tumor pain 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
 
 
Intracranial hemorrhage 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
 
 
Hematuria 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
 
 
Urinary fistula 
 Urinary fistula (Gr 2) 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
 
Reproductive system and 
breast disorders - Other 
(female genital tract fistula) 
 Reproductive system and breast 
disorders - Other (female genital 
tract fistula) (Gr 2) 
 
 
Uterine fistula 
 Uterine fistula (Gr 2) 
 
 
Vaginal fistula 
 Vaginal fistula (Gr 2) 
 
 
Vaginal hemorrhage 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
Respiratory hemorrhage7 
 
 Respiratory hemorrhage7 (Gr 2) 

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 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 5.0 Term) 
[n= 2383] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
 
Respiratory, thoracic and 
mediastinal disorders - 
Other (interstitial lung 
disease)8  
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
Hair color changes 
 
 
 Hair color changes (Gr 2) 
 
Palmar-plantar 
erythrodysesthesia syndrome 
 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
Skin hypopigmentation 
 
 Skin hypopigmentation (Gr 2) 
VASCULAR DISORDERS 
  
 
 
Arterial thromboembolism9   
Hypertension 
 
 
 Hypertension (Gr 3) 
 
 
Thromboembolic event9 
  
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal 
Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. 
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
 
2Thrombotic microangiopathy (TMA) which includes both Hemolytic uremic syndrome (HUS) and Thrombotic 
thrombocytopenic purpura (TTP) has been reported in clinical trials of GW786034. 
 
3Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Enterovesical fistula, Esophageal 
fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, Pancreatic fistula, 
Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS SOC.  
 
4Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 
hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal 
hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper 
gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC.  
 
5Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric 
perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the 
GASTROINTESTINAL DISORDERS SOC.  
 
6Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
7Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal hemorrhage, Mediastinal 
hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the RESPIRATORY, THORACIC AND 
MEDIASTINAL DISORDERS SOC.  
 
8Interstitial lung disease may include, Adult respiratory distress syndrome, Pneumonitis, Pulmonary fibrosis, 
Respiratory, thoracic and mediastinal disorders - Other (Acute respiratory distress syndrome), Respiratory, thoracic 
and mediastinal disorders - Other (Aveolitis), Respiratory, thoracic and mediastinal disorders - Other (Bronchiolitis 
obliterans), Respiratory, thoracic and mediastinal disorders - Other (Interstitial fibrosis), Respiratory, thoracic and 
mediastinal disorders - Other (Interstitial pneumonia), Respiratory, thoracic and mediastinal disorders - Other 
(Interstitial pneumonitis), Respiratory, thoracic and mediastinal disorders - Other (Organizing pneumonia), 

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Respiratory, thoracic and mediastinal disorders - Other (Pulmonary infiltrates), Respiratory, thoracic and mediastinal 
disorders - Other (Toxic pneumonitis). 
 
9These events can result in life-threatening pulmonary, cardiac, cerebral, and other complications. 
 
Adverse events reported on pazopanib (GW786034) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that pazopanib (GW786034) caused the adverse event:  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (sinus arrest); Cardiac disorders - Other 
(supraventricular extrasystoles); Cardiac disorders - Other (Takotsubo [Broken Heart Syndrome]); Chest pain - 
cardiac; Pericardial effusion; Supraventricular tachycardia 
ENDOCRINE DISORDERS - Adrenal insufficiency 
EYE DISORDERS - Blurred vision; Dry eye; Eye disorders - Other (asthenopia); Eye disorders - Other (foreign 
body sensation in eyes); Eye pain; Floaters; Glaucoma; Photophobia; Retinal tear 
GASTROINTESTINAL DISORDERS - Abdominal distension; Dry mouth; Duodenal obstruction; Dysphagia; 
Esophagitis; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (hyperactive bowel); 
Gastrointestinal disorders - Other (pneumatosis intestinalis); Gastrointestinal pain; Oral pain; Pancreatitis; 
Periodontal disease; Proctitis; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Malaise; Non-
cardiac chest pain; Pain 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Blood lactate dehydrogenase increased; Cardiac troponin T increased; Cholesterol high; 
GGT increased; INR increased; Investigations - Other (blood TSH increased); Lipase increased; Serum amylase 
increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Hypertriglyceridemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Chest wall pain; 
Generalized muscle weakness; Head soft tissue necrosis; Muscle cramp; Muscle weakness lower limb; Muscle 
weakness upper limb; Neck pain 
NERVOUS SYSTEM DISORDERS - Extrapyramidal disorder; Ischemia cerebrovascular; Memory impairment; 
Paresthesia; Peripheral sensory neuropathy; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Suicide attempt 
RENAL AND URINARY DISORDERS - Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; Reproductive system and 
breast disorders - Other (vaginal necrosis); Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Laryngeal edema; Oropharyngeal pain; 
Pharyngolaryngeal pain; Pleural effusion; Pleuritic pain; Pneumothorax; Postnasal drip; Sore throat; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Pruritus; Purpura; Skin 
hyperpigmentation; Skin ulceration 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Vasculitis 
 
 
Note: Pazopanib (GW786034) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
 
 
 

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17.0 REFERENCES 
1. Oberg K, Ferone D, Kaltsas G, et al: ENETS Consensus Guidelines for the Standards of Care in 
Neuroendocrine Tumors: biotherapy. Neuroendocrinology 90:209-13, 2009 
2. Kulke MH, Anthony LB, Bushnell DL, et al: NANETS treatment guidelines: well-differentiated 
neuroendocrine tumors of the stomach and pancreas. Pancreas 39:735-52, 2010 
3. Rinke A, Muller HH, Schade-Brittinger C, et al: Placebo-controlled, double-blind, prospective, 
randomized study on the effect of octreotide LAR in the control of tumor growth in patients with 
metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 
27:4656-63, 2009 
4. Terris B, Scoazec JY, Rubbia L, et al: Expression of vascular endothelial growth factor in 
digestive neuroendocrine tumours. Histopathology 32:133-8, 1998 
5. La Rosa S, Uccella S, Finzi G, et al: Localization of vascular endothelial growth factor and its 
receptors in digestive endocrine tumors: correlation with microvessel density and 
clinicopathologic features. Hum Pathol 34:18-27, 2003 
6. Boudreaux JP, Klimstra DS, Hassan MM, et al: The NANETS consensus guideline for the 
diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors 
of the Jejunum, Ileum, Appendix, and Cecum. Pancreas 39:753-66, 2010 
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consortium. Oncologist 15:810-18, 2010 

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20. Bible K, Suman V, Molina J, et al: Efficacy of pazopanib in progressive, radioiodine-refractory, 
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39. Cohen J. Statistical Power Analysis for the Behavioral Sciences, Second Edition. LEA, 
Publishers, Hillsdale, NJ. 1988. pp. 273-406. 
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Neuroendrocrine Tumors. JCO (2008), vol 26, no 20, 3403-3410. 
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59. Martenson JA, Bollinger JW, Sloan JA, et al: Sucralfate in the prevention of treatment-induced 
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clinical trials., Proc Am Soc Clin Onc, 1998, pp abstract # 
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quality of life end points in clinical trials. J Biopharm Stat 14:73-96, 2004 
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67. Tran, H.T., et al., Prognostic or predictive plasma cytokines and angiogenic factors for patients 
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79. Xu C-F, Bing N, Ball H, et al: Pazopanib efficacy in renal cell carcinoma:  Evidence for predictive 
genetic markers in angiogenesis-related and exposure-related genes. J Clin Oncol 29:2557-2564, 
2011 
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in breast cancer by heterotypic signaling. Proc Natl Acad Sci USA 107:8231-6, 2010 
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82. Gottesman I, Gould T: The endophenotype concept in pyschiatry:  etymology and strategic 
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83. Bass M, Sherman S, Schlumberger M, et al: Biomarkers as perdictors of response to treatment with 
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identifies markers associated with tumor shrinkage in early-stage non-small cell lung cancer 
patietns treated with pazopanib. Cancer Res 70:2171-9, 2010 
 
 

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APPENDIX I: 
COLLABORATIVE AGREEMENT PROVISIONS 
The pazopanib and placebo supplied by CTEP, DCTC, NCI used in this protocol are provided to the 
NCI under Collaborative Agreement (CRADA, CTA, CSA) between Novartis (hereinafter referred 
to as “Collaborator”) and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the 
following obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to 
the 
Collaborator” 
(at 
http://ctep.cancer.gov/industrycollaborations2/intellectual_property.htm) 
contained within the terms of award, apply to the use of the pazopanib/placebo in this study: 
1. Pazopanib/placebo may not be used for any purpose outside the scope of this protocol, nor can it 
be transferred or licensed to any party not participating in the clinical study. Collaborator’s data 
for agents are confidential and proprietary to Collaborator and shall be maintained as such by the 
investigators. The protocol documents for studies utilizing pazopanib/placebo 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 in which there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements, the 
access to and use of data by each Collaborator and Provider shall be as follows (data pertaining 
to such combination use shall hereinafter be referred to as "Multi-Party Data.”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the proposed 
combination protocol, and the existence of any obligations that would tend to restrict NCI's 
participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree 
in writing prior to the commencement of the trials that it will use the Multi-Party Data solely 
for development, regulatory approval, and commercialization of its own investigational 
Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will 
be made available exclusively to Collaborator, the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order, as described in the IP Option to 
Collaborator 
(http://ctep.cancer.gove/industryCollaborations2/intellectual_propert.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health Information 
set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, 
or PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for this Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC 
for the clinical trial. 
 
 

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6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group 
Office for Cooperative Group studies or by the principal investigator for non-cooperative Group 
studies for immediate delivery to 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 
Collaborator’s intellectual property rights, are protected. Copies of abstracts must be provided to 
CTEP for forwarding to 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 presentations must also be 
forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press release/ 
media presentation should be sent to: 
email: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator. No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/proprietary information. 
 
 

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APPENDIX II: DRUGS ASSOCIATED WITH QTC PROLONGATION 
 
The following table presents a list of drugs that prolong, may prolong or are unlikely to prolong the QTc.  
Please note that this list is frequently updated.  For the most current list of medications, users should be 
directed to the following website: http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm.   
 
Drugs that are generally 
accepted to have a risk of 
causing Torsades de Pointes 
Drugs that in some reports have 
been associated with Torsades de 
Pointes and/or QTc prolongation 
but at this time lack substantial 
evidence for causing Torsades de 
Pointes 
Drugs that, in some reports, have been 
weakly associated with Torsades de 
Pointes and/or QTc prolongation but 
that are unlikely to be a risk for 
Torsades de Pointes when used in usual 
recommended dosages and in patients 
without other risk factors (e.g., 
concomitant QTc prolonging drugs, 
bradycardia, electrolyte disturbances, 
congenital long QTc syndrome, 
concomitant drugs that inhibit 
metabolism) 
  
  
  
Generic/Brand Name 
Generic/Brand Name 
Generic/Brand Name 
Amiodarone /Cordarone® 
Alfuzosin /Uroxatral® 
Amitriptyline /Elavil® 
Amiodarone /Pacerone® 
Amantadine /Symmetrel® 
Ciprofloxacin /Cipro® 
Arsenic trioxide /Trisenox® 
Atazanavir /Reyataz® 
Citalopram /Celexa® 
Astemizole /Hismanal® 
Azithromycin /Zithromax® 
Clomipramine /Anafranil® 
Bepridil /Vascor® 
Chloral hydrate /Noctec® 
Desipramine /Pertofrane® 
Chloroquine /Aralen® 
Clozapine /Clozaril® 
Diphenhydramine /Benadryl® 
Chlorpromazine /Thorazine® 
Dolasetron /Anzemet® 
Diphenhydramine /Nytol® 
Cisapride /Propulsid® 
Dronedarone /Multaq® 
Doxepin /Sinequan® 
Clarithromycin /Biaxin® 
Felbamate /Felbatrol® 
Fluconazole /Diflucan® 
Disopyramide /Norpace® 
Flecainide /Tambocor® 
Fluoxetine /Sarafem® 
Dofetilide /Tikosyn® 
Foscarnet /Foscavir® 
Fluoxetine /Prozac® 
Domperidone /Motilium® 
Fosphenytoin /Cerebyx® 
Galantamine /Reminyl® 
Droperidol /Inapsine® 
Gatifloxacin /Tequin® 
Imipramine /Norfranil® 
Erythromycin /Erythrocin® 
Gemifloxacin /Factive® 
Itraconazole /Sporanox® 
Erythromycin /E.E.S.® 
Granisetron /Kytril® 
Ketoconazole /Nizoral® 
Halofantrine /Halfan® 
Indapamide /Lozol® 
Mexiletine /Mexitil® 
Haloperidol /Haldol® 
Isradipine /Dynacirc® 
Nortriptyline /Pamelor® 
Ibutilide /Corvert® 
Lapatinib /Tykerb® 
Paroxetine /Paxil® 
Levomethadyl /Orlaam® 
Lapatinib /Tyverb® 
Protriptyline /Vivactil® 
Mesoridazine /Serentil® 
Levofloxacin /Levaquin® 
Sertraline /Zoloft® 

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Drugs that are generally accepted 
to have a risk of causing Torsades 
de Pointes 
 
Drugs that in some reports have 
been associated with Torsades de 
Pointes and/or QTc prolongation 
but at this time lack substantial 
evidence for causing Torsades de 
Pointes 
 
Drugs that, in some reports, have 
been weakly associated with 
Torsades de Pointes and/or QTc 
prolongation but that are unlikely 
to be a risk for Torsades de 
Pointes when used in usual 
recommended dosages and in 
patients without other risk factors 
(e.g., concomitant QTc prolonging 
drugs, bradycardia, electrolyte 
disturbances, congenital long QTc 
syndrome, concomitant drugs that 
inhibit metabolism) 
  
  
  
Generic/Brand Name 
Generic/Brand Name 
Generic/Brand Name 
Methadone /Dolophine® 
Lithium /Lithobid® 
Solifenacin /VESIcare® 
Methadone /Methadose® 
Lithium /Eskalith® 
Trimethoprim-Sulfa /Sulfa® 
Pentamidine /Pentam® 
Moexipril/HCTZ /Uniretic® 
Trimethoprim-Sulfa /Bactrim® 
Pentamidine /NebuPent® 
Moxifloxacin /Avelox® 
Trimipramine /Surmontil® 
Pimozide /Orap® 
Nicardipine /Cardene® 
  
Probucol /Lorelco® 
Nilotinib /Tasigna® 
  
Procainamide /Pronestyl® 
Octreotide /Sandostatin® 
  
Procainamide /Procan® 
Ofloxacin /Floxin® 
  
Quinidine /Cardioquin® 
Ondansetron /Zofran® 
  
Quinidine /Quinaglute® 
Oxytocin /Pitocin® 
  
Sotalol /Betapace® 
Paliperidone /Invega® 
  
Sparfloxacin /Zagam® 
Perflutren lipid microspheres 
/Definity® 
  
Terfenadine /Seldane® 
Quetiapine /Seroquel® 
  
Thioridazine /Mellaril® 
Ranolazine /Ranexa® 
  
  
Risperidone /Risperdal® 
  
  
Roxithromycin* /Rulide® 
  
  
Sertindole /Serlect® 
  
  
Sertindole /Serdolect® 
  
  
Sunitinib /Sutent® 
  
  
Tacrolimus /Prograf® 
  
  
Tamoxifen /Nolvadex® 
  
  
Telithromycin /Ketek® 
  
  
Tizanidine /Zanaflex® 
  
  
Vardenafil /Levitra® 
  
  
Venlafaxine /Effexor® 
  
  
Voriconazole /VFend® 
  
  
Ziprasidone /Geodon® 
  
* QTc prolongation associated with doses greater than 16 mg/day 
 
 

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APPENDIX III: MEDICATION LOGS 
 
 

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Pazopanib/Placebo Medication Log 
 
Number of Pills Given:____________  
Pill Bottle(s) returned:  Circle Yes or No 
Total Daily Dose:________________ 
 
Number of Pills returned:_____________ 
 
(To be completed by RN)  
    
 
 
PLEASE FILL OUT AND BRING THIS SHEET TO ALL VISITS. 
 
SPECIAL INSTRUCTIONS  
1. Pazopanib/Placebo should be taken orally without food at least 1 hour before OR 2 hours after a 
meal. 
2. The tablets should be swallowed whole and must not be crushed or broken. 
3. If a dose is missed, please take the dose as soon as possible, but only if there are 12 or more hours 
remaining before the next dose 
a. If the dose is due in less than 12 hours, skip the missed dose and take the next dose as 
scheduled 
4. If vomiting occurs after taking pazopanib/placebo, do not take a replacement dose on that day. 
Resume drug the next day. 
a. Even if you can see a whole tablet, do not take a replacement dose that day. 
b. If consistent vomiting occurs please notify the study doctor. 
5. Pazopanib/placebo tablets should be stored at room temperature. 
 
 

ALLIANCE A021202 
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Version Date: 04/08/2019 
 
 
 
 
 
 
 
Update #12 
CYCLE #: _______    # of WEEKS___________ 
D
A
Y 
Medication 
DATE 
TIME 
Number of 
200mg tablets 
taken 
Comments 
Exam
ple 
Pazopanib/placebo 
07/01/2012 
9:00 
AM 
4 x 200 
 
1 
Pazopanib/placebo 
 
 
 
 
 
2 
Pazopanib/placebo 
 
 
 
 
 
3 
Pazopanib/placebo 
 
 
 
 
 
4 
Pazopanib/placebo 
 
 
 
 
 
5 
Pazopanib/placebo 
 
 
 
 
 
6 
Pazopanib/placebo 
 
 
 
 
 
7 
Pazopanib/placebo 
 
 
 
 
 
8 
Pazopanib/placebo 
 
 
 
 
 
9 
Pazopanib/placebo 
 
 
 
 
 
10 
Pazopanib/placebo 
 
 
 
 
 
11 
Pazopanib/placebo 
 
 
 
 
 
12 
Pazopanib/placebo 
 
 
 
 
 
13 
Pazopanib/placebo 
 
 
 
 
 
14 
Pazopanib/placebo 
 
 
 
 
 
15 
Pazopanib/placebo 
 
 
 
 
 
16 
Pazopanib/placebo 
 
 
 
 
 
17 
Pazopanib/placebo 
 
 
 
 
 
18 
Pazopanib/placebo 
 
 
 
 
 
19 
Pazopanib/placebo 
 
 
 
 
 
20 
Pazopanib/placebo 
 
 
 
 
 
21 
Pazopanib/placebo 
 
 
 
 
 
22 
Pazopanib/placebo 
 
 
 
 
 
23 
Pazopanib/placebo 
 
 
 
 
 
24 
Pazopanib/placebo 
 
 
 
 
 
25 
Pazopanib/placebo 
 
 
 
 
 
26 
Pazopanib/placebo 
 
 
 
 
 
27 
Pazopanib/placebo 
 
 
 
 
 
28 
Pazopanib/placebo 
 
 
 
 
 
 
Patient Signature: _________________________________________Date:__________ 
Consenting Professional/Research RN Signature: ______________Date:__________  
 
 
 
 

ALLIANCE A021202 
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Version Date: 04/08/2019 
 
 
 
 
 
 
 
Update #12 
Open Label Pazopanib Medication Log 
 
Number of Pills Given:____________  
Pill Bottle(s) returned:  Circle Yes or No 
Total Daily Dose:________________ 
 
Number of Pills returned:_____________ 
 
(To be completed by RN)  
    
 
 
PLEASE FILL OUT AND BRING THIS SHEET TO ALL VISITS. 
 
SPECIAL INSTRUCTIONS  
1. Pazopanib should be taken orally without food at least 1 hour before OR 2 hours after a meal. 
2. The tablets should be swallowed whole and must not be crushed or broken. 
3. If a dose is missed, please take the dose as soon as possible, but only if there are 12 or more hours 
remaining before the next dose 
a. If the dose is due in less than 12 hours, skip the missed dose and take the next dose as 
scheduled 
4. If vomiting occurs after taking pazopanib, do not take a replacement dose on that day. Resume 
drug the next day. 
a. Even if you can see a whole tablet, do not take a replacement dose that day. 
b. If consistent vomiting occurs please notify the study doctor. 
5. Pazopanib tablets should be stored at room temperature. 
 
 

ALLIANCE A021202 
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Version Date: 04/08/2019 
 
 
 
 
 
 
 
Update #12 
CYCLE #: _______    # of WEEKS___________ 
D
A
Y 
Medication 
DATE 
TIME 
Number of 
200mg tablets 
taken 
Comments 
Exa
mple 
Pazopanib 
07/01/2012 
9:00 
AM 
4 x 200 
 
1 
Pazopanib 
 
 
 
 
 
2 
Pazopanib 
 
 
 
 
 
3 
Pazopanib 
 
 
 
 
 
4 
Pazopanib 
 
 
 
 
 
5 
Pazopanib 
 
 
 
 
 
6 
Pazopanib 
 
 
 
 
 
7 
Pazopanib 
 
 
 
 
 
8 
Pazopanib 
 
 
 
 
 
9 
Pazopanib 
 
 
 
 
 
10 
Pazopanib 
 
 
 
 
 
11 
Pazopanib 
 
 
 
 
 
12 
Pazopanib 
 
 
 
 
 
13 
Pazopanib 
 
 
 
 
 
14 
Pazopanib 
 
 
 
 
 
15 
Pazopanib 
 
 
 
 
 
16 
Pazopanib 
 
 
 
 
 
17 
Pazopanib 
 
 
 
 
 
18 
Pazopanib 
 
 
 
 
 
19 
Pazopanib 
 
 
 
 
 
20 
Pazopanib 
 
 
 
 
 
21 
Pazopanib 
 
 
 
 
 
22 
Pazopanib 
 
 
 
 
 
23 
Pazopanib 
 
 
 
 
 
24 
Pazopanib 
 
 
 
 
 
25 
Pazopanib 
 
 
 
 
 
26 
Pazopanib 
 
 
 
 
 
27 
Pazopanib 
 
 
 
 
 
28 
Pazopanib 
 
 
 
 
 
 
Patient Signature: _________________________________________Date:__________ 
Consenting Professional/Research RN Signature: ______________Date:__________  
 
 
 
 

ALLIANCE A021202 
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Version Date: 04/08/2019 
 
 
 
 
 
 
 
Update #12 
APPENDIX IV: REGISTRATION FATIGUE/UNISCALE ASSESSMENT 
 
At patient registration, this form is to be administered by a nurse/CRA, completed by the patient, 
and entered into RAVE. 
 
If needed, this appendix can be adapted to use as a source document.  A booklet containing this 
assessment does not exist – please do not order this booklet. 
 
A translator may be used to administer the assessment. Additionally, a French version of the 
assessment has been provided on the following page. 
 
 
 
How would you describe: 
 
your level of fatigue, on the average in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Fatigue 
 
 
 
 
 
 
 
 
 
Fatigue 
as bad  
as it can 
be 
 
your overall quality of life in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As 
bad as 
it can 
be 
 
 
 
 
 
 
 
 
 
As 
good 
as it 
can be 

ALLIANCE A021202 
91 
Version Date: 04/08/2019 
 
 
 
 
 
 
 
Update #12 
Fatigue/Uniscale Évaluation 
 
Instructions: S'il vous plaît, pour chaque article ci-dessous, encerclez le 
numéro (0-10) qui vous décrit le mieux. 
 
Comment décririez-vous : 
 
 
1. Votre niveau de fatigue moyen au cours de la dernière semaine, aujourd'hui inclus? 
  
0  
1  
2  
3  
4  
5  
6  
7 
 8  
9  
10  
Aucune fatigue  
 
La pire fatigue possible 
 
 
 
 
 
 
 
2. Votre qualité de vie globale dans la semaine écoulée, y compris aujourd'hui? 
 
 0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
Aussi mauvaise  
 
 
 
 
 
 
Aussi bonne 
que possible   
 
 
 
 
 
 
que possible 
 
 

ALLIANCE A021202 
92 
Version Date: 04/08/2019 
 
 
 
 
 
 
 
Update #12 
APPENDIX V: QUALITY OF LIFE MEASURES 
 
 
 
 

ALLIANCE A021202 
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Version Date: 04/08/2019 
 
 
 
 
 
 
 
Update #12 
EORTC QLQ-C30 (version 3) 
We are interested in some things about you and your health. Please answer all of the questions yourself 
by circling the number that best applies to you. There are no "right" or "wrong" answers.  The 
information that you provide will remain strictly confidential. 
Your birthdate (Day, Month, Year):                       
Today's date (Day, Month, Year):   
 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk outside of the 
house? 
1 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
 
 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other daily 
activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or 
other leisure time activities? 
1 
2 
3 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. 
Did you need to rest? 
1 
2 
3 
4 
11. 
Have you had trouble sleeping? 
1 
2 
3 
4 
12. 
Have you felt weak? 
1 
2 
3 
4 
13. 
Have you lacked appetite? 
1 
2 
3 
4 
14. 
Have you felt nauseated? 
1 
2 
3 
4 
15. 
Have you vomited? 
1 
2 
3 
4 
   
Please go on to the next page 
 
 
 

ALLIANCE A021202 
94 
Version Date: 04/08/2019 
 
 
 
 
 
 
 
Update #12 
During the past week: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
 
16. 
Have you been constipated?  
1 
2 
3 
4 
 
17. 
Have you had diarrhea?  
1 
2 
3 
4 
 
18. 
Were you tired? 
1 
2 
3 
4 
 
19. 
Did pain interfere with your daily activities?  
1 
2 
3 
4 
 
20. 
Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television?  
1 
2 
3 
4 
 
21. 
Did you feel tense? 
1 
2 
3 
4 
 
22. 
Did you worry? 
1 
2 
3 
4 
 
23. 
Did you feel irritable?  
1 
2 
3 
4 
 
24. 
Did you feel depressed?  
1 
2 
3 
4 
 
25. 
Have you had difficulty remembering things? 
1 
2 
3 
4 
 
26. 
Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
 
27. 
Has your physical condition or medical treatment 
interfered with your social activities?  
1 
2 
3 
4 
 
28. 
Has your physical condition or medical treatment 
caused you financial difficulties?  
1 
2 
3 
4 
 
 
For the following  questions  please  circle  the  number  between  1  and  7  that  best applies to 
you 
 
29. How would you rate your overall health during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
30. How would you rate your overall quality of life during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
Please go on to the next page 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 
 

ALLIANCE A021202 
95 
Version Date: 04/08/2019 
 
 
 
 
 
 
 
Update #12 
 
EORTC QLQ – GI.NET21 
 
Patients sometimes report that they have the following symptoms or problems. Please indicate the 
extent to which you have experienced these symptoms or problems during the past week. Please answer by 
circling the number that best applies to you. 
© QLQ-G.I.NET21 Copyright 2004 EORTC Quality of life Group. All rights reserved. Date: 20th February 2006 
 
During the past week: 
Not 
at 
A 
little 
Quite 
a bit 
Very 
much 
31. 
Did you have hot flushes? 
1 
2 
3 
4 
32. 
Have you noticed or been told by others that you looked flushed/red? 
1 
2 
3 
4 
33. 
Did you have night sweats? 
1 
2 
3 
4 
34. 
Did you have abdominal discomfort? 
1 
2 
3 
4 
35. 
Did you have a bloated feeling in your abdomen? 
1 
2 
3 
4 
36. 
Have you had a problem with passing wind/gas/flatulence? 
1 
2 
3 
4 
37. 
Have you had acid indigestion or heartburn? 
1 
2 
3 
4 
38. 
Have you had difficulties with eating? 
1 
2 
3 
4 
39. 
Have you had side-effects from your treatment? 
(If you are not on treatment please circle N/A) 
N/A 
1 
2 
3 
4 
40. 
Have you had a problem from repeated injections? 
(If not having injections please circle N/A) 
N/A 
1 
2 
3 
4 
41. 
Were you worried about the tumour recurring in other areas of the body? 
1 
2 
3 
4 
42. 
Were you concerned about disruption of home life? 
1 
2 
3 
4 
43. 
Have you worried about your health in the future? 
1 
2 
3 
4 
44. 
How distressing has your illness or treatment been to those close to you? 
1 
2 
3 
4 
45. 
Has weight loss been a problem for you? 
1 
2 
3 
4 
46. 
Has weight gain been a problem for you? 
1 
2 
3 
4 
47. 
Did you worry about the results of your tests? 
(If you have not had tests please circle N/A) 
N
1 
2 
3 
4 
48. 
Have you had aches or pains in your muscles or bones? 
1 
2 
3 
4 
49. 
Did you have any limitations in your ability to travel? 
1 
2 
3 
4 
During the past four weeks: 
50. 
Have you had problems receiving adequate information 
about your disease and treatment? 
1 
2 
3 
4 
51. 
Has the disease or treatment affected your sex life (for the worse)? 
(If not applicable please circle N/A) 
N/
A
1 
2 
3 
4 

ALLIANCE A021202 
96 
Version Date: 04/08/2019 
 
 
 
 
 
 
 
Update #12 
LINEAR ANALOGUE SELF ASSESSMENT 
Patient Name: ________________________________ Date: ______________________ 
Patient Number:  ______________________________ 
  
Directions: Please circle the number (0-10) best reflecting your response to the following 
 
  
that describes your feelings during the past week, including today. 
How would you describe: 
 
1. your overall Quality of Life? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be 
 
 
 
 
 
 
 
 
it can be 
 
2. your overall mental (intellectual) well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be 
 
 
 
 
 
 
 
 
it can be 
 
3. your overall physical well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be 
 
 
 
 
 
 
 
 
it can be 
 
4. your overall emotional well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be 
 
 
 
 
 
 
 
 
it can be 
 
5. your level of social activity? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be 
 
 
 
 
 
 
 
 
it can be 
 
6. your overall spiritual well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be 
 
 
 
 
 
 
 
 
it can be 
 
7. the frequency of your pain? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No pain 
 
 
 
 
 
 
 
 
Constant pain 
 
8. the severity of your pain, on the average? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No pain 
 
 
 
 
 
 
 
 
Pain as bad as  
 
 
 
 
 
 
 
 
 
 
 
you can imagine 
9. your level of fatigue, on the average? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No fatigue 
 
 
 
 
 
 
 
 
Constant tiredness 
 
10. your level of support from friends and family? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   

ALLIANCE A021202 
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Version Date: 04/08/2019 
 
 
 
 
 
 
 
Update #12 
 
No support  
 
 
 
 
 
 
 
 
Highest level of  
 
 
 
 
 
 
 
 
 
 
 
 
support 
 
11. your financial concerns? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Constant concerns 
 
 
 
 
 
 
 
No concerns 
 
12. your legal concerns (will, advanced directives, etc.)? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Constant concerns 
 
 
 
 
 
 
 
No concerns 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
© 1996  Mayo Foundation for Medical Research