Perfusion CT as Predictive Biomarker in a Phase II Study of Ziv-Aflibercept in Patients With Advanced Pancreatic Neuroendocrine Tumors
Phase: PHASE2
Conditions: Multiple Endocrine Neoplasia Type 1, Pancreatic Neuroendocrine Carcinoma
Sponsor: National Cancer Institute (NCI)

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SUMMARY OF CHANGES - PROTOCOL 
 
Protocol Amendment # 6: 
This protocol is being submitted to update the Comprehensive 
Adverse Events and Potential Risks list (CAEPR) and the study 
design in the protocol 
 
NCI Protocol #:  
 
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NEW TEXT:     
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Version 6 / Version Date: January 11, 2018 
 
RATIONALE: 
Updated Version Date 
 
2.  
7.ADVERSE 
EVENTS:  
LIST AND 
REPORTIN
G 
REQUIREM
ENTS 
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RATIONALE:  To update the Comprehensive Adverse Events and 
Potential Risks list (CAEPR) in the protocol 
 
 
3.  
Study 
Design/Sam
ple Size 
 
Stopping 
Rule 1 
60 
OLD TEXT:      
Stopping rule 1: The first early stopping rule applies to all patients by 
applying the Simon’s optimal two-stage design. In the first stage, we 
will enroll 21 evaluable patients. If 0 or 1 of the first 21 patients 
achieve RECIST response (PR or CR), the study will terminate.  If at 
least 2 of the first 21 evaluable patients achieve RESCIST response 
(PR or CR), an additional 20 patients will be enrolled.  If at the end of 

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the second stage, at least 5 out of 41 patients achieve RECIST 
response, the treatment will be considered acceptable for further 
testing.  This design has a 3.9% chance of accepting the treatment for 
further testing if the true response rate is ≤ 5% (type 1 error = 0.046), 
and 90% power (type 2 error = 0.1) of accepting the treatment for 
further testing if the true response rate is at least 20%.  The maximal 
accrual will be 41 evaluable patients.  The probability of early 
termination is 72% under the null hypothesis. 
 
NEW TEXT:      
 
The first early stopping rule applies to all patients by applying the 
Simon’s optimal two-stage design. In the first stage, we will enroll 21 
evaluable patients. If 0 or 1 of the first 21 patients achieve RECIST 
response (PR or CR), the study will terminate.  If at least 2 of the first 
21 evaluable patients achieve RESCIST response (PR or CR), an 
additional 20 patients will be enrolled.  If at the end of the second 
stage, at least 5 out of 41 patients achieve RECIST response, the 
treatment will be considered acceptable for further testing.  This 
design has a 4.6% chance of accepting the treatment for further testing 
if the true response rate is ≤ 5% (type 1 error = 0.046), and 85% power 
(type 2 error = 0.15) of accepting the treatment for further testing if the 
true response rate is at least 20%.  The maximal accrual will be 41 
evaluable patients.  The probability of early termination is 72% under 
the null hypothesis. 
 
RATIONALE: 
Given the inclusion of more heavily pretreated patients, the response 
rate under the null hypothesis was reduced, and the response rate 
under the alternative hypothesis was simultaneously adjusted (from 
0.21 to 0.2) for simplicity.  Type I and type II error rates were 
simultaneously adjusted (from 0.084 to 0.05 and from 0.1 to 0.15, 
respectively) based on our own recent work regarding the predictive 
value of phase II studies, demonstrating that smaller type I errors with 
compensatory increases in type II error rates result in phase II designs 
more likely to predict for eventual drug efficacy and approval.  These 
changes resulted in changes to the total number of patients anticipated 
to be accrued, resulting in new calculations for the imaging parameter 
power calculations. 
 
 
 

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NCI Protocol #: 
9604 
 
Local Protocol #: 
2013-0954 
 
TITLE:  Perfusion CT as predictive biomarker in a phase II study of ziv-aflibercept in patients 
with advanced pancreatic neuroendocrine tumors 
 
Coordinating Center: 
 
 
University of Texas MD Anderson Cancer Center 
 
*Principal Investigator: 
Daniel M. Halperin, MD 
 
1515 Holcombe Blvd, Unit 426 
 
Houston, Texas 77030 
 
713-792-2828 (Office) 
 
713-745-1163 (Fax) 
 
dmhalperin@mdanderson.org 
 
Co-Investigators: 
Chaan Ng, MD (Radiology Perfusion CT Lead) 
 
1400 Pressler St, FCT 15.6090 
 
Houston, Texas 77030 
 
713-792-6759 
 
cng@mdanderson.org 
 
 
Moffitt Cancer Center: 
Johnathan R. Strosberg, MD (Co-PI) 
 
Moffitt Cancer Center, faculty buidling 2nd floor 
 
12902 Magnolia Dr. 
 
Tampa, Florida 33612 
813-745-3636 (Office) 
813-745-7229 (Fax) 
 
Jonathan.strosberg@moffitt.org 
 
Moffitt Cancer Center International Plaza: 
 
Johnathan R. Strosberg, MD (Co-PI) 
Moffitt Cancer Center International Plaza 
4101 Jim Walter Boulevard  
Tampa, Florida 33067 
813-745-3636 (Office) 
813-745-7229 (Fax) 
Jonathan.strosberg@moffitt.org 
 
 

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Statistician: 
 
Study Coordinator:  
 
J. Jack Lee 
Mary Brimer, RN 
 
1400 Pressler St, FCT 4.6012 
1515 Holcombe, Unit 0426 
 
Houston, Texas 77030 
Houston, Texas  77030 
 
713-794-4158 (Office) 
713-563-7757 (Office) 
 
jjlee@mdanderson.org 
713-563-9188 (Fax) 
 
 
mebrimer@mdanderson.org   
 
Responsible Research Nurse: 
Responsible Data Manager: 
 
Michiko Iwasaki, RN 
Roxana Galvis 
 
1515 Holcombe, Unit 0426 
1515 Holcombe, Unit 0426 
 
 Houston, Texas  77030 
Houston, Texas 77030 
 
713-794-4869 (Office) 
713-563-4314 (Office) 
 
713-745-2846 (Fax) 
713-745-2846 (Fax) 
 
miwasaki@mdanderson.org   
rgalvis@mdanderson.org  
 
 
NCI-Supplied Agent(s):   
Ziv-aflibercept (NSC 724770) 
Other Agent(s):   
Not applicable 
 
IND #: 100137 
 
IND Sponsor: NCI Division of Cancer Treatment and Diagnosis (DCTD) 
 
Protocol Type / Version # / Version Date: 
 
Original / Version 4 / Version Date: January 15, 2016 
Version 5 / Version Date: September 29, 2016 
Version 6/ Version Date: January 11, 2018

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TABLE OF CONTENTS 
SCHEMA ................................................................................................................................3 
1. 
OBJECTIVES ...............................................................................................................6 
1.1 
Primary Objectives.............................................................................................6 
1.2 
Secondary Objectives .........................................................................................6 
1.3 
Exploratory Objectives.......................................................................................6 
2. 
BACKGROUND ..........................................................................................................6 
2.1 
Pancreatic NETs ................................................................................................6 
2.2 
CTEP IND Agent: Ziv-aflibercept ......................................................................8 
2.3 
Rationale ......................................................................................................... 11 
2.4 
Correlative Studies Background........................................................................ 15 
3. 
PATIENT SELECTION .............................................................................................. 15 
3.1 
Eligibility Criteria ............................................................................................ 15 
3.2 
Exclusion Criteria ............................................................................................ 16 
3.3 
Inclusion of Women and Minorities .................................................................. 18 
4. 
REGISTRATION PROCEDURES .............................................................................. 18 
4.1 
General Guidelines........................................................................................... 18 
4.2 
Registration Process ......................................................................................... 18 
5. 
TREATMENT PLAN ................................................................................................. 19 
5.1 
Agent Administration ....................................................................................... 19 
5.2 
General Concomitant Medication and Supportive Care Guidelines .................... 20 
5.3 
Duration of Therapy ......................................................................................... 20 
5.4 
Duration of Follow Up ..................................................................................... 20 
5.5 
Criteria for Removal from Study ...................................................................... 21 
6. 
DOSING DELAYS/DOSE MODIFICATIONS............................................................ 21 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS........................... 27 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) .............. 27 
7.2 
Adverse Event Characteristics .......................................................................... 31 
7.3 
Expedited Adverse Event Reporting ................................................................. 31 
7.4 
Routine Adverse Event Reporting..................................................................... 34 
7.5 
Secondary Malignancy ..................................................................................... 34 
7.6 
Second Malignancy.......................................................................................... 34 
8. 
PHARMACEUTICAL and/or IMAGING AGENT INFORMATION ........................... 35 
8.1 
CTEP IND Agent(s) ......................................................................................... 35 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ...................................... 37 
9.1 
Perfusion CT.................................................................................................... 38 
9.2 
Laboratory Correlative Studies ......................................................................... 39 
9.3 
Special Studies................................................................................................. 40 

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10. 
STUDY CALENDAR ................................................................................................. 41 
11. 
MEASUREMENT OF EFFECT .................................................................................. 42 
11.1 
Antitumor Effect – Solid Tumors...................................................................... 42 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ........................................ 48 
12.1 
Data Reporting................................................................................................. 48 
12.2 
CTEP Multicenter Guidelines ........................................................................... 49 
12.3 
Collaborative Agreements Language ................................................................ 49 
13. 
STATISTICAL CONSIDERATIONS.......................................................................... 51 
13.1 
Study Design/Endpoints/Objectives .................................................................. 51 
13.2 
Study Design/Sample Size/Accrual Rate ........................................................... 51 
13.3 
Analysis of Secondary and Exploratory Endpoints ............................................ 54 
13.4 
For phase 2 protocols only: Reporting and Exclusions ....................................... 56 
REFERENCES....................................................................................................................... 57 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ............................................... 59 
APPENDIX B 
CTEP MULTICENTER GUIDELINES................................................. 60 
APPENDIX C 
NEW YORK HEART ASSOCIATION CLASSIFICATION OF 
FUNCTIONAL CARDIAC CAPACITY ............................................... 62 
APPENDIX D 
REGISTRATION FORM...................................................................... 63 
APPENDIX E 
NCISS MULTICENTER STUDY MANAGEMENT PLAN .................. 67 
 

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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 Estimate the objective response rate (RR) of ziv-aflibercept among patients with 
advanced pancreatic neuroendocrine tumors (NET)s according to RECIST 1.1 
 
1.1.2 Test the following hypotheses: that baseline perfusion CT parameters can predict which 
patients with advanced pNETs will respond to treatment with ziv-aflibercept. 
Specifically: 
a. Pancreatic NETs with high baseline blood volume (BV > 5.25 ml/100gram) measured 
by pCT will have a higher response rate to therapy with ziv-aflibercept than those 
with low baseline BV (BV ≤ 5.25ml/100gram).  
b. Pancreatic 
NETs 
with 
high 
baseline 
permeability 
surface 
(PS 
> 
25 
ml/minute/100gram) measured by pCT will have a higher response rate to therapy 
with ziv-aflibercept than those with low baseline PS (PS ≤ 25 ml/minute/100gram). 
 
1.2 
Secondary Objectives 
 
1.2.1 Estimate progression free survival (PFS) duration among patients treated with ziv-
aflibercept  
 
1.2.2 Evaluate the relationship between response rate and baseline BV and between response 
rate and baseline PS  
 
1.3 
Exploratory Objectives 
 
1.3.1 Determine whether post-treatment changes in BV expressed as relative change from 
baseline correlate with response to ziv-aflibercept 
1.3.2 Determine whether post-treatment tumor blood flow (BF) (absolute measurement) 
correlates with response to ziv-aflibercept 
1.3.3 Determine whether post-treatment changes in BF and, BV, expressed as relative change 
from baseline, correlate with relative change in sum of tumor diameters (RECIST 
1.1measurements) 
1.3.4 Determine the effect of ziv-aflibercept therapy on post-treatment blood flow (BF), BV, 
mean transit time (MTT), and PS at 4 weeks after treatment 
1.3.5 Evaluate the changes in tumor perfusion parameters at time of progression 
 
2. BACKGROUND 
 
2.1 
Pancreatic NETs 
 
Pancreatic NETs are low- to intermediate-grade neoplasms that are thought to arise from the 
pancreatic islets. Also known as pancreatic endocrine tumors and, islet cell tumors, or pancreatic 
carcinoid, PNETs account for a minority of pancreatic neoplasms and can be either functional or 

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nonfunctional. The functional status of pancreatic NETs is generally influenced by several 
factors, including disease bulk, stage, secretory status, and whether the peptide secreted is intact 
and causes distinct clinical symptoms. Pancreatic NETs are generally considered functional if 
they are associated with a hormonal syndrome. Those pancreatic NETs not causing a clinical 
hormonal syndrome are considered nonfunctional.  It is also recognized that the functional status 
of these tumors may change over time or with treatment.  Moreover, some of these tumors can 
produce multiple hormones simultaneously, although symptoms related to one of these hormones 
often will dominate. 
 
Pancreatic NETs are reputed to be relatively rare neoplasms, but their exact incidence and 
prevalence are somewhat elusive. This is in part because most registries, including the 
Surveillance, Epidemiology, and End Results (SEER) Program, only include neoplasms that are 
deemed malignant.  For most epithelial malignancies, invasion of the basement membrane 
defines malignant behavior, but for pancreatic NETs, the definition of malignant behavior is 
more complex.  In absence of malignant behavior such as direct invasion of adjacent organs or 
metastases to regional lymph nodes or distant sites, size is typically used to classify pancreatic 
NETs as benign or malignant.  We recently undertook comprehensive population-based analyses 
of NETs from SEER registries between 1973 and 2004.  The annual age-adjusted incidence of 
NETs arising from the pancreas in the periods covered by the SEER 17 (2000-2004) was 0.32 
per 100,000 population, respectively.(1) Malignant well-differentiated pancreatic NETs accounts 
for approximately 1% of pancreatic cancers by incidence and 10% of pancreatic cancers by 
prevalence. (2) 
 
The incidence of smaller pancreatic NETs in the general population, however, is likely to be 
much higher.  For example, surgical series suggest that most insulinomas are small and localized, 
yet in the SEER registries, 61% of insulinomas had distant metastases at diagnosis,(2) a finding 
that suggests that most of the small insulinomas are not being included in those statistics.  
Furthermore, in an analysis of 11,472 autopsies performed at a Hong Kong hospital, pancreatic 
NETs were found in 0.1% of all cases.(3)  This suggest that the prevalence of small 
asymptomatic islet cell tumors, many of which are never diagnosed, may be 100 fold more 
common than the data suggested by SEER registries.   
 
Pancreatic NETs are usually more indolent than the more common forms of pancreatic cancer 
are. Management of pancreatic NETs generally can be categorized into management of the 
problems caused by secreted hormone(s) and oncologic issues related to tumor growth and 
management of metastasis.  While somatostatin analogues are quite active and standard of care 
for hormonal syndromes from pancreatic NETs, the oncologic management of advanced 
pancreatic NETs remains an area of unmet need.  
 
Streptozocin-based chemotherapy was approved by the Food and Drug Administration for the 
treatment of pancreatic NET nearly three decades ago. Analyses of 2 large case-series using 
Response Evaluation Criteria of Solid Tumors (RECIST) criteria have reported objective tumor 
response rates of 38 and 39% (4, 5). However, the exact role of streptozocin-based chemotherapy 
is still debated due to potentially serious adverse events and conflicting data about efficacy. 
 
Genetic cancer syndromes (TSC-2, NF-1, and vHL), somatic mutations identified using an 

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exome sequencing approach, and expression profiling have consistently implicated a dysfunction 
of the mammalian target of rapamycin (mTOR) pathway as a critical event in pancreatic NETs 
(6-8). Everolimus, an oral inhibitor of mTOR, was studied in a multi-national double blind 
placebo controlled phase III study (9). The study demonstrated that everolimus significantly 
prolonged median progression free survival (PFS) from 4.6 to 11 months compared to placebo 
(Hazard Ratio [HR] = 0.35, 95% Confidence Interval [CI], 0.27 - 0.45; P<0.0001). Everolimus 
also significantly reduced insulin, glucagon and gastrin secretions among patients with functional 
pancreatic NETs (10, 11).  
 
NETs are vascular tumors.  Hence, there is also strong rationale to study anti-angiogenic agents 
in NETs. Sunitinib, an inhibitor of vascular endothelial growth factor (VGEF) and platelet-
derived growth factor (PDGF) receptors, was also studied in a double-blinded placebo-controlled 
phase III study (12).  Treatment with sunitinib 37.5 mg daily was associated with an 
improvement in median PFS from 5.5 to 11.4 months (HR = 0.42, 95% CI, 0.26 - 0.66) (12). 
Although the study failed to achieve statistical significance due to unplanned interim analyses 
and early termination, its results are supported by other studies of VEGF inhibitors in pancreatic 
NET (13-15).  Additionally, evidence from renal cell carcinoma suggests that multiple VEGF 
inhibiting agents can be used in series with continued efficacy.  In a study of renal cell carcinoma 
patients who had previously received sunitinib, pazopanib resulted in objective responses in 6/31 
(19%) patients, including 3/18 (17%) of the patients who discontinued sunitinib due to disease 
progression(16). 
 
Results from these two randomized phase III studies led to the approval of everolimus and 
sunitinib for the treatment of pancreatic NET and changed the treatment paradigm. However, it 
should be noted that the objective response rates for everolimus and sunitinib are low and 
predictive markers of benefit remains undefined.  
 
2.2 
CTEP IND Agent: Ziv-aflibercept 
 
Background and pharmacological mode of action 
 
Ziv-aflibercept is also referred to as “AVE0005,” “AVE0005 (VEGF Trap),” “VEGF Trap,” “V-
Trap,” and “VGFT” in various clinical study protocols and other documents. However, it will be 
referred to by its international non-proprietary name (INN), ziv-aflibercept, throughout this 
protocol (Investigator’s Brochure, 2011). 
 
Ziv-aflibercept is a recombinant fusion protein consisting of human vascular endothelial growth 
factor (VEGF) receptor extracellular domains fused to the Fc portion of human immunoglobulin 
G1 (IgG1). Ziv-aflibercept contains portions of the extracellular domains of 2 different vascular 
endothelial growth factor receptors (VEGFRs): VEGFR1 (also known as Flt-1) and VEGFR2 
(also known as KDR or Flk-1). Ziv-aflibercept binds VEGF in the picomolar (pmol/L) range, 
and also binds placental growth factor (PlGF), although with lower affinity. The affinity 
constants (KD) for binding to 2 human isoforms of VEGF, VEGF165 and VEGF121, are 0.50 
pmol/L and 0.36 pmol/L, respectively. The KD for human PlGF2 is 39 pmol/L. The binding of 
ziv-aflibercept to its ligands in vivo is expected to block tumor angiogenesis and vascular 
permeability (Investigator’s Brochure, 2011). 

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Ziv-aflibercept drug product is formulated as a sterile liquid for intravenous (IV) administration. 
Ziv-aflibercept has been found to be active with a broad pharmacological index against early and 
advanced stage disease in a variety of preclinical solid tumor models including sarcomas, and 
ovarian, prostate, mammary, colon, and gastric carcinomas when used as a single agent or in 
combination with cytotoxic agents. In mouse models of ascites formation with ovarian and renal 
cell carcinoma, ziv-aflibercept inhibited ascites formation and reduced tumor burden 
(Investigator’s Brochure, 2011). 
 
Two analytes were assayed in animal models specifically by enzyme linked immunosorbent 
assay (ELISA) methods: free ziv-aflibercept (compound not complexed to VEGF), and bound 
ziv-aflibercept (complexed ziv-aflibercept: VEGF [ratio 1/1]) (Investigator’s Brochure, 2011). 
 
Following IV administration in all animal species evaluated, free ziv-aflibercept was 
characterized by a low clearance (0.5 to 3 mL/hr/kg), a low volume of distribution (51 to 77 
mL/kg), and a long apparent elimination half-life (t1/2) of 48 to 98 hours.  Based on the 
correlation between exposure and activity in non-clinical models, the target pharmacological 
exposure in humans is proposed to be a safely administered dose of ziv-aflibercept at which an 
excess of free ziv-aflibercept is sustained (Investigator’s Brochure, 2011). 
 
Clinical overview 
 
The cutoff for data inclusion in this update is 31 July 2011. To date, the clinical development of 
ziv-aflibercept encompasses a total of 41 clinical oncology trials (25 sanofi trials and 16 national 
cancer institute [NCI] trials) in more than 3700 cancer patients mostly with advanced solid 
malignancies as well as 2 clinical trials in 76 healthy subjects (PDY6655 and PDY6656).  Doses 
have been administered up to 800 µg/kg SC twice weekly, 7 mg/kg IV every 2 weeks (q2w), and 
9 mg/kg IV every 3 weeks (q3w). 
 
Ziv-aflibercept was initially administered SC in 2 single-agent dose-escalation safety and 
pharmacokinetic (PK) studies (TED6113/6114) in patients with advanced solid tumors or 
lymphomas. However, the SC route of administration was discontinued due to the high volume 
of injection required for the formulated ziv-aflibercept concentration of 25 mg/mL. 
Subsequently, only IV administration was used in all clinical studies. 
 
Phase 1 single-agent dose escalation studies (TED6115/TED6116) evaluated safety, tolerability, 
PK and anti-tumor activity in patients with various solid tumor types. Phase 2 single-agent 
studies were designed to measure the effect of ziv-aflibercept in patients with ovarian cancers 
(ARD6122, ARD6772, and EFC6125), and non-small-cell lung adenocarcinoma ([NSCLA], 
ARD6123). 
 
Combination Phase 1 dose-escalation studies were conducted to evaluate safety, PK, and anti-
tumor activity in patients with solid malignancies. The recommended Phase 2 dose (RP2D) of 
ziv-aflibercept was confirmed in these Phase 1 combination studies as 4 mg/kg every 2 weeks 
(q2w) when combined with chemotherapy administered every 2 weeks, as was initially 
determined in single-agent studies TED6115/TED6116. 

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Combination Phase 3 studies’ primary objective was efficacy. In these studies, ziv-aflibercept 
was administered IV over 1 hour at 4 mg/kg q2w or 6 mg/kg q3w depending on the associated 
chemotherapy schedule. 
 
In the q2w regimen in Phase 1 and Phase 3 combination studies, ziv-aflibercept was combined 
with standard doses of the following cytotoxic agents: oxaliplatin/5-fluorouracil/leucovorin 
(FOLFOX4), 
[TCD6117]), 
irinotecan/leucovorin/5-fluorouracil 
(irinotecan/LV5FU2, 
[TCD6118]), 
and 
gemcitabine 
or 
gemcitabine 
and 
erlotinib 
(TCD6121), 
gemcitabine 
(EFC10547/VANILLA), and irinotecan/5-FU/leucovorin (FOLFIRI, [EFC10262/VELOUR]). 
 
In the q3w regimen in Phase 1 and Phase 3 combination studies, ziv-aflibercept was combined 
with standard doses of docetaxel (Taxotere®)/cisplatin/5-fluorouracil (TCF, [TCD6119]), 
docetaxel or docetaxel/cisplatin or pemetrexed (TCD6120), and docetaxel (EFC10261/VITAL). 
 
Clinical pharmacology 
 
Pharmacokinetics measurements were also performed during clinical trials and to characterize 
the PK of ziv-aflibercept, 2 analytes were quantified in healthy subjects and in patients: free ziv-
aflibercept (compound not complexed to VEGF) and bound ziv-aflibercept (VEGF:aflibercept 
complex in a ratio 1:1). Bound ziv-aflibercept is pharmacologically inert. In addition, population 
PK analyses were conducted based on pooled PK data from Phase 1, Phase 2 and Phase 3 
studies. 
 
Free ziv-aflibercept is thought to be cleared by 2 mechanisms in humans: a fast clearance 
resulting from binding VEGF to form bound ziv-aflibercept, and a slower pathway where the 
free ziv-aflibercept is eliminated by other biological mechanisms, such as protein catabolism. 
The results in humans are consistent with those from animal studies. Renal elimination of ziv-
aflibercept has not been investigated in humans. However, since high molecular weight (MW) 
proteins are not cleared by this route, renal elimination of ziv-aflibercept is expected to be 
minimal. This has been confirmed in rat studies. 
 
Ziv-aflibercept exhibits a non linear PK with higher clearance at lowest dose levels whilst the PK 
of free ziv-aflibercept is linear over the 2-9 mg/kg dose range. This could be related to saturable 
high- affinity binding of ziv-aflibercept to endogenous VEGF at higher doses, limited by VEGF 
availability. At doses greater than 2 mg/kg, free ziv-aflibercept clearance is 1.0 L/day with a 
terminal half-life of 6 days and a volume of distribution (Vss=7.8 L) slightly greater than blood 
compartment. Elimination of VEGF-bound ziv-aflibercept is slower with an apparent clearance 
of 
0.182 L/day and a half-life of 15 days. At 4 mg/kg q2w and 6 mg/kg q3w, concentrations of free 
ziv-aflibercept were near steady-state levels by the second cycle with essentially no 
accumulation (accumulation ratio of 1.2 and 1.1, respectively). 
 
According to simulations conducted using the population PK model, at 4 mg/kg q2w, the free to 
bound ziv-aflibercept ratio exceeds 1 throughout all the dosing intervals for 89% of the 
population. Consistently, the mean free over bound ziv-aflibercept ratio measured in all studies 

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showed that free was in excess of bound ziv-aflibercept throughout treatment period at dose 
levels greater than 2 mg/kg every 2 weeks or greater than 4 mg/kg every three weeks. 
 
In combination therapies, no impact of ziv-aflibercept was observed on the PK of cytotoxic 
agents including oxaliplatin, cisplatin, 5-FU, irinotecan, docetaxel, pemetrexed, gemcitabine and 
erlotinib. 
 
Pharmacodynamics (PD) and PK/PD evaluations were also undertaken during clinical trials to 
determine the effect of ziv-aflibercept on blood pressure (PDY6655 and PDY6656), on the Q-T 
interval (TES10897), and on the relationship between PK parameters and safety and efficacy 
variables in Phase 3 studies (EFC10547/VANILLA, EFC10261/VITAL, EFC10262/VELOUR). 
 
The results on blood pressure (BP) from PDY6655 and PDY6656, suggested a renin-independent 
mechanism of hypertension induced by ziv-aflibercept. No clear mechanism of the dose-related 
increase in BP was revealed in both studies, in particular, no change in renin angiotensin 
aldosterone system was observed. 
 
In the randomized, double-blind trial (TES10897) of docetaxel combined with either ziv-
aflibercept 6 mg/kg q3w or placebo, it was concluded that ziv-aflibercept 6 mg/kg did not affect 
the ventricular repolarization in humans to an extent that would require substantial risk-benefit 
evaluation. 
 
Across the Phase 3 trials, individual free ziv-aflibercept clearance and AUCs were consistently 
correlated with both clinical efficacy outcomes and some class event safety endpoints. Overall, 
the lower the free ziv-aflibercept clearance, and the higher the free ziv-aflibercept AUC, the 
longer the overall survival (OS) and progression-free survival (PFS); but the higher the 
incidences of hypertension (in each Phase 3 trial) and hemorrhage (in the EFC10262/VELOUR 
MCRC pivotal Phase 3 trial).  Considering these findings and the clinical results of 
EFC10262/VELOUR, the ziv-aflibercept dose of 4mg/kg q2w appears to correspond to an 
adequate dose when combined with FOLFIRI in MCRC and for general use in combination 
therapy. 
 
In clinical studies, serum levels of anti-aflibercept antibodies were measured in all patients 
during and after treatment. A low incidence of positive responses in the assays was reported and 
no or limited effect of positive response in the assays was observed on PK. 
 
2.3 
Rationale 
 
2.3.1 Rationale for ziv-aflibercept in pNETs 
 
Well-differentiated neuroendocrine tumors (WDNET) can originate from cells scattered 
throughout the body. While generally thought to be rare, its diagnosed incidence is on the rise.(1) 
WDNETs are vascular and known to express vascular endothelial growth factor (VEGF).(17, 18) 
Prior studies with VEGF monoclonal antibody, bevacizumab,(19) and VEGF tyrosine kinase 
inhibitors sunitinib,(13, 20) sorafenib,(14) and pazopanib(15) have demonstrated promising 
activity. The response rates for VEGF tyrosine kinase inhibitors have generally been higher for 

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patients with pancreatic NETs. A recent phase III study reported improved  Progression Free 
Survival (PFS) among patients with advanced pancreatic NET treated with sunitinib compared to 
placebo.(21) 
 
There is also data to support that PlGF may be of critical importance in pNETs. In RADIANT-3, 
largest phase III study to have been ever conducted in pNETs, Everolimus significantly 
improved PFS compared with placebo (11 vs 4.6 months; HR=0.35; 95% CI, 0.27 to 0.45; 
P<.001).(9) We recently reported the analysis of VEGF pathway biomarkers from the study.(22) 
In univariate analyses, patients with elevated baseline VEGF-A (P =0.001), PlGF (P =0.004) or 
sVEGFR1 (P <0.001) had significantly shorter PFS compared to those with low marker levels. In 
multivariate analysis using a Cox proportional hazards model stratified by treatment arm, which 
included all baseline angiogenesis markers (high vs low), only sVEGFR1 and PlGF were 
significantly associated with PFS (HR 1.54 [95% CI, 1.20–1.98; P<0.001] and 1.35 [95% CI, 
1.01–1.81; P=0.46] respectively).(22) These analyses suggest PlGF plays a significant role in 
pNET and there is rationale to study ziv-aflibercept in pNETs. 
 
2.3.2 Rationale for baseline perfusion CT as predictive biomarker 
 
There is urgent need for the development of predictive and prognostic biomarker in oncology to 
accelerate advances in novel therapeutics, and to develop personalized therapy. Biomarkers for 
therapies targeting angiogenesis have been particularly challenging. This is in part due to fact 
that tumor response rates with these and other molecularly targeted therapies have generally been 
low. Nonetheless, treatment can be associated with significant improvements in progression-free 
survival and overall survival. Predictive, prognostic, and pharmacodynamic biomarkers that will 
enable development of novel drugs and novel drug combinations targeting angiogenesis are 
needed. 
 
Since the initial report that a greater reduction in Ktrans, measured by DCE-MRI, was associated 
with disease stabilization in a phase I study of VEGF tyrosine kinase inhibitor, PTK/ZK,(12) 
many have attempted to correlate dynamic imaging findings with clinical outcome with varying 
degrees of success.(4, 13-16) In our prior study with bevacizumab and PEG interferon, perfusion 
CT (pCT), demonstrated that bevacizumab led to rapid and sustained decrease in tumor blood 
flow (BF), and suggested that lower post-treatment blood volume (BV) correlated with PFS.(4) 
One limitation of many past studies, including our prior study,(4) is that dynamic imaging was 
optional and not uniformly performed among all patients, limiting statistical power and raising 
the issue of potential selection bias. Other retrospective studies have included heterogeneous 
groups of patients treated with different VEGF inhibitors. Nonetheless, many of these studies 
suggested that dynamic imaging has the potential to select patients likely to benefit from anti-
angiogenic therapy. (4, 13-16)  
 
In our more recent study with bevacizumab and everolimus, we confirmed that the absolute 
decrease in tumor BF following bevacizumab and everolimus, correlated with baseline BF, and 
that such therapy decreased tumor BF by a percentage.(17)  In this study, pre-treatment 
permeability surface (PS), percent reduction in BF, BV, and post-treatment mean transit time 
(MTT) correlated with RECIST response.(17) Scatter plot of parameters with best change in 
RECIST target lesion diameters are included below. 

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Figure 1. Correlation of perfusion CT parameters with best changes RECIST target lesion 
measurement following treatment with VEGF inhibitors. 
 
Baseline PS (ml/min/100gm)
50
40
30
20
10
0
Sum of target lesion diameters
20%
0%
-20%
-40%
-60%
-80%
R2 = .19; P = .009
BF change at week 9 relative to baseline
150%
100%
50%
0%
-50%
-100%
Sum of target lesion diameters
20%
0%
-20%
-40%
-60%
-80%
R2 = .14; P = .03
 
 
BV change at week 9 relative to baseline
150%
100%
50%
0%
-50%
-100%
Sum of target lesion diameters
20%
0%
-20%
-40%
-60%
-80%
R2 = .26; P = .002
MTT at week 9
16.0
14.0
12.0
10.0
8.0
6.0
4.0
2.0
Sum of target lesion diameters
20%
0%
-20%
-40%
-60%
-80%
R2 = .25; P = .003
 
 
The high number of parameters correlating with outcome is likely related to the high degree of 
correlation between these parameters. In a recent pooled-analysis of pancreatic NET patients 
treated with VEGF inhibitors at MD Anderson, baseline BV also correlated with response. Of 
particular interest are the correlations between pre-treatment BV and PS with tumor response. 
This suggests that one can select patient likely to benefit from anti-angiogenic therapy based on 
one pre-treatment scan. We will formally test this hypothesis in the current study. 
 
If the pCT can be confirmed to select patients who will benefit from VEGF inhibitors such as 
ziv-aflibercept, this approach could be used for further development of ziv-aflibercept in NET as 
well, as identification of subgroups of patients with other solid tumors likely to benefit from 
agents targeting the VEGF pathway. 
 
 

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2.4 
Correlative Studies Background 
 
See section 2.3.2. As perfusion CT is co-study primary objective, background is described in 
above section. 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed low or intermediate grade 
pancreatic NET.  Patients with neuroendocrine tumors associated with MEN1 syndrome 
will be eligible.  
 
3.1.2 Patients must have unresectable or metastatic disease.  
 
3.1.3 Patients must have at least one measurable site of disease according to RECIST 1.1 that 
has not been previously irradiated. 
 
3.1.4 Patients must have at least one lesion suitable for perfusion CT.  The lesion should be 
greater than or equal to 3 cm in size in the cranial caudal direction. 
 
3.1.5 Patient must have no contraindication for CT with iodinated contrast 
 
3.1.6 Patients who are on a somatostatin analogue for control of hormonal syndromes must be 
on a stable dose (no change in mg dose of long acting octreotide or lanreotide, changes in 
dosing interval of +/- 1 week is allowed) for 2 months prior to date of study entry. 
 
3.1.7 Women of child-bearing potential must have a negative serum pregnancy test within 7 
days prior to date of study entry.  Women who have had menses within the past 2 years, 
who have not had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy are 
considered to be of child-bearing potential. Patients with elevated hCG at baseline that is 
judged to be related to the tumor are eligible if hCG levels do not show the expected 
doubling when repeated 5-7 days later, or pregnancy has been ruled out by vaginal 
ultrasound. 
 
3.1.8 Any number of prior lines of systemic anti-neoplastic therapy are allowed. Treatment 
with ≤ 1 prior VEGF inhibitor will be allowed. 
 
3.1.9 Patients must have normal organ and marrow function as defined below: 
 
leukocytes 
≥3,000/mcL 
 
absolute neutrophil count 
≥1,500/mcL 
 
platelets 
≥100,000/mcL 
 
total bilirubin 
≤1.5 × institutional upper limit of normal 
 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal 
 
creatinine 
within normal institutional limits 
OR 

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 
creatinine clearance 
 ≥60 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal. 
 
Urine protein:creatinine ratio  
≤ 1.0.  
OR 
 
24-hour urine protein  
≤ 500 mg (24-hour total urine protein only need be 
obtained if urine protein : creatinine ratio < 1.0) 
 
3.1.10 Patients must have PT/INR/PTT within 1.2 X the upper limit of normal. 
 
3.1.11 Patients must have resting blood pressure (BP) no greater than 140 mmHg (systolic) or 
90 mmHg (diastolic) for eligibility.  Initiation or adjustment of BP medication is 
permitted prior to study entry.   
 
3.1.12 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 Exclusion Criteria 
 
3.2.1 Less than 28 days elapsed from prior radiotherapy, from prior surgery and prior 
chemotherapy to the time of randomization. Less than 42 days elapsed from prior major 
surgery to the time of randomization. 
 
3.2.2 Adverse events (with exception of alopecia, peripheral sensory neuropathy and those 
listed in specific exclusion criteria) from any prior anti cancer therapy of grade >1 
(National Cancer Institute Common terminology Criteria [NCI CTCAE] v.4.0). 
 
3.2.3 Age < 18 years. 
 
3.2.4 ECOG PS > 2. 
 
3.2.5 History of brain metastases, uncontrolled spinal cord compression, or carcinomatous 
meningitis or new evidence of brain or leptomeningeal disease. 
 
3.2.6 Other prior malignancy. Adequately treated basal cell or squamous cell skin cancer, 
carcinoma in situ of the cervix or any other cancer from which the patient has been 
disease free for > 5 years are allowed. 
 
3.2.7 Participation in another clinical trial and any concurrent treatment with any 
investigational drug within 30 days prior to study entry. 
 
3.2.8 Any of the following within 6 months prior to study entry: myocardial infarction, 
severe/unstable angina pectoris, coronary/peripheral artery bypass graft, NYHA class III 
or IV congestive heart failure, stroke or transient ischemic attack. 
 

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3.2.9 Any of the following within 3 months prior to study entry: Grade 3-4 gastrointestinal 
bleeding/hemorrhage, treatment resistant peptic ulcer disease, erosive oesophagitis or 
gastritis, infecttious or inflammatory bowel disease, diverticulitis, pulmonary embolism 
or other uncontrolled thromboembolic event. 
 
3.2.10 Occurrence of deep vein thrombosis within 4 weeks, prior to study entry. 
 
3.2.11 Acquired immuno deficiency syndrome (AIDS-related illnesses) or known HIV disease 
requiring antiretroviral treatment. 
 
3.2.12 Any severe acute or chronic medical condition, which could impair the ability of the 
patient to participate to the study or to interfere with interpretation of study results. 
 
3.2.13 Pregnant or breast feeding women. Positive pregnancy test (serum or urine β-HCG) for 
women of reproductive potential. 
 
3.2.14 Patient with reproductive potential (female and male) who do not agree to use an 
accepted effective method of contraception (hormonal or barrier methods, abstinence) 
during the study treatment period and for at least 3 months following completion of study 
treatment. For female patient enrolled, the following methods of contraception are 
acceptable: oral contraceptives accompanied by the use of a second method of 
contraception, as it is not known how oral contraceptives interact with all study 
medications or Intra Uterine Device (IUD) or women who are surgically sterile, or 
women who are post –menopausal or other reasons have no chance of becoming 
pregnant. 
 
3.2.15 Absence of signed and dated Institutional Review Board-approved patient informed 
consent from prior to enrollment in the study. 
 
Exclusion criteria related to ziv-aflibercept: 
 
3.2.16 Urine protein-creatinine ratio (UPCR ) >1 urinalysis or total urine protein > 500 mg/24h. 
 
3.2.17 Serum creatinine > 1.5 x upper limit of normal (ULN). If creatinine 1.0-1.5 x ULN, 
creatinine clearance, calculated according to Cockroft-Gault formula, < 60 ml/min will 
exclude the patient. 
 
3.2.18 History of uncontrolled hypertension, defined as systolic blood pressure > 150 mmHg 
while simultaneous diastolic blood pressure >100 mmHg, or systolic blood pressure >180 
mmHg when diastolic blood pressure < 90 mmHg, on at least 2 repeated determinations 
on separate days within 3 months prior to study enrollment. 
 
3.2.19 Patients on anticoagulant therapy with unstable dose of warfarin and/or having an out-of- 
therapeutic range INR (>3) within the 4 weeks prior to study entry. 
 

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3.2.20 Evidence of clinically significant bleeding diathesis or underlying coagulopathy (e.g. 
INR>1.5 without vitamin K antagonist therapy), non-healing wound. 
 
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
Eligible patients will be entered on study centrally at the MD Anderson Cancer Center 
(Coordinating Center) by the Study Coordinator. The required forms Registration Form can be 
found in Appendix D. 
 
Following registration, patients should begin protocol treatment within 14 days.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP.  Agents may be ordered by a participating site only after the initial 
IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov). 
 
4.2 
Registration Process 
 
To register a patient, the following documents should be completed by the research nurse or data 
manager and faxed 713-563-9188 or e-mailed mebrimer@mdanderson.org  to the Study 
Coordinator: 
• Copy of required laboratory tests 
• Signed patient consent form 
• HIPAA authorization form 
• Registration Form)  
 
The research nurse or data manager at the participating site will then call 713-563-9188 or e-mail 
mebrimer@mdanderson.org  the Study Coordinator to verify eligibility.  To complete the 
registration process, the Coordinator will 
• assign a patient study number 
• register the patient on the study 
• assign the patient a dose 
• fax or e-mail the patient study number and dose to the participating site 

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• call the research nurse or data manager at the participating site and verbally confirm 
registration. 
 
 
5. TREATMENT PLAN 
 
One cycle consists of 21 days (3 weeks). See section 10.0 for acceptable window for testing and 
treatment. Ziv-aflibercept will be given intravenously on day 1 of each cycle. Treatment 
response will be evaluated every 3 cycles (approximately 9 weeks depending on any treatment 
delays). 
 
Perfusion CT will be performed at baseline (pre-treatment), cycle 1 day 21 (± 2 days, prior to 
cycle 2 dose), and at time of progression. The progression perfusion CT will not be performed if 
> 28 days have elapsed from the last ziv-aflibercept treatment (i.e. canceled or delayed treatment 
due to adverse event).  
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
 
Regimen Description 
Agent 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Ziv-
aflibercept 
SBP must be 
≤140 and DBP 
must be ≤90 prior 
to administration 
6 mg/kg at 
concentration of 
.06 – 8 mg/mL. 
Ziv-aflibercept 
will be diluted in 
NS 
IV over 60 
minutes (up to 
120 minutes is 
permitted and not 
considered a 
deviation).  
Days 1 
21 days  
(3 weeks) 
 
Management of Hypersensitivity Reactions: Stop infusion of Ziv-aflibercept for 30-60 
minutes.  Medicate with diphenhydramine 25 – 50 mg IV (or a similar antihistamine) and 
steroids such as hydrocortisone 50-100 mg IV or dexamethasone 10-20 mg IV approximately 30 
minutes before re- starting the ziv-aflibercept.  If the subject re-develops a hypersensitivity 
reaction despite treatment with diphenhydramine and steroids, the infusion should be stopped for 
another 30 – 60 minutes, depending upon the severity of the reaction.  The infusion may be 
resumed by administering a histamine H2-receptor antagonist approximately 30 minutes before 
restarting the ziv-aflibercept infusion and meperidine 25-50 mg IV if patient still had chills and 
rigors.  Famotidine 20 mg IV or ranitidine 50 mg IV are recommended rather than cimetidine 
because of the lack of likely metabolic/pharmacologic interactions with the former drugs.  The 
rate of the ziv-aflibercept infusion may also be slowed from 60 minutes to 2 hours.  Also, it is 

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permissible to premedicate overnight with steroids such as dexamethasone or prednisone.  All 
subjects should be monitored while receiving the ziv-aflibercept infusion and emergency medical 
equipment and health care personnel must be readily available to respond to hypersensitivity 
reactions or other medical emergencies. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Use of somatostatin analogues for the control of hormone related syndrome from neuroendocrine 
tumors is allowed. Both Octreotide LAR at doses of ≤30 mg IM every 3 to 4 weeks, and 
Lanreotide autogel ≤120 mg SC every 3 to 4 weeks can be used as long acting agent. Octreotide 
short-acting SC 2 – 4 times per day can also be used for supplemental therapy 
 
The use of interferon or everolimus for control of hormonal syndrome is not allowed. 
 
Other medications used for the supportive therapy of hormonal syndrome are allowed. Other 
medications for diarrhea may be used on an as needed basis.  Steatorrhea due to somatostatin 
analogue may be managed by the usage of pancrealipase.  Diarrhea due to short gut syndrome 
should be managed with cholestyramine.   
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
• 
Disease progression, 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Unacceptable adverse event(s), 
 
• 
Patient decides to withdraw from the study, or 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
 
5.4 
Duration of Follow Up 
 
Patients removed from study without progression will be followed until progression, start of new 
anti-neoplastic therapy, withdrawal of consent, or death, whichever occurs first.  Patients 
removed from study for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event. 
 
 
 

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5.5 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.3 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
For continuation treatment during subsequent cycles, patient should have recovered from any G3 
or G4 treatment-related AEs to ≤ G1. With exception of ziv-aflibercept doses withheld for 
proteinuria, the maximum delay for subsequent cycles is 4 weeks from when treatment was 
originally due (7 weeks from last dose). If a dose is delayed beyond 4 weeks for any reason other 
than proteinuria, patient will permanently discontinue therapy. Please see Table 3 for dose 
modification and interruptions due to proteinuria. 
 
Patients should be permanently discontinued for the following AEs: 
 
• Severe (G3 or G4) hemorrhage  
• Gastrointestinal perforation  
• Compromised wound healing (non-healing wounds) 
• Fistula formation  
• Hypertensive crisis or hypertensive encephalopathy (G4 hypertension) 
• Arterial thromboembolic events (any grade) 
• Nephrotic syndrome or thrombotic microangiopathy (TMA)  
• Reversible posterior leukoencephalopathy syndrome (RPLS) 
 
Temporarily hold ziv-aflibercept therapy for the following: 
 
• Elective surgery should be carried out at least 4 weeks after last dose of ziv-aflibercept. 
Do not resume ziv-aflibercept for at least 4 weeks following major surgery and until the 
surgical wound is fully healed.  
• For minor surgery such as central venous access port placement, biopsy, and tooth 
extraction, ziv-aflibercept may be initiated/resumed once the surgical wound is fully 
healed.  
 
Dose modification 
 
Ziv-aflibercept doses will be modified according to the dose level described in Table 1. Only one 
dose reduction is permitted. 
 
    Table 1 – Ziv-aflibercept dose reduction level 
 
Initial dose  
(mg/kg) 
Dose reduction,  
level - 1 
(mg/kg) 

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Ziv-aflibercept 
6 
3 
 
 
Actions to be taken for ziv-aflibercept according the type of toxicity are described in Table 2, 
Table 3 and Table 4. 
 
Table 2 – Dose modifications for ziv-aflibercept 
Toxicity 
Grade 
Action to be taken 
Hypertension 
Grade ≤ 2 
Initiate antihypertensive drug therapy (see recommendation 
below) and close monitoring of BP for further adjustment, as 
needed. No dose modification and no delay. 
 
 
Grade 3  
(resting 
systolic 
BP >=160 mm 
Hg or diastolic 
BP >=100 mm 
Hg, and  
requiring more 
than one drug 
or more 
intensive 
therapy than 
previously***) 
Modify antihypertensive drug therapy (see recommendation 
below). Delay the administration of ziv-aflibercept, for a 
maximum of 4 weeks, until recovery to blood pressure (BP) 
≤150/100 or to systolic BP < 180 if diastolic BP < 90 for 
patients with known history of isolated systolic hypertension: 
• 
If BP is controlled within 2 weeks delay: 
o First episode: readminister ziv-aflibercept at the 
same dose.  
o Second episode: readminister ziv-aflibercept, with 
ziv-aflibercept reduced to dose level-1. 
o Third episode, discontinue ziv-aflibercept. 
• 
If BP is still uncontrolled despite appropriate anti 
hypertensive treatment and after 2 - 4 weeks delay: Ziv-
aflibercept will be reduced to dose level -1. 
• 
In case of re-occurence of grade 3 BP despite dose 
reduction of ziv-aflibercept, or if BP is still uncontrolled 
despite delay of 4 weeks, the patients will be 
permanently discontinued from ziv-aflibercept. 
 
 
Grade 4 
Permanently discontinue study treatment 
 
Arterial 
thromboembolic 
events (e.g.: myocardial 
infarction, or stroke…) 
documented by 
appropriate tests 
Grade 3-4 
Permanently discontinue study treatment 
Hemorrhage 
Grade 3-4 
Permanently discontinue study treatment 
 
GI perforation/ fistula 
formation 
Any Grade 
Permanently discontinue study treatment 
Reversible posterior 
Leuko- encephalopathy 
syndrome documented 
with appropriate tests 
Any Grade 
Permanently discontinue study treatment 
Venous 
Thromboembolic 
Grade 3  
(DVT) 
First episode: Treat DVT with heparins and continue study 
treatment* 

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Toxicity 
Grade 
Action to be taken 
Event documented by 
appropriate tests 
Second episode despite appropriate anticoagulation: 
Permanently discontinue ziv-aflibercept 
 
 
Grade 4  
(PE) 
Permanently discontinue study treatment** 
* Based on investigator’s judgement in assessing potential risk of extesion and/or embolization. 
** Continuation of ziv-aflibercept may be considered, depending on individual benefit/risk assessment in case of 
incidental discovery of asymptomatic pulmonary embolism. 
*** Initial titration of anti-hypertensive medication following the start of a new drug (eg terazosin or calcium 
channel blocker) will not count as more intensive therapy. 
 
Hypertension therapy recommendations: 
 
• For patients without prior antihypertensive therapy, at the time of the hypertensive 
episode the initiation of calcium-channel blockers should be considered as a first-intent 
treatment. A close monitoring of the BP should be initiated for further adjustment in 
treatment, as needed. Ultimately, antihypertensive treatment must be individualized based 
on the presence of comorbidity factors such as diabetes, cardiovascular or renal disease, 
additionally taking into account the safety and the efficacy of any prior antihypertensive 
therapy received. In addition, oral and/or intravenous sodium intake should be carefully 
monitored in these patients. 
 
• For patients already under anti-hypertensive therapy efforts should be done to optimize 
the existing therapy before adding other agents as required to control the BP. 
 
When hypertension is accompanied by signs or symptoms of end organ damage such as 
hypertensive retinopathy, kidney function abnormalities (like progressive proteinuria), or any 
signs or symptoms of cardiovascular morbidity or central nervous system (CNS) morbidity, 
treatment with ziv-aflibercept should be interrupted. 
 
Proteinuria: 
 
Determination and management of proteinuria: 
Prior to each administration of ziv-aflibercept, perform an UPCR. 
 
Urinary protein creatinine ratio (UPCR) corresponds to the ratio of urinary protein and urinary 
creatinine concentrations (expressed in mg/dL). There is a high correlation between morning 
UPCR and 24-hour proteinuria in patients with normal or reduced renal function, UPCR 
demonstrated very good to excellent performance for the diagnosis of both abnormal and 
nephrotic proteinuria at all renal function levels. This ratio provides an accurate quantification of 
24-hours urinary protein excretion. 
 
UPCR to detect proteinuria, will be done on morning urine spot. If UPCR > 1, 24-hour urine 
collection to grade proteinuria will be performed. In addition, in case proteinuria is associated 
with hematuria (microscopic or macroscopic), schistocytes, orosomucoïd, haptoglobin, and LDH 
will be measured in blood and a nephrologist advice should be considered as detailed in Table 3. 
Proteinuria should always be assessed taking into account the presence or absence of 

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hematuria and the blood pressure status of the patient. 
Table 3 summarizes the course of action with regard to ziv-aflibercept dosing, which will depend 
on the presence of hematuria and the level of 24h proteinuria results. Only one dose level 
reduction is permitted for ziv-aflibercept. 
 
 

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25 
Table 3 – Management of proteinuria 
Prior to cycle n 
ziv-aflibercept 
administration 
Ziv-aflibercept 
dosing for cycle 
n 
During cycle n Repeat 24h 
proteinuria as necessary* 
Ziv-aflibercept dosing for 
cycle  
n +1 
During cycle n + 1 
Repeat 24h 
proteinuria as necessary * 
Ziv-aflibercept dosing for cycle  
n + 2 
UPCR [0-1] 
Dose 
aflibercept 
- 
- 
 
- 
 
- 
UPCR [1-2] 
Absence of 
hematuria 
Dose, then 
perform 24h 
proteinuria: 
 
 
 
 
 
 
 
if ≤3.5g/24h 
≤2g/24h prior n+1 dosing 
Dosing ziv-aflibercept 
- 
 
- 
 
 
 
>2g/24h prior n+1 dosing 
Omit dosing ziv-aflibercept 
≤2g/24h prior n+1dosing 
Resume ziv-aflibercept level -1** 
 
 
 
 
>2g/24h prior n+1 dosing 
Permanently discontinue 
aflibercept 
 
if > 3.5g/24h 
≤2g/24h prior n+1 dosing 
Dosing ziv-aflibercept level -1** 
- 
 
- 
 
 
 
>2 ≤ 3.5g/24h prior n+1 
dosing 
Omit dosing ziv-aflibercept 
≤2g/24h prior n+1 dosing 
Resume ziv-aflibercept level -1** 
 
 
 
 
>2g/24h prior n+1 dosing 
Permanently discontinue 
aflibercept 
 
 
>3.5g/24h prior n+1 dosing 
Permanently discontinue ziv-aflibercept 
 
 
UPCR [1-2] 
Presence of 
hematuria 
 
Or 
 
UPCR >2 
Omit dosing 
aflibercept 
Full nephrologic work-up 
and seek nephrologist 
opinion 
 
 
 
 
 
TMA ruled out and ≤2g/24h 
prior n+1 dosing 
Dosing ziv-aflibercept 
- 
- 
 
 
TMA ruled out and >2 ≤ 
3.5g/24h prior n+1 dosing 
Omit dosing ziv-aflibercept 
≤2g/24h prior n+1 dosing 
Resume ziv-aflibercept level -1** 
 
 
 
>2g/24h prior n+1 dosing 
Permanently discontinue ziv-
aflibercept 
 
TMA ruled out and 
>3.5g/24h prior n+1 
dosing*** 
 
 
 
TMA diagnosed 
Permanently discontinue ziv-aflibercept, seek nephrologist opinion  
Nephrotic 
syndrome 
Permanently discontinue ziv-aflibercept, perform nephrologic work-up, seek nephrologist opinion for continuation of chemotherapy 
TMA: Thrombotic micro-angiopathy 
*Patient can be monitored with UPCR as necessary, however 24h proteinuria should be performed prior to make dosing decision. 
** When patient is already treated at dose level -1, ziv-aflibercept should be discontinued. 

NCI Protocol #: 9604 
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26 
Reversible posterior leuko-encephalopathy (RPLS) or clinical symptoms related to vasogenic 
edema of the white matter: 
 
Clinical presentations are variable and may include headache, altered mental status, seizure and 
cortical visual deficit. Hypertension is a risk factor. MRI scans are key to diagnosis and typically 
demonstrate vasogenic edema (hyperintensity in T2 and FLAIR images and hypodensity in T1 
images) predominently in the white matter of the posterior parietal and occipital lobes; less 
frequently, the anterior distributions 
and the gray matter may also be involved. RPLS should be in the differential diagnosis in 
patients presenting with unexplained mental status change, visual disturbance, seizure, or other 
CNS findings. RPLS is potentially reversible with early recognition of symptoms and timely 
correction of the underlying causes, including control of BP and interruption of the offending 
drug, which are important in order to prevent progression to irreversible tissue damage. 
 
Gastro-intestinal perforation: 
 
In case a patient reported abdominal pain or increase in severity of pre-existing abdominal pain, 
with or without associated symptoms (such as nausea, vomiting, constipation), he/she should be 
evaluated by a physician for possible gastro-intestinal perforation, as this has been reported with 
anti-VEGF agents. 
 
Hypersensitivity reaction: 
 
In case of hypersensitivity reaction, institutional treatment guidelines for this type of 
AEs, or the following proposed guideline in Table 4 can be applied. 
 
Table 4 – Acute infusion reaction management 
Symptom Severity 
Intervention Recommendation 
Mild-Moderate  
E.g., NCI CTCAE grade ≤ 2 cutaneous 
reaction, pruritus, flushing, rash, dyspnea, 
tachycardia, hypotension, anxiety, headache, 
myalgias, edema, nausea 
Stop ziv-aflibercept infusion;  
Give diphenhydramine 50 mg IV and/or IV 
dexamethasone 10 mg; 
Resume ziv-aflibercept infusion after subject 
recovery. 
Severe  
e.g., symptomatic bronchospasm, generalized 
urticaria, systolic BP ≤ 80 mm Hg, 
angioedema, anaphylaxis 
Stop ziv-aflibercept infusion;  
Give IV diphenhydramine 50 mg and/or IV 
dexamethasone 10 mg and/or epinephrine as 
needed; 
Permanently discontinue ziv-aflibercept. 
 

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27 
 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting (via CTEP-AERS) in addition to 
routine reporting. 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Ziv-aflibercept (VEGF-Trap, AVE 0005, NSC 724770) 
 
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 941 patients. Below is the CAEPR for Ziv-
aflibercept (VEGF-Trap, AVE 0005). 
 
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 2.7, October 2, 20171 
 
 Adverse Events with Possible  
 Relationship to Ziv-aflibercept (VEGF-Trap, AVE 0005) 
 (CTCAE 4.0 Term) 
[n= 941] 
 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 Anemia (Gr 2) 
 
Febrile neutropenia 
 
 
Hemolytic uremic syndrome 
 
 
Thrombotic thrombocytopenic 
purpura 
 
CARDIAC DISORDERS 
 
 
Cardiac disorders - Other 
(intracardiac thrombus) 
 
 
Chest pain - cardiac 
 
 
Myocardial infarction 
 
 
Restrictive cardiomyopathy 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 Diarrhea (Gr 2) 

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28 
 
 Adverse Events with Possible  
 Relationship to Ziv-aflibercept (VEGF-Trap, AVE 0005) 
 (CTCAE 4.0 Term) 
[n= 941] 
 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Gastrointestinal fistula2 
 
 
Gastrointestinal perforation3 
 
Mucositis oral 
 
 
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
Fever 
 
 Fever (Gr 2) 
Pain 
 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
Wound complication 
 
 
INVESTIGATIONS 
 
Alanine aminotransferase 
increased 
 
 
Alkaline phosphatase 
increased 
 
 
Aspartate aminotransferase 
increased 
 
 
Creatinine increased 
 
 
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 
 
 
White blood cell decreased  
 White blood cell decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 Anorexia (Gr 2) 
Hyponatremia 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 Arthralgia (Gr 2) 
Myalgia 
 
 M yalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
 
Headache 
 
 
 Headache (Gr 3) 
 
Ischemia cerebrovascular 
 Ischemia cerebrovascular (Gr 2) 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
 
 
Transient ischemic attack 
 
RENAL AND URINARY DISORDERS 
 
 
Acute kidney injury 
 
Proteinuria 
 
 
 Proteinuria (Gr 3) 
 
Renal and urinary disorders - 
Other (nephrotic syndrome) 
 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
 
Genitourinary system fistula4  
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
 Cough (Gr 2) 

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29 
 
 Adverse Events with Possible  
 Relationship to Ziv-aflibercept (VEGF-Trap, AVE 0005) 
 (CTCAE 4.0 Term) 
[n= 941] 
 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Dyspnea 
 
 Dyspnea (Gr 3) 
Respiratory, thoracic and 
mediastinal disorders - 
Other (rhinorrhea) 
 
 
Voice alteration 
 
 
 Voice alteration (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
 
Skin hyperpigmentation 
 
 
VASCULAR DISORDERS 
 
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event  
 
 Thromboembolic event (Gr 3) 
Vascular disorders - Other 
(hemorrhage)5 
 
 Vascular disorders - Other 
(hemorrhage)5 (Gr 4) 
 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting  
PIO@CTEP.NCI.NIG.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Gastrointestinal fistulas may include: Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Gastric fistula, Gastrointestinal fistula, Rectal fistula, and other sites under the GASTROINTESTINAL 
DISORDERS SOC. 
 
3Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small 
intestinal perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
4Genitourinary fistulas may include: female genital tract fistula, uterine fistula, and vaginal fistula. 
 
5The majority of hemorrhage events were mild. Major events, defined as symptomatic bleeding in a 
critical area or organ (e.g., eye, GI hemorrhage, GU hemorrhage, respiratory hemorrhage), and nervous 
system [including fatal intracranial hemorrhage and cerebrovascular accident] have been reported. 
 
6Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on Ziv-aflibercept (VEGF-Trap, AVE 0005) trials but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that Ziv-aflibercept (VEGF-
Trap, AVE 0005) caused the event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(hemoglobin increased); Hemolysis 
CARDIAC DISORDERS - Acute coronary syndrome; Cardiac disorders - Other (left ventricular diastolic 
dysfunction); Heart failure; Left ventricular systolic dysfunction; Pericarditis; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 

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30 
EYE DISORDERS - Blurred vision; Extraocular muscle paresis; Eye disorders - Other (blindness 
transient); 
Eye disorders - Other (diplopia); Vitreous hemorrhage 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal mucositis; Colitis; Dental caries; Dry 
mouth; Dyspepsia; Dysphagia; Esophageal pain; Flatulence; Gastritis; Gastrointestinal disorders - Other 
(early satiety); Gastrointestinal disorders - Other (eructation); Gastrointestinal disorders - Other 
(gastrointestinal necrosis); Gastrointestinal disorders - Other (hiatal hernia); Gastrointestinal disorders - 
Other (intestinal ischemia); Gastrointestinal disorders - Other (peritonitis); Gastrointestinal disorders - 
Other (pneumatosis intestinalis); Gingival pain; Hemorrhoids; Ileus; Oral pain; Rectal mucositis; Rectal 
ulcer; Small intestinal mucositis; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Edema trunk; 
Facial pain; Infusion related reaction; Injection site reaction; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Cholecystitis 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INFECTIONS AND INFESTATIONS - Infection6 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Biliary anastomotic leak; Gastric 
anastomotic leak; Vascular access complication; Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; Cardiac 
troponin I increased; Ejection fraction decreased; GGT increased; Investigations - Other (elevated LDH); 
Lipase increased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Hypomagnesemia; 
Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Avascular necrosis; Back 
pain; Chest wall pain; Generalized muscle weakness; Head soft tissue necrosis; Joint range of motion 
decreased; Muscle weakness upper limb; Musculoskeletal and connective tissue disorder - Other 
(ischemic avascular osteonecrosis); Musculoskeletal and connective tissue disorder - Other (muscle 
spasms); Musculoskeletal and connective tissue disorder - Other (musculoskeletal stiffness); 
Musculoskeletal and connective tissue disorder - Other (rotator cuff tear); Myositis; Neck pain; 
Osteonecrosis of jaw; Pain in extremity; Pelvic soft tissue necrosis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)- Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (tumor hemorrhage) 
NERVOUS SYSTEM DISORDERS - Amnesia; Ataxia; Cognitive disturbance; Dizziness; Dysgeusia; 
Encephalopathy; Extrapyramidal disorder; Leukoencephalopathy; Memory impairment; Paresthesia; 
Peripheral sensory neuropathy; Seizure; Syncope; Vagus nerve disorder 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia; Psychiatric disorders - Other 
(mental status change); Psychosis 
RENAL AND URINARY DISORDERS - Hematuria 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Hoarseness; Hypoxia; Laryngeal 
mucositis; Nasal congestion; Pharyngeal mucositis; Pharyngolaryngeal pain; Pleural effusion; 
Pneumonitis; Pneumothorax; Pulmonary fibrosis; Respiratory, thoracic and mediastinal disorders - Other 
(nasal dryness); Respiratory, thoracic and mediastinal disorders - Other (septal perforation); Respiratory, 
thoracic and mediastinal disorders - Other (throat swelling); Respiratory, thoracic and mediastinal 
disorders - Other (tracheal fistula); Tracheal mucositis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Nail loss; Rash 
acneiform; Rash maculo-papular; Skin and subcutaneous tissue disorders - Other (hyperemia); Skin 
ulceration 
VASCULAR DISORDERS - Hematoma; Hypotension; Peripheral ischemia; Phlebitis 
 
Note: Ziv-aflibercept (VEGF-Trap, AVE 0005) 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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31 
7.1.1 Adverse Event List(s) for CIP (e.g. Study-Specific) Commercial Imaging Agents 
 
Commercial standard iodinated contrast agent will be used for perfusion CTs performed in this 
study. Known adverse events associated with iodinated contrast agents include: hot flashes3.4%; 
angina pectoris 3.0%; flushing 1.8%; bradycardia 1.3%; hypotension 1.0%; hives 1.0%. 
 
7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (http://ctep.cancer.gov).  The 
reporting procedures to be followed are presented in the “NCI Guidelines for 
Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and 
DCP INDs and IDEs” which can be downloaded from the CTEP Web site 
(http://ctep.cancer.gov).  These requirements are briefly outlined in the tables below 
(Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 The following text is required for multi-institutional studies only and may be deleted for 
single institution studies. 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 

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32 
Investigator, and the local treating physician.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 
provided. 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” 
under the system organ class (SOC) of the same name.  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.  
 
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, w hether 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 follow ing 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 w hen, 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 w ithin 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 

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33 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-A ERS w ithin 24 hours of learning 
of the AE, follow ed by a complete expedited report w ithin 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted w ithin 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follow s:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half -lives, 
rounded UP to the nearest w hole day, after the agent/intervention w as last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
FOR USE IN CIP STUDIES INVOLVING COMMERCIAL (NON-IND/IDE) AGENTS 
ONLY 
CIP Commercial Agent Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur in a CIP Non-IND/IDE trial within 30 Days of the Last Administration of a 
Commercial Imaging Agent 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, w hether 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 follow ing 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 w hen, 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 w ithin 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 

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34 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-A ERS w ithin 24 hours of learning 
of the AE, follow ed by a complete expedited report w ithin 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted w ithin 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follow s:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization Grade 3 adverse 
events 
2 For studies using PET or SPECT agents, the AE reporting period is limited to 10 radioactive half -lives, rounded 
UP to the nearest w hole day, after the agent/intervention w as last administered.  Footnote “1” above applies after 
this reporting period. 
Effective Date:  May 5, 2011 
 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified.  
 
 

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8. PHARMACEUTICAL AND/OR IMAGING AGENT INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
 
8.1 
CTEP IND Agent(s) 
 
8.1.1 Ziv-aflibercept (NSC #724770) 
 
Other Names: VEGF Trap, AVE0005 
 
Classification: Recombinant humanized fusion protein (Chinese hamster ovary source). 
 
M.W.: 115 kDa 
 
Approximate Solubility: at least 100mg/ml water (with 5 mM Na phosphate, 5 mM Na citrate, 100 
mM NaCl, 0.004-0.08% Polysorbate 20) at 5°C and 25°C. 
 
Mode of Action: The cytokine VEGF binds to and activates VEGFR1 and VEGFR2 on the 
vascular endothelium, promoting new vessel formation. VEGF Trap is a soluble recombinant decoy 
receptor that binds and inactivates extravascular and hematologic VEGF. It reduces tumor 
vasculature density, available nutrient supply, and tissue matrix components escaping from leaky 
tumor vessels. 
 
Description: The fusion protein VEGF Trap is 2 portions of human VEGF receptors extracellular 
domains, VEGFR1 and VEGFR2, fused to the Fc portion of human IgG1. 
 
How Supplied:  VEGF Trap is supplied by Sanofi-Aventis Pharmaceuticals and distributed by 
the CTEP, DCTD, NCI.  VEGF Trap is a sterile, nonpyrogenic, colorless to pale yellow solution in 
vials of 100 mg (4 mL) or 200 mg (8 mL) at a concentration of 25 mg/mL. The solution contains the 
following excipients:  sucrose, sodium chloride, sodium citrate dihydrate, citric acid 
monohydrate, polysorbate 20, sodium phosphate dibasic heptahydrate, sodium phosphate 
monobasic monohydrate, and water for injection. The pH of VEGF Trap is 6.2. The product is 
packaged in a type 1, clear borosilicate glass vial closed with a flanged cap with tear-off lid and 
inserted sealing disc, Flurotec® (PTFE) coated. 
 
Preparation:  Prior to infusion, the VEGF Trap dosage form must be diluted directly into 
infusion bags of 0.9% sodium chloride solution. The concentration of the diluted solution can 
range between 0.6 and 8 mg/mL. The pH of the diluted solution is about 6.2. 
 
Storage:  Store intact vials in the refrigerator (2o to 8o C). 
 
Stability: Shelf life stability studies of intact vials are ongoing. VEGF Trap’s provisional shelf-life 
is up to 36 months at 2o to 8°C.  
 

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Caution: The sterile single use vials contain no antibacterial preservatives.  Discard 
remaining agent 8 hours after initial entry. 
 
VEGF Trap diluted to a concentration of 0.6 to 8 mg/mL in 0.9% NaCl has demonstrated chemical 
and physical stability for up to 24 hours under refrigerated conditions (2 to 8°C) or up to 8 hours at 
ambient temperature (approximately 25°C) in infusion bags made of polyvinyl chloride (PVC) 
containing di(2-ethylhexyl)phthalate (DEHP) or polyolefin (PVC free DEHP free). 
 
Route of Administration: Intravenous  
 
Method of Administration: Administer VEGF Trap intravenously over 1 hour into a peripheral 
vein or central venous catheter using gravity, an infusion pump, or syringe pump.  The infusion 
should not exceed two hours at room temperature (approximately 25°C). 
 
VEGF Trap may be administered using infusion tubing made of PVC containing DEHP, 
polyethylene lined PVC, DEHP free PVC containing tris (2-ethylhexyl) trimellitate (TOTM), 
polypropylene, or polyurethane.   
 
The infusion set must contain a 0.2 micron polyethersulfone inline filter.   Polyvinylidene fluoride 
(PVDF) filters or Nylon filters should not be used. 
 
Availability 
 
Ziv-aflibercept is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
Ziv-aflibercept is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where 
the patient is to be treated.  PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained).  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational agents.  
The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent 

NCI Protocol #: 9604 
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37 
Order Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” account 
status and a “current” password.  For questions about drug orders, transfers, returns, 
or accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
8.1.2.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all 
agents received from DCTD using the NCI Drug Accountability Record Form 
(DARF).  (See the NCI Investigator’s Handbook for Procedures for Drug 
Accountability and Storage.) 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
There is urgent need for the development of predictive and prognostic biomarker in oncology to 
accelerate advances in novel therapeutics, and to develop personalized therapy. Biomarkers for 
therapies targeting angiogenesis have been particularly challenging. This is in part due to the fact 
that tumor response rates with these and other molecularly targeted therapies have generally been 
low. Nonetheless, treatment can be associated with significant improvements in progression-free 
survival and overall survival. Predictive, prognostic, and pharmacodynamic biomarkers that will 
enable development of novel drugs and novel drug combinations targeting angiogenesis are 
needed. 
 
Since the initial report that a greater reduction in Ktrans, measured by DCE-MRI, was associated 
with disease stabilization in a phase I study of VEGF tyrosine kinase inhibitor, PTK/ZK,(12) 
many have attempted to correlate dynamic imaging findings with clinical outcome with varying 
degrees of success.(4, 13-16) In our prior study with bevacizumab and PEG interferon, perfusion 
CT (pCT), demonstrated that bevacizumab led to rapid and sustained decrease in tumor blood 
flow (BF), and suggested that lower post-treatment blood volume (BV) correlated with PFS.(4) 
One limitation of many past studies, including our prior study,(4) is that dynamic imaging was 
optional and not uniformly performed among all patients limiting statistical power and raising 
the issue of potential selection bias. Other retrospective studies have included heterogeneous 
groups of patients treated with different VEGF inhibitors. Nonetheless, many of these studies 
suggested that dynamic imaging had potential to select patients likely to benefit from anti-
angiogenic therapy.(4, 13-16)  
 
In our more recent study with bevacizumab and everolimus, we confirmed that the absolute 
decrease in tumor BF following bevacizumab and everolimus, correlated with baseline BF, and 
that such therapy decreased tumor BF by a percentage.(17)  In this study, pre-treatment 
permeability surface (PS), percent reduction in BF, BV, and post-treatment MTT correlated with 
RECIST response.(17) In a recent pooled-analysis of pancreatic NET patients treated with VEGF 
inhibitors at M. D. Anderson, baseline BV also correlated with response.  
 
Of particular interest are the correlations between pre-treatment BV and PS with tumor response. 

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38 
This suggests that one can select patients likely to benefit from anti-angiogenic therapy based on 
one pre-treatment scan. We will formally test this hypothesis in the current study. 
 
9.1 
Perfusion CT 
 
9.1.1  
Perfusion CT Procedure and image acquisition  
 
Perfusion CTs will be performed at: 
1. Pre-treatment baseline (within 1 week of cycle 1 day 1) 
2. Cycle 1 day 21 (+/- 3 days) 
3. Time of radiologic disease progression (if patient is ≤ 28 days from last dose of Ziv-
aflibercept) 
 
Given the type of tumor studied, it is anticipated that most tumor lesions studied will be located 
in the liver, but any tumor location can also be studied.  Scans will be obtained with patients in 
the supine position on a 32 or 64-row multidetector CT scanner. Axial cine scans will be 
performed using a single level of 4 cm thickness at the midpoint of the selected target lesion.  CT 
data will be collected in two phases to cover 4 cm axial thickness through the midpoint of the 
selected target lesion:  there will be an initial 30-40 second breath hold cine acquisition, followed 
by intermittent breath hold short helical scans extending out to 600 seconds. Data acquisition 
will start approximately 5 seconds after intravenous injection of 50 mL of a nonionic contrast 
agent (ioversol [Optiray™] or equivalent,, 320-350 mg of iodine/100 mL, Mallinckrodt Inc., St 
Louis, MO) using an automatic injector at 7 mL/second, through an 18-gauge needle placed in an 
antecubital vein. The initial first phase cinecine images, eight contiguous slices each of 5 mm 
thickness, will be acquired in cine mode with a 1 second rotation speed, and will be 
reconstructed at the CT console at half rotation intervals, giving an effective temporal resolution 
of 0.5 seconds; the second phase intermittent short helical images will be anatomically registered 
with the cine images.  
 
9.1.2 
Perfusion CT image analyses 
 
The images will be analyzed centrally at M.D. Anderson using CT-perfusion software on a 
workstation (CT Perfusion version 3 or higher, Advantage Windows 4.2; GE Medical Systems, 
Milwaukee, WI). This uses a deconvolution physiological model.(29) A region of interest (ROI) 
will be placed in the largest available artery in the cine sections, typically the abdominal aorta, 
which providesprovides the arterial input function for generation of perfusion maps, using the 
Body Perfusion protocol. In the case of liver lesions, the Liver Perfusion protocol will be used 
where possible; this utilizes a dual vascular input, consisting of arterial and portal vein inputs. 
ROIs will be drawn freehand around the periphery of target lesions with reference to the source 
cine CT images and perfusion parametric maps, on each axial section in which tumor was 
visualized.  This will generate mean BF, BV, MTT, and PS (and in the case of Liver Protocol, 
also hepatic arterial fraction (HAF)) values for each tumor ROI on each level.  The pCT 
parameter values obtained for each level were then averaged for each lesion evaluated.  
 
9.1.3 
Perfusion CT data analyses 
 

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See Statistical Section for the analyses of study primary endpoints. 
 
For perfusion CT exploratory endpoints, descriptive statistics will be provided with confidence 
intervals where appropriate. To explore optimal cut-points for perfusion CT parameters in 
predicting response, response rate for each parameter with cut-off set at median of the parameter 
will be computed. In addition, receiver operating characteristic curve will be used to graph the 
effect of cut-points in perfusion CT parameters on RECIST response classified as a binary 
outcome. 
 
9.2 
Laboratory Correlative Studies 
 
9.2.1.1 
Baseline plasma VEGF-A & PlGF  
 
We recently reported the analysis of VEGF pathway biomarkers from RADIANT-3, the largest 
phase III study to have been ever conducted in pNETs.(9, 22) In univariate analyses, patients 
with elevated baseline VEGF-A (P =0.001), or PlGF (P =0.004) had significantly shorter PFS 
compared to those with low marker levels. We plan to analyze baseline levels in current study 
and correlate with outcome as well as baseline perfusion CT parameters. 
 
PlGF levels will be obtained by the R&D Quantikine Human PlGF Immunoassay (#DPG00) and 
analyzed on a BioTek Synergy HT Multi-detection microplate reader, and analyzed on Gen5 
software (BioTek Winooski, Vermont).  All samples will be analyzed in duplicate, and each 
plate will contain positive and negative controls.  The assay requires 200 µL of plasma for a 
duplicated analysis.  The lower limits of detection is 7pg/ml, with upper limit for the assay of 
1,000 pg/mL.  Intra-assay precision is <10%.  The variance of the duplicate samples will be 
determined, and analytes with %CV >15% will be repeated. 
 
9.2.1.2 
Handling of Specimens(s) 
 
10 ml of blood should be collected in EDTA (Lavender) tube and centrifuged at 1600 RCF for 
15 minutes. Plasma should transferred into two push cap tubes and can be stored at either -20 C 
or -80 C freezer. 
 
9.2.1.3 
Shipping of Specimen(s) 
 
Specimens should be stored locally until study is closed to new patient entry. At that time, the 
specimens collected outside of M. D. Anderson should be shipped frozen on a Tuesday by 
overnight courier delivery to: 
 
James C. Yao 
University of Texas MD Anderson Cancer Center 
FC 10.3000 
1400 Holcombe Blvd 
Houston, Texas 77030 
Phone:  713-792-2828 
Email:  jyao@mdanderson.org 

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40 
 
Please notify principle investigator by email prior to shipment. 
 
9.2.1.4 
Site(s) Performing Correlative Study 
 
All participating sites. 
 
9.3 
Special Studies 
 
9.3.1 Molecular testing  
 
Patients from University of Texas M. D. Anderson Cancer center will be offered and approached 
for consent to participate on separate IRB-approved protocol “Molecular testing for the MD 
Anderson Cancer Center Personalized Cancer Therapy Program, PA11-0852”. 
 
Archival tumor specimens will be used among patients who consent to above study. 
 
9.3.1.1 
Mutational status using a targeted sequencing approach  
 
9.3.1.2 
Assessment 
 
Relevant CLIA Testing will be done through the MD Anderson Molecular Diagnostics 
Laboratory (CLIA Cert #:45D0994328). First line testing will be done with the Actionable 
Cancer Gene Scan CLIA panel in the MD Anderson Molecular Diagnostic Laboratory. Currently 
this is an Ion Torrent Ampliseq-based hot-spot analysis of 46 genes. This includes following 
mutations: AKT1, PIK3CA, BRAF, KRAS, NRAS, GNAQ, GNAS, MET, IDH1/2, RET, ABL1, 
ALK, APC, ATM, CDH1, CDKN2A, CSF1R, CTNNB1, EGFR, ERBB2, ERBB4, FBXW7, 
FGFR1, FGFR2, FGFR3, FLT3, HNF1A, HRAS, JAK2, JAK3, KDR, KIT, MLH1, MPL, 
NOTCH1, NPM1, PDGFRA, PTEN, PTPN11, RB1, SMAD4, SMARCB1, SMO, SRC, STK11, 
TP53, VHL.  
 
For patients with adequate DNA available, a portion of the DNA will be kept in the CLIA 
environment, and the test of the DNA will undergo research testing, T200 panel, a targeted 
whole exome sequencing assay, will be performed. CLIA confirmation of any positive research 
findings, if ordered, may be performed in the MDACC Diagnostic Laboratory. These studies are 
sponsored by the Institute of Personalized Cancer Therapy at M.D. Anderson Cancer Center.

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10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. A standard window of -1 day to + 3 days will be 
considered acceptable for all testing, visits, and treatments (will not be considered study 
deviation). 
 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Off Study 
Ziv-aflibercept 
 
A 
 
 
A 
 
 
A 
 
 
A 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
 
Physical exam 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Vital signs 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Performance status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
CBC w/diff, plts, PT/PTT 
X 
X* 
 
  
X 
 
 
X 
 
 
X 
 
 
X 
Serum chemistrya 
X 
X* 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Urine protein creatinine ratio 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------X 
X 
Tumor measurements 
X 
Tumor measurements are repeated every 3 cycles.  Documentation (radiologic) must 
be provided for patients removed from study for progressive disease. 
X 
Radiologic evaluation for 
tumor assessmentf 
X 
Radiologic measurements should be performed every 3 cycles (9 weeks) 
X 
B-HCG 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perfusion CT 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Xd 
Blood VEGF-A, PlGF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional consent for 
molecular testing on 
Clearinghouse protocol (PA11 
- 0852) 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
A: 
Ziv-aflibercept:  Dose as assigned; administration schedule 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium. 
b: 
Cross-sectional imaging (CT or MRI) of abdomen, pelvis, and any other sites of know disease should be performed. 
c: 
Serum pregnancy test (women of childbearing potential). 
d:  
Performed at time of document progression and patient is ≤ 28 days from last dose of Ziv-aflibercept. Patients who discontinue for 
reasons other than progression will not have this off study perfusion CT. 
e: 
MD Anderson patients only 
f: 
CT or MRI of abdomen, pelvis and any known site of active disease. CXR if no chest CT planned. 
* 
Week 1 labs need not be repeated if pre-study labs were done within 10 days of cycle 1 day 1. 
 

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42 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 3 cycles (9 
weeks).  In addition to a baseline scan, confirmatory scans should also be obtained 9 (not less 
than 4) weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with Ziv-aflibercept. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest 
x-ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area will only be 
considered measureable if there has been evidence of progression in those lesions. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 

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43 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 

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44 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up 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. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 

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45 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
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, 
additional follow-up CT  scans are needed to determine if there is truly progression 
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. 
 

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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. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  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 at a later time by the review panel (or Principal 
Investigator). 
 

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11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
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 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as 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.”  Every effort should be made to document the 
objective 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 

NCI Protocol #: 9604 
Version Date: 1/11/18 
48 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
For phase 2 protocols: This study will be monitored by the Clinical Data Update System 
(CDUS) Version 3.0.  Cumulative protocol- and patient-specific CDUS data will be 
submitted electronically to CTEP on a quarterly basis, either by FTP burst of data or via 
the CDS web application.  Reports are due January 31, April 30, July 31, and October 31.  
Instructions for submitting data using the CDUS can be found on the CTEP Web site 
(http://ctep.cancer.gov/reporting/cdus.html).  
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory 
CDUS reporting guidelines must be reported via the monitoring method identified above.  
If your study has been assigned to CDUS-Abbreviated reporting, no adverse event 
reporting (routine or expedited) is required to be reported via CDUS. 
 
12.1.2 Responsibility for Data Submission 
 
Study participants are responsible for submitting CDUS data and/or data forms to either 
the Coordinating Center or to the Lead Organization on the study quarterly.  The date for 
submission to the Coordinating Center or to the Lead Organization will be set by them.  
CDUS does not accept data submissions from the participants on the study.  When setting 
the dates, allow time for Coordinating Center compilation, Principal Investigator review, 
and timely submission to CTEP by the quarterly deadlines (see Section 12.1.1).  For trials 
monitored by CTMS, a quarterly report of data will be provided by Theradex to the 

NCI Protocol #: 9604 
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49 
Coordinating Center. 
 
Either the Coordinating Center or the Lead Organization is responsible for compiling and 
submitting CDUS data to CTEP for all participants and for providing the data to the 
Principal Investigator for review.   
12.2 
CTEP Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix B. 
• The Principal Investigator/Coordinating Center is responsible for distributing all IND 
Action Letters or Safety Reports received from CTEP to all participating institutions for 
submission to their individual IRBs for action as required. 
 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the CTEP PIO (PIO@ctep.nci.nih.gov) except for Group studies. 
 
12.3 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 

NCI Protocol #: 9604 
Version Date: 1/11/18 
50 
nature of any agreements governing their collaboration with NCI, 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 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 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 

NCI Protocol #: 9604 
Version Date: 1/11/18 
51 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints/Objectives 
 
This is a single arm, open-label, phase II study of Ziv-aflibercept in patients with advanced 
pancreatic NET. The study endpoint is objective response rate according to RECIST 1.1.  The 
primary objectives are to estimate the objective response rate of Ziv-aflibercept among patients 
with advanced pancreatic NETs and to test the hypotheses that baseline perfusion CT parameters 
can predict which patients with advanced pNETs will respond to treatment with Ziv-aflibercept. 
 
13.2 
Study Design/Sample Size/Accrual Rate 
 
A sequential two-stage design will be used to estimate the response rate of Ziv-aflibercept in 
pNETs and test the hypothesis that baseline pCT can predict which patients with advanced 
pNETs will respond to treatment with Ziv-aflibercept. 
 
In a recent phase III study of sunitinib versus placebo, treatment with VEGF TKI sunitinib was 
associated with significant improvement in PFS (11.4 (7.4–19.8) versus 5.5 (3.6–7.4) month; HR 
= 0.42 (0.26–0.66)) and objective response rate of 9% versus 0%. Given the inclusion of 
treatments who have received prior VEGF inhibitor therapy, a true response rate of 5% or less 
(H0) would be considered uninteresting for further development. A true response rate of at least 
20% (H1) would be considered of interest for further investigation. These hypotheses are 
informed in part by the understanding that response rate will be expected to be somewhat lower 
among patients previously treated with VEGF inhibitors, despite the continued efficacy of serial 
VEGF inhibitor therapy, as demonstrated in the second-line pazopanib study in renal cell 
carcinoma, which estimated the response rate to be 19%(16), as compared with a 31% response 
rate in a randomized study of untreated renal cell carcinoma patients(30). 
 
A two-stage design will be used to test whether there is sufficient evidence that the treatment 
could be a candidate for further study, with early stopping rules to terminate the study early for 
poor results. 
 
Early stopping rules: 
The following stopping rules will be applied hierarchically. Accrual will be held at time of 
interim analysis pending application of Stopping rule 1. Accrual will not be held for Stopping 
rule 2 or 3 at time of interim analysis, if random variation preclude adequate number of patients 
in subgroups at time of interim analysis. 
 
Stopping rule 1: The first early stopping rule applies to all patients by applying the Simon’s 
optimal two-stage design. In the first stage, we will enroll 21 evaluable patients. If 0 or 1 of the 
first 21 patients achieve RECIST response (PR or CR), the study will terminate.  If at least 2 of 
the first 21 evaluable patients achieve RESCIST response (PR or CR), an additional 20 patients 

NCI Protocol #: 9604 
Version Date: 1/11/18 
52 
will be enrolled.  If at the end of the second stage, at least 5 out of 41 patients achieve RECIST 
response, the treatment will be considered acceptable for further testing.  This design has a 4.6% 
chance of accepting the treatment for further testing if the true response rate is ≤ 5% (type 1 error 
= 0.046), and 85% power (type 2 error = 0.15) of accepting the treatment for further testing if the 
true response rate is at least 20%.  The maximal accrual will be 41 evaluable patients.  The 
probability of early termination is 72% under the null hypothesis. 
 
Stopping rule 2: The second early stopping rule applies to the high perfusion CT subgroup.  
Analyses will be applied after completion of stage 1 of the minimax design and application of 
Stopping rule 1. Our target response rate in this putatively favorable subgroup (baseline BV > 
5.25 and baseline PS > 25) is at least 30%.  If the observed response rate is unlikely to reach 30% 
in this subgroup, the trial will be stopped early.  The second early stopping rule will be evaluated 
after at least 9 evaluable patients are enrolled in the subgroup with both high BV (baseline BV > 
5.25) and high PS (baseline PS > 25). If there is no responder in both the high BV and the high 
PS subgroup when at least 9 evaluable patients are enrolled, the trial will be stopped early.  
Otherwise, that is, if at least one response is observed in this subgroup, the trial will continue.  
This stopping rule will have at least 96% power if the response rate is 30% of higher in this 
favorable subgroup.   
 
When both the first and second stopping rules are considered together, the trial will be stopped 
early when either of the rules reaches the stopping boundaries. As a result, the trial will be 
stopped early when either the response rate is low in the overall group or in the favorable 
subgroup. 
 
Stopping rule 3: The third early stopping rule applies to the low perfusion CT subgroups. 
Analysis will be applied after completion of stage 1 of the minimax design and application of 
Stopping rules 1 and 2 if there are at least 18 patients in the low BV subgroup or the low PS 
group. The goal of the stopping rule is to stop enrollment of patients to the putative unfavorable 
group if patients in the group are unlikely to benefit from therapy. Based on the historical 
sunitinib phase 3 study, the response rate to sunitinib is 9% (90% CI, 5% – 16%). If no 
responders are observed among at least 18 evaluable patients, we can rule out a response rate of 
16% or higher with 95% power and the subgroup would terminate.  
 
At the end of the study, 90% exact confidence interval will be constructed for the overall group 
and for all the marker subgroups respectively. In addition, we will test the hypothesis that 
baseline perfusion CT parameters can predict which patients with advanced pNETs will 
respond to treatment with Ziv-aflibercept. All enrolled patients will have baseline perfusion 
CT. Threshold for baseline BV (5.25 ml/100gram) and PS (25 ml/minute/100gram) were 
established from prior studies of VEGF inhibitors among patients with pancreatic NET treated at 
M. D. Anderson. Approximately 60% of pancreatic NET had baseline BV > 5.25 and 
approximately 60% had baseline PS > 25. The following RECIST response rates were observed 
by baseline measurements.  
 
Baseline BV 
Baseline PS 
BV < 5.25 
BV > 5.25 
PS < 25 
PS > 25 

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NCI Protocol #: 9604 
Version Date: 1/11/18 
54 
 
The planned sample size is 41 patients. The expected accrual rate is approximately 3 patients per 
months. 
 
The following accrual targets for gender, race, and ethnicity are based on analyses of 371 
patients with pancreatic NETs seen at University of Texas M. D. Anderson Cancer Center. By 
gender 47% were female; 53% were male. By ethnicity, 8% were Hispanic or Latino. By race, 
3% were Asian; 8% were black; 88% were white. 
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
1 
+ 
2 
= 
3 
Not Hispanic or Latino 
18 
+ 
20 
= 
38 
Ethnic Category: Total of all subjects 
19 
(A1) + 
22 
(B1) = 
41 
(C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
0 
+ 
1 
= 
1 
Black or African American 
1 
+ 
2 
= 
3 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
0 
= 
0 
White 
18 
+ 
19 
= 
38 
Racial Category: Total of all subjects 
19 
(A2) + 
22 
(B2) = 
41 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
13.3 
Analysis of Secondary and Exploratory Endpoints 
 
Due to the phase II nature of this study and the high correlation between the two pCT endpoints, 
no formal adjustment will be made for multiple analyses of secondary and exploratory study 
objectives.  
 
Analysis plan for secondary study objectives: 
▪ Estimate progression free survival (PFS) duration among patients treated with ziv-
aflibercept.  
PFS will be calculated from the date of study registration for all eligible patients using the 
Kaplan Meier method and reported with confidence interval. 
 
▪ Evaluate the relationship between response rate and baseline BV and between response rate 
and baseline PS. 
In addition to hypothesis testing using externally generated cut-points, refinement of optimal 
cut points in baseline BV and baseline PS separating responders and non-responders will be 
performed.  
• Receiver operating characteristic (ROC) curves will be generated for both parameters.  

NCI Protocol #: 9604 
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55 
• Response rates of pCT subgroups defined by these cut-points will be compared using chi-
square test.  
• Response profiles of pCT subgroups defined by these cut-points will be compared using 
non-parametric test (Wilcoxon rank sum test). 
 
Analysis plan for exploratory study objectives: 
• Determine whether post-treatment changes in BV expressed as relative change from baseline 
correlate with response to ziv-aflibercept. 
o Median will be used as cut point for correlation of post-treatment changes in BV 
expressed as relative change from baseline with response.  
o Response rates will be compared using chi-square test or Fisher’s exact test whenever 
appropriate.  
o Response profiles will be compared using non-parametric test (Wilcoxon rank sum 
test). 
 
• Determine whether post-treatment tumor blood flow (BF) (absolute measurement) correlates 
with response to ziv-aflibercept 
o Median will be used as cut point for correlation of post-treatment tumor blood flow 
(BF) (absolute measurement) with response.  
o Response rates will be compared using chi-square test or Fisher’s exact test whenever 
appropriate.  
o Response rates will be compared using chi-square test or Fisher’s exact test whenever 
appropriate.  
 
• Determine whether post-treatment changes in BF and, BV, expressed as relative change from 
baseline, correlate with relative change in sum of tumor diameters (RECIST 1.1 
measurements) 
o Continuous parameters in relative change in pCT parameters will be plotted against 
best relative change in sum of tumor diameters from RECIST 1.1 tumor 
measurements. 
o Pearson correlation will be used to test statistical significance. Non-parametric test 
will be used if appropriate. 
 
• Determine the effect of ziv-aflibercept therapy on post-treatment blood flow (BF), BV, mean 
transit time (MTT), and PS at 4 weeks after treatment 
o Descriptive statistics of pre and post treatment values will be given. 
o Distribution of pre and post treatment values will be graphed 
o Treatment induced change in values will be compared using paired-t test. Non-
parametric test will be used if appropriate. 
 
• Evaluate the changes in tumor perfusion parameters at time of progression 
o Summary statistics will be given to describe change from baseline and change from 
post treatment pCT.  
o Differences will be compared using paired-t test. Non-parametric test will be used if 
appropriate. 
 

NCI Protocol #: 9604 
Version Date: 1/11/18 
56 
 
13.4 
For phase 2 protocols only: Reporting and Exclusions 
 
13.4.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with Ziv-
aflibercept. 
 
13.4.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided.  

NCI Protocol #: 9604 
Version Date: 1/11/18 
57 
 
REFERENCES 
 
 
1. 
Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years 
after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 
cases in the United States. J Clin Oncol. 2008;26(18):3063-72. 
2. 
Yao JC, Eisner MP, Leary C, Dagohoy C, Phan A, Rashid A, et al. Population based 
study of islet cell carcinoma. Ann Surg Oncol. 2007:in press. 
3. 
Lam KY, Lo CY. Pancreatic endocrine tumour: a 22-year clinico-pathological 
experience with morphological, immunohistochemical observation and a review of the literature. 
Eur J Surg Oncol. 1997;23(1):36-42. 
4. 
Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, et al. Fluorouracil, 
doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic 
pancreatic endocrine carcinomas. J Clin Oncol. 2004;22(23):4762-71. 
5. 
Turner NC, Strauss SJ, Sarker D, Gillmore R, Kirkwood A, Hackshaw A, et al. 
Chemotherapy with 5-fluorouracil, cisplatin and streptozocin for neuroendocrine tumours. Br J 
Cancer. 2010;102(7):1106-12. 
6. 
Yao JC. Molecular targeted therapy for carcinoid and islet-cell carcinoma. Best Pract 
Res Clin Endocrinol Metab. 2007;21(1):163-72. 
7. 
Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, et al. DAXX/ATRX, 
MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. 
Science. 2011;331(6021):1199-203. 
8. 
Missiaglia E, Dalai I, Barbi S, Beghelli S, Falconi M, della Peruta M, et al. Pancreatic 
endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol. 
2010;28(2):245-55. 
9. 
Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for 
advanced pancreatic neuroendocrine tumors. The New England journal of medicine. 
2011;364(6):514-23. 
10. 
Kulke MH, Bergsland EK, Yao JC. Glycemic control in patients with insulinoma 
treated with everolimus. N Engl J Med. 2009;360(2):195-7. 
11. 
Yao JC, Ito T, Oberg K. Advances in pancreatic neuroendocrine tumor treatment. N 
Engl J Med. 2011;364(19):1874-5. 
12. 
Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. 
Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J 
Med.364(6):501-13. 
13. 
Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, et al. Activity of 
sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26(20):3403-10. 
14. 
Hobday TJ, Rubin J, Holen K, Picus J, Donehower R, Marschke R, et al. MC044h, a 
phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A 
Phase II Consortium (P2C) study. J Clin Oncol. 2007;25(18S):abstr 4504. 
15. 
Phan AT, Yao JC, Fogelman DR, Hess KR, Ng CS, Bullock SA, et al. A prospective, 
multi-institutional phase II study of GW786034 (pazopanib) and depot octreotide (sandostatin 
LAR) in advanced low-grade neuroendocrine carcinoma (LGNEC). J Clin Oncol. 
2010;28(7s):abstr 4001. 
16. 
Rautiola J, Utriainen T, Peltola K, Joensuu H, Bono P. Pazopanib after sunitinib 

NCI Protocol #: 9604 
Version Date: 1/11/18 
58 
failure in patients with metastatic renal cell carcinoma. Acta Oncol. 2014;53(1):113-8. 
17. 
Terris B, Scoazec JY, Rubbia L, Bregeaud L, Pepper MS, Ruszniewski P, et al. 
Expression of vascular endothelial growth factor in digestive neuroendocrine tumours. 
Histopathology. 1998;32(2):133-8. 
18. 
Ambs S, Bennett WP, Merriam WG, Ogunfusika MO, Oser SM, Khan MA, et al. 
Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer 
and the relation to p53. Br J Cancer. 1998;78(2):233-9. 
19. 
Yao JC, Phan A, Hoff PM, Chen HX, Charnsangavej C, Yeung SC, et al. Targeting 
vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II 
study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol. 
2008;26(8):1316-23. 
20. 
Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. 
Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 
2011;364(6):501-13. 
21. 
Raymond E, Raoul J, Niccoli P, Bang Y, Brobath I, Lombard-Bohas C, et al. Phase 
III, randomized, double-blind trial of sunitinib versus placebo in patients with progressibe well-
differentiated pancreatic islet cell tumours. Annals of Oncology. 2009;20(Supplement 7):vii11. 
22. 
Yao JC, Tsuchihashi Z, Panneerselvam A, Winkler RE, Bugarini R, Pavel M. Effect 
of Everolimus Treatment on Markers of Angiogenesis in Patients With Advanced Pancreatic 
Neuroendocrine Tumours (pNET) – Results From the Phase III RADIANT-3 Study. Eur J 
Cancer. 2011;47(Suppl 1):S463. 
23. 
Ch'ng JL, Anderson JV, Williams SJ, Carr DH, Bloom SR. Remission of symptoms 
during long term treatment of metastatic pancreatic endocrine tumours with long acting 
somatostatin analogue. British medical journal (Clinical research ed). 1986;292:981-2. 
24. 
Angeletti S, Corleto VD, Schillaci O, Marignani M, Annibale B, Moretti a, et al. Use 
of the somatostatin analogue octreotide to localise and manage somatostatin-producing tumours. 
Gut. 1998;42:792-4. 
25. 
Ruszniewski P, Rougier P, Roche a, Legmann P, Sibert a, Hochlaf S, et al. Hepatic 
arterial chemoembolization in patients with liver metastases of endocrine tumors. A prospective 
phase II study in 24 patients. Cancer. 1993;71:2624-30. 
26. 
Inoue M, Hager JH, Ferrara N, Gerber H-P, Hanahan D. VEGF-A has a critical, 
nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer cell. 
2002;1:193-202. 
27. 
Lam KY, Lo CY. Pancreatic endocrine tumour: a 22-year clinico-pathological 
experience with morphological, immunohistochemical observation and a review of the literature. 
European journal of surgical oncology : the journal of the European Society of Surgical 
Oncology and the British Association of Surgical Oncology. 1997;23:36-42. 
28. 
Yuan J, Adamow M, Ginsberg BA, Rasalan TS, Ritter E, Gallardo HF, et al. 
Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in 
advanced melanoma patients treated with ipilimumab. Proceedings of the National Academy of 
Sciences of the United States of America. 2011;108(40):16723-8. 
29. 
Lee TY. Functional CT: physiological models. Trends in Biotechnology. 
2002;20(8):S3-10. 
30. 
Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib versus 
sunitinib in metastatic renal-cell carcinoma. The New England journal of medicine. 
2013;369(8):722-31. 

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

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

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Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
➢ The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
➢ The Coordinating Center must be designated on the title page. 
➢ Central registration of patients is required.  The procedures for registration must be 
stated in the protocol. 
➢ Data collection forms should be of a common format.  Sample forms should be 
submitted with the protocol.  The frequency and timing of data submission forms to 
the Coordinating Center should be stated. 
➢ Describe how AEs will be reported from the participating institutions, either directly 
to CTEP or through the Coordinating Center. 
➢ Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
 
Agent Ordering 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP.  Investigational agents may be 
ordered by a participating site only after the initial IRB approval for the site has been 
forwarded by the Coordinating Center to the CTEP PIO.  
 
 
 

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APPENDIX C 
NEW YORK HEART ASSOCIATION CLASSIFICATION OF 
FUNCTIONAL CARDIAC CAPACITY  
 
 
Class I 
Patients with cardiac disease but without resulting limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or 
anginal pain. 
Class II 
Patients with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
Class IV 
Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or the anginal syndrome may be 
present even at rest. If any physical activity is undertaken, discomfort is increased. 
*The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart 
and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256. 

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APPENDIX D 
REGISTRATION FORM 
 
Registration Form 
 
 
Date:  _____________ 
 
Registration Site  
______________         
Site Number ______________ 
Date subject signed consent _____________ 
 
Subject Initials _____________  
Date of Birth (Mo/Day/Year) _________________ 
Subject number _____________  
Enrolling Investigator ______________________________ 
 
Research Nurse  
____________________________________ 
Telephone  
____________________________________ 
Fax Number   
____________________________________ 
Email address  
____________________________________ 
 
Data Coordinator 
___________________________________ 
Telephone  
___________________________________ 
Fax Number  
___________________________________ 
Email address 
___________________________________ 
 

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Met 
Not met 
INCLUSION 
 
 
Patients must have histologically or cytologically confirmed low or 
intermediate grade pancreatic NET.  Patients with neuroendocrine 
tumors associated with MEN1 syndrome will be eligible.  
 
 
Patients must have unresectable or metastatic disease.  
 
 
Patients must have at least one measurable site of disease according to 
RECIST 1.1 that has not been previously irradiated. 
 
 
Patients must have at least one lesion suitable for perfusion CT.  The 
lesion should be greater than or equal to 3 cm in size in the cranial 
caudal direction. 
 
 
Patient must have no contraindication for CT with iodinated contrast 
 
 
Patients who are on a somatostatin analogue for control of hormonal 
syndromes must be on a stable dose (no change in mg dose of long 
acting octreotide or lanreotide, changes in dosing interval of +/- 1 week 
is allowed) for 2 months prior to date of study entry. 
 
 
Women of child-bearing potential must have a negative serum 
pregnancy test within 7 days prior to date of study entry.  Women who 
have had menses within the past 2 years, who have not had a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy are 
considered to be of child-bearing potential. Patients with elevated hCG 
at baseline that is judged to be related to the tumor are eligible if hCG 
levels do not show the expected doubling when repeated 5-7 days later, 
or pregnancy has been ruled out by vaginal ultrasound. 
 
 
Any number of prior lines of systemic anti-neoplastic therapy are 
allowed. For purpose of this criterion, somatostatin analogues will not 
be counted toward lines of systemic anti-neoplastic therapy and only 
one prior VEGF inhibitor will be allowed. 
 
 
Patients must have normal organ and marrow function as defined 
below: 
 
 
leukocytes  
 
≥3,000/mcL 
 
 
absolute neutrophil count 
≥1,500/mcL 
 
 
platelets 
 
 
≥100,000/mcL 
 
 
total bilirubin   
          ≤1.5 × institutional upper limit of normal 
 
 
AST(SGOT)/ALT(SGPT)   ≤2.5 × institutional upper limit of normal 
 
 
creatinine within normal institutional limits 
 
 
creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal. 
 
 
Urine protein:creatinine ratio ≤ 1.0.  
 
 
OR 
 
 
24-hour urine protein ≤ 1000 mg (24-hour total urine protein only need 
be obtained if urine protein : creatinine ratio < 1.0) 
 
 
Patients must have PT/INR/PTT within 1.2 X the upper limit of normal. 
 
 
Patients must have resting blood pressure (BP) no greater than 140 
mmHg (systolic) or 90 mmHg (diastolic) for eligibility.  Initiation or 
adjustment of BP medication is permitted prior to study entry.   
 
 
Ability to understand and the willingness to sign a written informed 

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consent document. 
Met 
Not met 
EXCLUSION 
 
 
Less than 28 days elapsed from prior radiotherapy, from prior surgery 
and prior chemotherapy to the time of randomization. Less than 42 days 
elapsed from prior major surgery to the time of randomization. 
 
 
Adverse events (with exception of alopecia, peripheral sensory 
neuropathy and those listed in specific exclusion criteria) from any prior 
anti cancer therapy of grade >1 (National Cancer Institute Common 
terminology Criteria [NCI CTCAE] v.4.0). 
 
 
Age < 18 years 
 
 
ECOG PS > 2 
 
 
History of brain metastases, uncontrolled spinal cord compression, or 
carcinomatous meningitis or new evidence of brain or leptomeningeal 
disease. 
 
 
Other prior malignancy. Adequately treated basal cell or squamous cell 
skin cancer, carcinoma in situ of the cervix or any other cancer from 
which the patient has been disease free for > 5 years are allowed. 
 
 
Participation in another clinical trial and any concurrent treatment with 
any investigational drug within 30 days prior to randomization. 
 
 
Any of the following within 6 months prior to randomization: 
myocardial infarction, severe/unstable angina pectoris, 
coronary/peripheral artery bypass graft, NYHA class III or IV 
congestive heart failure, stroke or transient ischemic attack. 
 
 
Any of the following within 3 months prior to randomization: Grade 3-
4 gastrointestinal bleeding/hemorrhage, treatment resistant peptic ulcer 
disease, erosive oesophagitis or gastritis, infecttious or inflammatory 
bowel disease, diverticulitis, pulmonary embolism or other uncontrolled 
thromboembolic event. 
 
 
Occurrence of deep vein thrombosis within 4 weeks, prior to 
randomization. 
 
 
Acquired immuno deficiency syndrome (AIDS-related illnesses) or 
known HIV disease requiring antiretroviral treatment. 
 
 
Any severe acute or chronic medical condition, which could impair the 
ability of the patient to participate to the study or to interfere with 
interpretation of study results. 
 
 
Pregnant or breast feeding women. Positive pregnancy test (serum or 
urine β-HCG) for women of reproductive potential. 
 
 
Patient with reproductive potential (female and male) who do not agree 
to use an accepted effective method of contraception (hormonal or 
barrier methods, abstinence) during the study treatment period and for 
at least 3 months following completion of study treatment. For female 
patient enrolled, the following methods of contraception are acceptable: 
oral contraceptives accompanied by the use of a second method of 
contraception, as it is not known how oral contraceptives interact with 
all study medications or Intra Uterine Device (IUD) or women who are 
surgically sterile, or women who are post –menopausal or other reasons 
have no chance of becoming pregnant. 
 
 
Absence of signed and dated Institutional Review Board-approved 
patient informed consent from prior to enrollment in the study. 
 
 
Exclusion criteria related to ziv-aflibercept: 

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Urine protein-creatinine ratio (UPCR ) >1 urinalysis or total urine 
protein > 500 mg/24h. 
 
 
Serum creatinine > 1.5 x upper limit of normal (ULN). If creatinine 1.0-
1.5 x ULN, creatinine clearance, calculated according to Cockroft-Gault 
formula, < 60 ml/min will exclude the patient. 
 
 
History of uncontrolled hypertension, defined as blood pressure > 
150/100 mmHg (grade ≥2 according to NCI CTCAE v. 3.0), or systolic 
blood pressure >180 mmHg when diastolic blood pressure < 90 mmHg, 
on at least 2 repeated determinations on separate days within 3 months 
prior to study enrollment. 
 
 
Patients on anticoagulant therapy with unstable dose of warfarin and/or 
having an out-of- therapeutic range INR (>3) within the 4 weeks prior 
to study entry. 
 
 
Evidence of clinically significant bleeding diathesis or underlying 
coagulopathy (e.g. INR>1.5 without vitamin K antagonist therapy), 
non-healing wound. 
 

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APPENDIX E 
NCISS MULTICENTER STUDY MANAGEMENT PLAN 
 
 
 
 
Multi-Center Study Management Plan  
 
For 
 
National Cancer Institute (NCI) / 
Cancer Therapy Evaluation Program (CTEP)  
Phase I/II & Phase II Studies 
Version 4/10 
 
 
 

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Table of Contents 
 
 
 
 
 
1.0 
Introduction 
 
 
 
 
 
68 
 
2.0 
Purpose  
 
 
 
 
 
68 
 
3.0 
General Roles and Responsibilities 
 
 
 
68 
3.1 
MD Anderson Cancer Center Principal Investigator 
 
 
 
Protocol Development 
 
Study Oversight 
 
 
 
 
Research Team Teleconferences  
 
3.2 
MD Anderson Cancer Center NCI Support Services  
 
69 
 
Administrative Support  
 
Regulatory Management  
 
 
Regulatory Document Collection 
 
Study Management Support 
 
Data Management Support 
 
Quality Assurance 
 
3.3 
Participating Institution Principal Investigator 
 
 
70 
 
Regulatory   
 
 
Study Contact List 
 
 
NCI Investigator Registration 
 
 
IRB Approval 
 
 
Regulatory Documents 
Adverse Events 
 
 
IND Safety Reports 
 
Study Management 
 
 
Eligibility 
 
 
Protocol Compliance 
 
Data Collection 
 
 
Patient Registration 
 
 
Data Entry 
 
 
Data Locks 
 
4.0 
Patient Confidentiality and Authorization Statement 
 
74 
 
5.0 
On-Site Audit 
 
 
 
 
 
74 
 
Purpose of Audit 
 
Selection for Audit 
 
Audit Notification 
 
Responsibilities of Participants in the Audit 
 
Conducting the Audit 
 
Audit Findings 
 
Audit Summary and Outstanding Corrective Action Items 
 
Audit Outcome 

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1.0 
INTRODUCTION 
 
This Study Management Plan (SMP) outlines the procedures and requirements for 
institutions collaborating with MD Anderson Cancer Center (MDACC) in the conduct of a 
National Cancer Institute (NCI)/Cancer Therapy Evaluation Program (CTEP) sponsored 
research protocol. 
 
2.0 
PURPOSE 
 
To establish standards that will ensure compliance with Federal Regulations, Good Clinical 
Practice (GCP) Guidelines; and Health Insurance Portability and Accountability Act 
(HIPAA) requirements in accordance with the CTEP Multicenter Guidelines. 
 
 
3.0 
GENERAL ROLES AND RESPONSIBILITIES 
 
In accordance with the CTEP Multicenter Guidelines, the MDACC Principal Investigator, 
MDACC NCI Support Services (MDACC NCISS), and the participating institution will all 
agree to the general responsibilities as follows (specific procedures for these general 
responsibilities are detailed in the SMP): 
 
3.1 
MDACC Principal Investigator (MDACC PI) 
 
The MDACC PI will accept responsibility for all aspects of the Study Management Plan to 
include: 
 
Protocol Development 
• Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments by the NCI and the MDACC IRB. 
 
• List each participating investigator and institution on the protocol title page including 
address, phone number, and email and designate the lead institution on the title page. 
 
• Assure all participating institutions are using the correct version of the protocol. 
 
Study Oversight 
• Monitor progress and overall conduct of study at all participating institutions.  
 
• Ensure all CTEP reporting requirements are met.  
 
• Review data and maintain timely submission of data for study analysis.  
 
• Research Team Teleconferences: The MDACC PI & research team, MDACC 
NCISS, and participating institution PI and research staff will participate in a 

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teleconference every 2 – 4 weeks, as needed, and will discuss the following 
information 
 
• Patients enrolled at participating sites including 
o Brief history 
o Eligibility for trial 
o Status of treatment 
o Adverse Events 
o Response evaluation 
 
• Review of safety data 
o Unexpected toxicities 
o Serious Adverse Events 
o IND safety reports 
 
 
3.2 
MDACC NCI Support Services (MDACC NCISS) 
 
To assist the MDACC PI in meeting his/her responsibilities MDACC NCISS will assume the 
following general responsibilities: 
 
Administrative Support 
• Act as the central liaison between the MDACC PI, participating institution, and NCI 
CTEP/PIO Office. 
 
• Maintain a contact list of all study participants at MDACC and the participating 
institution. 
 
Regulatory Management 
• Distribute 
approved 
protocols 
to 
participating 
institutions, 
notify 
them 
of 
amendments, and provide them with copies of approved amended protocols. 
 
• Ensure that each participating institution has the appropriate assurance on file with 
the Office of Human Research Protection (OHRP form 310) and this has been 
submitted to the CTEP PIO. 
 
Regulatory Document Collection:  Refer to Section 3.3 (page 70) for a list of documents that 
must be submitted to MDACC NCISS prior to protocol activation and submitted on an ongoing 
basis for the duration of the study. 
 
Study Management Support 
• Conduct study initiation meetings with MDACC PI and provide support to the 
participating institution research staff, as required. 
 
• Distribute external Serious Adverse Event safety reports to participating sites. 
 

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• Notify participating institutions of protocol hold or closure. 
 
 
Data Management Support 
• Provide participating sites with access, training, and support for electronic data entry. 
 
• Notify participating institution research teams of data locks prior to quarterly data 
transmission due dates 
 
• Monitor data quality and issue data queries / error log findings. 
 
Quality Assurance 
• Coordinate and participate in regularly scheduled teleconferences with the MDACC 
PI, the participating institution PI and their respective research teams to review study 
conduct. 
 
• Audit participating institutions by on-site inspection of selected patient records and / 
or by requesting source documents and research records as requested.  
 
3.3 
Participating Institution Principal Investigator 
 
The general responsibilities for each participating institution are as follows: 
 
Regulatory Compliance 
• Study Contact List: Provide a list of key study personnel and update MDACC 
NCISS with research staff changes on a timely basis. 
 
• NCI Investigator Registration: Maintain an active NCI Investigator Registration 
number for any physician who will be consenting / treating patients to the study and 
provide confirmation of annual renewal.  
 
• IRB Approval: Submit protocol and amendments to local IRB prior to initiating any 
protocol activity / changes. 
Note: If IRB approval for amendments is not obtained within the timeframe 
specified at time of amendment distribution accrual will be suspended until 
IRB approval is obtained. 
 
• Regulatory Documents: Provide copy of required regulatory documents to MDACC 
NCISS prior to activation. 
 
1. Federal Wide Assurance (FWA) number 
2. Laboratory certifications (CLIA / CAP) 
3. Normal laboratory values 
4. NCI Investigator Registration Number/expiration dates for all physicians  
5. Delegation of authority log 
6. Copy of initial IRB approval documents 

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The following regulatory documents must be submitted on an ongoing basis for the 
duration of the study: 
 
1. Copy of IRB annual approval documents.  Note:  If IRB annual approval is 
not received prior to the anniversary of the previous approval, accrual will 
be suspended until the annual approval is received. 
2. Copy of IRB approval documents for any protocol or informed consent 
revisions.  Note:  If IRB approvals for amendments are not received within 
the timeframe indicated at the time of distribution, accrual will be 
suspended until IRB approval is obtained. 
3. Confirmation of renewal of NCI Investigator Registration Number 
4. Copy of CTEP-AERS reports for Serious Adverse Events 
5. Evidence of IRB review of external safety reports 
6. Protocol violations and deviations submitted to the participating institution 
IRB. 
7. Copy of all signed informed consents for patients enrolled on the trial, if 
requested by the MDACC PI. 
8. Copy of IRB approval documents for any protocol status changes:  
activation, study closed to new patient enrollment, study closure, study 
termination.  Note:  If IRB annual review is not provided on or before the 
anniversary of the previous approval, accrual will be suspended until the 
annual re-approval is received. 
 
 
 
• IND Safety Reports: MDACC NCISS will distribute IND safety reports and 
appropriate guidance regarding IRB submissions and patient notification to the 
participating institutions.   
 
Study Management 
• Eligibility: Ensure patients meet all eligibility criteria prior to registering the patient 
on study. 
 
• Adverse Events: Submit Expedited Adverse Event reports directly to CTEP (via 
CTEP-AERS) as required per protocol and provide copies to the MDACC PI and 
NCISS. Submit Routine Adverse Events via Clinical Oncology Research System 
(CORe.) 
 
• Protocol Compliance: Adhere to the MDACC IRB definition of protocol deviation 
and protocol violation and requirements for reporting. 
 
Protocol Deviation: Noncompliance with the protocol that does not have a 
significant effect on the subject’s rights, safety, welfare, and/or the integrity of 
the data. Deviations may be caused by the action of the subject, the 
investigator, the research staff, or natural events. 
 

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Protocol Violation: Changes to protocol procedures without prior approval of 
the IRB/Sponsor. These changes may have a significant effect on the subject’s 
rights, safety, welfare, and/or the integrity of the data, and may cause an 
unanticipated problem to the subject or others. Violations may also 
significantly alter the clinical effectiveness of the treatment or the evaluation of 
its toxicity.  
 
Procedures for Reporting Protocol Violations/Deviations  
 
Participating Institutions: Protocol violations/deviations occurring at a 
participating institution will be submitted to that site’s own IRB.   A copy of 
the 
participating 
institution’s 
IRB 
violation/deviation 
report 
will 
be 
forwarded to the MDACC NCISS within 7 calendar days after the original 
submission.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the 
participating institution, MDACC NCISS will submit the report to the MDACC 
PI for review.  
 
Data Collection 
 
The Clinical Oncology Research System (CORe) is a web based database that is used for 
patient registration (for Phase I, Phase I/II and Phase II trials) and data entry (for Phase 
I/II, II trials).  CORe can be accessed at www.oncologyresearch.org .  Study staff at 
participating institutions will be provided with a username and password for CORe at the 
time of study activation. 
  
• Patient Registration: All patients, regardless of the phase of the trial, will be 
registered in CORe prior to beginning treatment.   
At the time of registration portions of a patient’s protected health information 
will need to be entered. In order for the site to enter this information the 
patient must have signed an informed consent document, which includes an 
authorization for the release of protected personal health information (IC/A). 
The authorization that each institution obtains to use and disclose protected 
health information must include MD Anderson Cancer Center as an entity that 
they will share data with. This consent and authorization (IC/A) document 
authorizes MD Anderson Cancer Center to collect and retain documents, 
reports, and/or information which relate to the patient’s participation on the 
protocol. This document also authorizes MD Anderson Cancer Center to send 
data and/or composite data for the entire study to each site participating in the 
trial.  
 
• Data Entry: Enter data in CORe according to the following data schedule 
 
At time of registration 
(Phase I/II and II trials) 
• Assign patient number 
• Name & demographics 

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• Eligibility checklist 
 
Within 1 week of 
registration 
(Phase I/II and II trials) 
• Pre-study data including 
o Registering institution  
o Disease subgroup code (NCI CDU)  
o Disease code (NCI CDU)  
o Payment method (NCI)  
o Zubrods PS  
o Baseline abnormalities 
o Prior therapy 
o Number of prior chemo regimens  
 
 
Within 3 weeks after the 
completion of each cycle. 
 (Phase I/II and II trials) 
• Treatment Course 
o Course Number 
o Cycle start date 
o Treatment code (NCI CDU) 
o Height (cm) 
o Weight (kg) 
o AE Experienced 
o Treating institution 
• 
Treatment Agent 
o Agent code (NCI CDU) 
o Total dose this course 
o Dose change 
 
• Adverse Events 
o Adverse event 
o Symptoms (required if AE other used) 
o Grade 
o Onset date 
o Resolved date 
o Relationship 
o AE report sent to CTEP 
 
Within 1 week after the 
completion of the cycle 
required for response 
assessment 
(Phase I/II and II trials) 
• Protocol Summary 
o Last dose date (date of last treatment) 
o Off treatment reason (if applicable) 
o Evaluability 
o Evaluable for response 
o Protocol response 
o Response date 
o Progression date (if applicable) 
Within 1 week after 
completing treatment or 
taken off study 
(Phase, I/II and II trials) 
• Off Protocol 
o Off date 
o Death date (if applicable) 
o Death date source 
o Death comment 
o Cause of death 
 

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Specifics Regarding Phase II Trials 
• Data Locks: Data will be transmitted to NCI quarterly on January 31, April 30, July 
31, and October 31.  Approximately 3 weeks prior to the transmission date, the 
participating institution will be informed by MDACC NCISS that the data will be 
locked during data transmissions.  During this period of data lock, no new patient 
data and/or changes to previously entered data should be made unless instructed by 
MDACC NCISS.  
 
• Data Queries: Following data transmission NCI will issue an error log to MDACC 
NCISS detailing any corrections that need to be made to data prior to protocol 
acceptance.  MDACC NCISS will communicate the required changes to the 
participating institution. NCISS will periodically review the data for completeness. 
You may receive queries directly from NCISS prior to data submission to the NCI. 
Required data corrections must be completed as instructed by MDACC NCISS.  
 
4.0 
PATIENT CONFIDENTIALITY AND AUTHORIZATION STATEMENT 
 
The Health Insurance Portability and Accountability Act of 1996 contains,  as one of its six 
major components, the requirement to create privacy standards for health care information that is 
used or disclosed in the course of treatment, payment or health care operations.  The original 
Privacy Rule, as it has come to be known, was published in December 2000.  The Final Rule was 
published on August 14, 2002, which has modified the privacy rule in significant ways vis-à-vis 
research. 
 
In order for covered entities to use or disclose protected health information during the course of 
an MDACC Multicenter trial the participant in the trial must sign an authorization form.  This 
Authorization may or may not be separate from the Informed Consent.  The Authorization may 
require local IRB approval before presentation to a potential trial participant.  The participating 
institution, with the approval from the NCI/CTEP and MDACC, will provide an Informed 
Consent template, which covered entities, must use.  
 
MDACC and participating institutions will attempt to limit its use of protected health 
information in its trials.  However, because of the nature of these trials, certain protected health 
information must be collected per National Cancer Institute requirements. These are the primary 
reasons why MDACC has chosen to use Authorizations, signed by the participant on the trial, 
rather than limited data sets with data use agreements.  
 
 
5.0 
ON-SITE AUDITING 
 
Purpose of Audit 
 
To ensure that the data analyzed to determine study results accurately reflect the primary 
source documents and that any clinical study was conducted in accordance with an 
Institutional Review Board (IRB)-approved protocol. The audit program reviews protocol 
management in the following categories: eligibility, informed consent, treatment, disease 

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outcome/response, toxicity, and general data quality. Compliance with all federal, National 
Cancer Institute and institutional requirements for the protection of human subjects is also 
assessed.  
 
In addition, the audit program provides education to the research staff regarding issues 
identified during the audit and assists research teams to develop appropriate ways to correct 
deficiencies identified by the audit.  
 
 
Selection for Audit 
 
Participating institutions can be selected for audit at any time.  Audit will generally be 
performed on a random basis and may occur at 6 – 12 month intervals. 
 
 
Audit Notification 
 
The participating institution principal investigator (PI) and study coordinator shall be notified 
two to four weeks in advance of the audit start date.  If the audit is initiated due to suspected 
deficiencies the advance notice may be shorter than 2 weeks.  All audit notifications shall be 
delivered to the PI and study coordinator by e-mail.  It is important that a person who is 
familiar with the research protocol and the study subjects enrolled on the trial be available 
(but not necessarily present) during the audit to assist the auditors in locating documentation 
that may be difficult to find in the primary medical record.  
 
The notification will include: 
• The date of the audit 
• A list of the patient records to be audited 
• A list of documents required for the audit 
 
 
Responsibilities of Participants in the Audit 
 
Clinical Trials Auditors: If more than one auditor visits the site a lead auditor will be 
designated to guide the audit process.  It shall be the auditor’s responsibility to print a copy 
of the protocol and be familiar with the study prior to the start of the audit. 
 
Principal Investigator and Research Staff: The principal investigator is responsible for 
assuring that all requested audit materials are available at the time of the audit.  These 
materials shall include the following: 
 
• One copy of an original signed and dated informed consent document (ICD) for 
each participant. For patients who have been re-consented while on study, an 
original signed and dated informed consent must be available for each IRB-
approved version of the informed consent. 

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• All patient records:  in-patient charts (if applicable), protocol-specific patient 
source documents (signed and dated pill diaries, symptom records), database 
printouts, and patient research files 
• Correspondence and source documentation from outside institutions pertaining to 
patient research data 
• Radiology films and other specified studies, if requested 
• Any operative, pathology and radiotherapy reports required by protocol 
• Regulatory Binder 
  
The research staff must have all patient research charts and the Regulatory Binder 
organized in a systematic and consistent fashion. The presence of organized study records 
reduces the potential for queries and helps prevent repeated questions to the study 
coordinator / PI requesting assistance in locating items during the audit.  
 
Conducting the Audit 
 
Medical Record Review: At the time of the medical record audit, source documentation 
shall be reviewed and used to independently verify study data. Data quality shall be 
assessed by measuring it against the standards for optimal data collection as defined in the 
research protocol.  Data entered in CORE should match precisely with the corresponding 
information on the primary source document.  
 
The research team shall also be evaluated on protocol compliance with the study schedule, 
regulatory requirements, and guidelines for Good Clinical Practice (GCP).  Although the 
PI may delegate responsibilities for various aspects of the protocol management, the PI 
alone retains ultimate responsibility for the conduct of the clinical trial. 
 
The following elements are reviewed during the audit: 
 
Activation/Continuing Review Information: The auditor shall verify that: 
• IRB approval has been obtained prior to study activation and patient enrollment;  
• An annual continuing review has been completed within 365 days from initial 
date of approval;  
• Confirmation that all consenting physicians have a current NCI Investigator 
Registration number 
• Protocol amendment, informed consent, and IRB approval dates are appropriate;  
• Patients were treated following CORe registration. 
• All regulatory documents are in the regulatory binder(s) 
 
Informed Consent Document:  The ICD must: 
• Be the appropriate IRB-approved version at the time the patient was enrolled. For 
NCI studies, the ICD must also have received NCI’s approval before it is used in 
obtaining informed consent.  
• Contain the patient’s signature and date; 
• Contain the signature and date of the person who is obtaining the informed 
consent; 

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• Contain the signature of the witness and date it was signed; if applicable 
• Indicate selection of optional studies verified by patient initials  
• List M. D. Anderson as an authorized reviewer on ICD's from outside institutions 
(where M. D. Anderson serves as the lead institution on a multicenter trial). On 
multicenter trials where M. D. Anderson is not the lead site, any institution that 
may request protected health information should be listed in the HIPAA section of 
the M. D. Anderson ICD. 
 
The informed consent process must be documented in the on-study note located in each 
patient’s medical record. 
 
Eligibility: The eligibility checklist is compared against the primary medical record to 
confirm that all criteria were met prior to registration on the trial. If documentation cannot 
be located, eligibility is noted as “unable to confirm” due to insufficient data. The patient 
shall be considered ineligible if one or more of the eligibility requirements were not 
satisfied.  
 
Protocol Compliance: Source documentation is used to verify that the performance status 
has been assessed and that the results of all required tests have been obtained within the 
protocol-specified time frame prior to the start of treatment. On-study visits, lab tests, and 
diagnostic studies shall be checked for adherence to the study schedule. If testing or visits 
were missed, the auditor shall verify that a protocol deviation/violation report was 
completed for each occurrence and submitted to the IRB, and a copy placed in the 
Regulatory Binder. A deviation log may be utilized as per institutional policy. 
 
Treatment Administration:  The audit team confirms that patients receive the correct dose, 
route, dosing interval, and timing of the treatment administered.  Dose modifications shall 
also be checked and compared against the protocol.  The auditor shall assure that the 
proper body surface area (BSA) was calculated. The auditor shall also check the medical 
record for correct and consistent recording of the study subject’s weight and shall look for 
dose adjustments based on body weight changes as defined in the protocol.  
 
Disease Outcome / Response: The auditor shall verify baseline and on-study disease status 
by reviewing tumor measurements analyses in the medical record/research file. Solid 
tumor measurements shall be compared to imaging reports and/or original radiology films 
to confirm tumor response. For hematologic tumors, documented response shall be verified 
using appropriate analyses as stated in the protocol. If the auditor cannot verify the 
outcome response, a physician auditor shall be consulted for a final decision. 
 
Toxicity: All toxicities shall be documented in the medical record or recorded on patient 
data forms.  These shall include the appropriate Common Toxicity Criteria term to 
describe the toxicity, the grade of toxicity, the attribution, date of onset, and date of 
resolution.  The auditor shall confirm that all patients have been followed for toxicities for 
thirty days from the last date of protocol therapy. When a SAE occurs, the auditor shall 
verify that initial and follow-up reporting is appropriate as required in the Code of Federal 
Regulations and in accordance to NCI / CTEP’s policy. 

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General Data Quality: This category concerns the quality and completeness of source 
documentation as well as the accuracy of data transcription from the source document to 
the case report form.  Emphasis shall be placed on clear and complete reporting of the 
findings and correct matching of all data elements.  Any inconsistent, incomplete, illegible, 
or hard to follow records shall be noted.  Comments shall be made regarding repeated 
discrepancies that appear to affect the validity of the data or indicate that the management 
of the protocol needs more oversight. 
 
Audit Findings 
 
• Following completion of the audit, a preliminary audit findings report will be completed 
and be presented at the Audit Findings meeting or the “Exit Interview meeting”. 
• The purpose of the exit interview is to provide an opportunity for education, clarification, 
immediate dialogue, and feedback. It is not intended as a time to resolve all of the issues 
noted in the audit findings. 
• The principal investigator and the study coordinator responsible for the study being audited 
are required to attend.  Additional research staff associated with the study is encouraged to 
attend as well. 
• As time allows, the lead auditor shall educate the research team in interpretation of the 
various regulatory requirements / institutional policies and shall provide guidance on the 
development of a corrective action plan to address issues involving major deficiencies. 
• At the conclusion of the exit interview, the lead auditor may also discuss best practice 
guidelines and offer suggestions for improvement on data collection and protocol 
management.   
• Following the exit interview the lead auditor shall amend the audit findings to include any 
corrections/clarifications noted during the exit interview.    
• Once the audit findings have been modified, the lead auditor shall send a return receipt e-
mail containing a copy of the audit findings to the PI and study coordinator.   
• Upon receipt of the e-mail, the research team shall have two weeks to respond and return 
the audit findings to the lead auditor.   
• The PI/study coordinator shall be responsible for providing a written response to each of 
the findings cited during the audit. 
• To properly respond to the audit findings, the research team must enter a response 
immediately below each query.  All research team responses shall be entered in red directly 
onto the audit findings document.   
• When appropriate, a corrective action plan shall be included to complete the response. 
• In situations where the lead auditor must review a source document to verify a research 
team response, the study coordinator shall provide a photocopy of this source document. 
All photocopies must be provided to the lead auditor by the deadline for audit response 
noted in the e-mail. 
• Once all of the queries have been addressed and the response is complete, both the 
individual preparing the document and the PI for the study must print out and sign one 
copy of the audit findings report.  An electronic copy of the same document shall be e-
mailed to the lead auditor.  

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• Once the lead auditor receives the electronic copy of the response to the audit findings, he 
or she shall review the explanations/corrective action plans and shall create a summary 
report of outstanding audit findings, PI responses and any other audit activities. 
• The final audit report will be forwarded to the Lead PI, the MD Anderson IRB.