Perfusion CT to Predict Progression-Free Survival and Response Rate in Bevacizumab Treatment of Platinum-Resistant Persistent or Recurrent Epithelial Ovarian, Fallopian Tube, or Peritoneal Carcinoma
Phase: NA
Conditions: Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma
Sponsor: ECOG-ACRIN Cancer Research Group

 
EAE161 
1 
Perfusion CT to Predict Progression-free Survival and 
Response Rate in Bevacizumab and Paclitaxel Treatment 
of Platinum-Resistant Persistent or Recurrent Epithelial 
Ovarian, Fallopian Tube, or Peritoneal Carcinoma 
STUDY CHAIR: 
Susanna Lee, M.D., Ph.D. 
STUDY CO-CHAIR: 
Avinash Kambadakone, MBBS, M.D., DNB, FRCR, 
FSAR, FSCBT-MR 
MODALITY CO-CHAIR(S): 
Russell Schilder M.D. 
Robert Mannel M.D. 
Andrew Smith, M.D., Ph.D., FSAR, FSCBT-MR 
STUDY STATISTICIAN: 
Bradley S. Snyder, M.S. 
GYNECOLOGY COMMITTEE CHAIR: 
Susanna Lee, M.D., Ph.D. 
  
 
Version Date:  June 13, 2018 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in Oncology  
February 4, 2018 
NRG / NRG Oncology 
 
Addendum #1 
SWOG / SWOG 
 
 
 
 
 
 
 
 
NCTN GROUP STUDY CHAMPIONS 
 
 
NRG: Russell Schilder, M.D. 
 
 
 
Robert Mannel, M.D. 
 
 
 
 
 
 
 
Agents 
IND# 
NSC# 
Supply 
Bevacizumab 
IND Exempt Study 
NSC# 704865 
Commercial 
 

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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 Abstract ..................................................................................................... 7 
1.2 Background and Rationale for a Phase II Study ........................................ 7 
1.3 Rationale for Perfusion CT ........................................................................ 9 
1.4 Significance of the Study ......................................................................... 11 
2. Objectives ......................................................................................................... 14 
2.1 Primary Aim:............................................................................................ 14 
2.2 Secondary Aims ....................................................................................... 14 
2.3 Exploratory Aims ..................................................................................... 14 
3. Selection of Patients ......................................................................................... 15 
3.1 Eligibility Criteria ..................................................................................... 15 
4. Registration Procedures.................................................................................... 18 
4.1 CTEP Registration Procedures ................................................................. 18 
4.2 CTSU Registration Procedures ................................................................ 18 
4.3 IRB Approval ............................................................................................ 18 
4.4 Downloading Site Registration Documents ............................................ 19 
4.5 Requirements for EAE161 Site Registration:........................................... 19 
4.6 Submitting Regulatory Documents ......................................................... 19 
4.7 Required Protocol Specific Regulatory Documents ................................ 20 
4.8 Checking Your Site’s Registration Status ................................................. 20 
4.9 Patient Enrollment .................................................................................. 21 
4.10 Step 0 Registration Content Requirements ............................................ 22 
4.11 Step 1 Registration Content Requirements ............................................ 22 
4.12 Patients must meet all of the eligibility requirements listed in Section 3, 
including ACR Imaging Core Lab Confirmation of a target lesion for 
perfusion CT. ........................................................................................... 23 
4.13 Additional Requirements ........................................................................ 24 
4.14 Instructions for Patients Who Do Not Start Assigned Protocol Treatment24 
5. Treatment Plan ................................................................................................. 26 
5.1 Perfusion CT with Iodinated Contrast ..................................................... 26 
5.2 Perfusion CT Scan Timeline and Analysis ................................................ 26 
5.3 Perfusion CT Scanning Procedures .......................................................... 27 
5.4 Standard of Care Systemic Therapy ........................................................ 29 
5.5 Adverse Event Reporting Requirements ................................................. 29 
5.6 Off-study Criteria..................................................................................... 34 
5.7 Duration of Follow-up ............................................................................. 35 
6. Measurement of Effect ..................................................................................... 36 
6.1 Antitumor Effect – Solid Tumors ............................................................. 36 
7. Study Parameters .............................................................................................. 44 
7.1 Study Parameters .................................................................................... 44 

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7.2 Schedule of Procedures .......................................................................... 47 
7.3 Continuing Quality Assurance of Perfusion CT Scans ............................. 48 
7.4 Central Reader Study .............................................................................. 49 
8. Statistical Considerations .................................................................................. 51 
8.1 Endpoints ................................................................................................ 51 
8.2 Aims ......................................................................................................... 51 
8.3 Sample Size Considerations .................................................................... 55 
8.4 Gender and Ethnicity .............................................................................. 57 
8.5 Study Monitoring .................................................................................... 57 
9. Electronic Data Capture .................................................................................... 59 
10. Patient Consent and Peer Judgment ................................................................ 59 
11. References ........................................................................................................ 59 
Appendix I  Patient Thank You Letter ...................................................................... 63 
Appendix II  ECOG Performance Status ................................................................... 64 
 

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STUDY CHAIR 
Susanna Lee, M.D., Ph.D. 
Massachusetts General Hospital 
Department of Radiology 
55 Fruit St., White 270 
Boston, MA 02114 
Phone: (617) 643-2009 
Fax: (617) 726-4891 
Email: slee0@mgh.harvard.edu 
 
STUDY CHAIR LIAISON (SCL) 
EAE161 Study Team 
Phone: 215-717-0833 
Email: EAE161@acr.org 
 
 
 

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

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Schema 
Step 1
1.
Conventional chest abdomen and pelvis CT images demonstrating recurrent tumor must be submitted to the ACR Core Lab within 21 days from acquisition. T0 and T1 perfusion CT scan must be 
submitted within 48 hours to ACR Core Lab from acquisition.
2.
Trial Radiologist (via the ACR Core Lab) identifies target lesion amenable to perfusion CT imaging. (See imaging manual for perfusion CT target lesion description.)
3.
ACR Core Lab will inform site within 5 business days if patient is eligible.
4.
CA-125 to be collected +/-2 days of T0 and T1 perfusion CT.
5.
Patient continues chemotherapy and is followed for survival up to 18 months after last patient is enrolled. 
Patients with 
suspected platinum-
resistant recurrent or 
persistent epithelial 
ovarian, peritoneal or 
tubal carcinoma
Submit CT 
imaging to 
ACR Core Lab 
for review1,2
R
E
G
I
S
T
R
A
T
I
O
N
T0 perfusion CT1,4
Within 4 weeks after 
imaging for target 
lesion and within 7 
days prior to 
bevacizumab initiation
Bevacizumab IV 10mg/
kg every 2 weeks. 
Given in combination 
with paclitaxel 80 mg/
m2 IV on either days 1, 
8 and 15 or days 1,8,15 
and 22 every 4 weeks.5
T1 perfusion CT1
15 days (± 2 days) 
post- bevacizumab 
initiation and before 
second dose
P
R
E
-
R
E
G
I
S
T
R
A
T
I
O
N
Step 0
ACR Core 
Lab confirms 
perfusion 
target lesion 
eligibility3
F
O
L
L
O
W
-
U
 P5
 
 
Rev. Add1

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1. 
Introduction 
1.1 
Abstract 
Bevacizumab in combination with cytotoxic chemotherapy has been shown to 
prolong PFS in epithelial ovarian cancer patients, both in the primary and 
recurrent setting. Perfusion CT changes have been associated with anti-
angiogenesis therapy response independent of tumor type and treatment setting. 
We hypothesize that in patients with platinum-resistant, recurrent ovarian cancer, 
changes in tumor vascularity parameters, as measured by perfusion CT from 
baseline (T0) to 15 days (+/- 2 days) post initiation (T1) of bevacizumab therapy, 
are associated with progression-free survival (PFS) and rates of objective tumor 
response assessed by standard anatomic response evaluation criteria (RECIST 
1.1). 
1.2 
Background and Rationale for a Phase II Study 
In 2014, the FDA approved bevacizumab (Avastin®, made by Genentech, Inc.) in 
combination with paclitaxel, pegylated liposomal doxorubicin (PLD), or topotecan 
for the treatment of patients with platinum-resistant recurrent epithelial ovarian, 
fallopian tube, or primary peritoneal cancer. Three Phase III trials (OCEANS, 
AURELIA and GOG-0213) showed that antiangiogenic therapy using 
bevacizumab, which targets vascular endothelial growth factor (VEGF)-A, in 
combination with cytotoxic chemotherapy has efficacy in treating recurrent 
disease. OCEANS tested gemcitabine and carboplatin with or without the 
addition of bevacizumab given concurrently and then as maintenance in patients 
considered to have platinum-sensitive disease. Progression-free survival (PFS) 
in patients who received bevacizumab plus chemotherapy was 12.4 months, 
compared to 8.4 months for patients who received chemotherapy alone 
(P<0.001) [1]. AURELIA studied platinum-resistant recurrent disease and 
observed a statistically significant increase in PFS from 3.4 months in the single-
agent chemotherapy-alone arm (weekly paclitaxel, PLD, topotecan or 
investigator’s choice) to 6.7 months in the chemotherapy plus bevacizumab arm 
(P<0.001) [2] and increased the proportion of patients (12.7% greater in 
bevacizumab arm, p = .002) achieving a 15% improvement in patient-reported 
abdominal or gastrointestinal symptoms during chemotherapy [3]. On subgroup 
analysis by conventional chemotherapy, the response rate by RECIST was 
higher with bevacizumab-containing therapy versus chemotherapy alone in the 
paclitaxel cohort (53.3% v 30.2%, respectively) and the topotecan cohort (17.0% 
v 0.0%), with a less pronounced effect in the PLD cohort (13.7% v 7.8%). Median 
PFS with bevacizumab and paclitaxel was the longest at 10.4 months [35]. These 
findings established addition of bevacizumab as standard of care for the 
recurrent ovarian cancer population. 
Improvements in efficacy attained by adding bevacizumab are offset by some 
disadvantages. Addition of the agent increases chemotherapy costs up to 7-fold. 
Added cost and morbidity are incurred by higher rates of treatment-related 
toxicities in the bevacizumab plus chemotherapy vs. chemotherapy alone arm. 
These include grade > 2 hypertension (20% vs. 7%) and bowel perforation, 
fistula, or abscess (7% vs. 0%). Moreover, emerging molecular analysis indicates 
a subgroup of patients in whom survival outcomes is adversely affected by 
bevacizumab [4]. Thus, a biomarker that can successfully distinguish the patient 

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subgroup that is unlikely to benefit from bevacizumab could serve as a tool to 
identify the cohort most likely to benefit from future trials of targeted agents for 
ovarian cancer therapy.  Further, a validated biomarker could enable precision-
medicine tailoring of the therapy regimen in recurrent ovarian cancer patients to 
maximize its potential benefits while minimizing morbidity and cost [5,6]. 
ACRIN 6695/GOG-0262, carried out by this study team, demonstrated that 
perfusion CT could serve as a quantitative early biomarker in ovarian cancer 
therapy in a multicenter trial setting [7,8]. In brief, from August 2011 to July 2013, 
120 patients were screened, yielding 76 evaluable patients from 19 centers, and 
completed perfusion CT scans on scanners from four different vendors before 
and after start of therapy. Ninety-one percent of the analyzable cohort received 
bevacizumab. Blood volume (BV) increase was significantly associated with 
lower chance of PFS-6 (p=0.028), while blood flow (BF) achieved borderline 
significance (p=0.053). BF and BV increases were both significantly associated 
with lower treatment response rate (p=0.032 and 0.026, respectively). However, 
on Cox regression analysis, BF increase was the parameter most strongly 
associated with shorter PFS (HR 2.9, 95% CI 1.3-6.4, p=0.008), and remained 
significant after adjusting for age, change in tumor volume and surgery status 
(p=0.007).    
Figure 1. ACRIN 6695/GOG-0262 Kaplan-Meier PFS curve comparing subjects 
with increase versus decrease in BF. 
 
Of note, changes in perfusion CT parameters during the first cycle of cytotoxic 
chemotherapy prior to initiation of bevacizumab demonstrated no association 
with PFS.  

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ACRIN 6695/GOG-0262 was the first trial to demonstrate the feasibility of 
quantitative perfusion CT assessment across multiple sites, vendors, and 
scanner platforms. Image intervals, CT noise, spatial uniformity, and temporal 
stability was identified and monitored as important factors affecting the precision 
of the derived perfusion parameters. No technical failures in scanning were 
observed at any individual site after the first or second exam, indicating a 
relatively low barrier for implementation. All scans were within acceptable 
radiation dose range. This study established a practical quality assurance 
protocol for site scanner qualification, image acquisition, dose monitoring and a 
real-time feedback communication between the trial radiologists and site 
investigators to ensure reproducibility and safety of perfusion CT. Ninety-five 
percent of the subjects on this trial were treated with bevacizumab. Current 
clinical practice standard uses bevacizumab in combination with conventional 
cytotoxic chemotherapy in patients with platinum-resistant recurrent tumor. 
Consequently, there is a need to verify that the utility of perfusion CT as a 
biomarker demonstrated with bevacizumab therapy in ACRIN 6695/GOG-0262 
holds true in a clinical setting where anti-angiogenesis therapy is considered 
standard of care. Moreover, beyond the phase I proof of principle setting, the 
generalizability of perfusion CT prediction to multiple readers and post-
processing vendor platforms must be demonstrated. 
1.3 
Rationale for Perfusion CT 
1.3.1 
Imaging Science 
Perfusion CT is a dynamic contrast-enhanced CT exam, in which the 
scanner is used to follow the passage of contrast bolus through the 
target lesion after injection. The acquired images are then processed 
to calculate quantitative parameters that include tumor blood flow 
(BF), blood volume (BV), and permeability surface product (PS). 
Bevacizumab targets VEGF-A overexpressed in tumor-associated 
angiogenesis to reduce proliferation of neovessels, which are more 
permeable than normal vessels [9]. This leads to normalization of the 
tumor vasculature, manifested as a decrease in microvessel blood 
flow (or perfusion) and permeability. As seen in ACRIN 6695/GOG-
0262, where perfusion CT outputs were performed in ovarian cancer 
patients undergoing conventional chemotherapy, with a subset in 
combination with bevacizumab, the test appears to specifically image 
microvascular changes resulting from VEGF inhibition and does not 
seem to serve as a predictive biomarker in the setting of conventional 
chemotherapeutics [7,8]. Finally, the exam can be readily integrated 
with morphologic RECIST 1.1 CT protocols in the same exam [10].  
Currently, a number of software packages based on different kinetic 
models of tumor perfusion are used for post-processing of the CT 
images, resulting in a lack of standardization. Studies using these 
models have yielded different values and perfusion maps in similar or 
even the same cohorts. All of these studies have been performed in 
brain imaging of acute stroke patients at a single time point [11,12]. In 
contrast, development of perfusion CT as an oncologic biomarker has 
relied on measuring the magnitude or direction of change of a specific 
variable (e.g., BF, BV) between two time points during therapy. This 
theoretically increases the likelihood that any associations seen in 

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perfusion CT output with treatment outcome will be software-
independent. Hence, one of the secondary aims of this trial is to study 
whether a biomarker relying on measuring perfusion CT changes over 
a therapy course is robust when different post-processing platforms 
are used. Testing the direction of change of BF (the variable with the 
strongest association with PFS in ACRIN 6695/GOG-0262) rather 
than its absolute value will increase the likelihood that any association 
we demonstrate will be generalizable to multiple perfusion CT 
platforms.   
MRI is the other imaging modality in which perfusion imaging has 
been studied. Major advantages compared to CT are lack of ionizing 
radiation and a greater dynamic range of signal. Exam performance is 
similar where a target volume of tissue is imaged during transit of a 
bolus of intravenous contrast. Several phase I, single-center trials 
have demonstrated that perfusion MR output can serve as a 
biomarker in VEGF inhibition, such as hepatocellular carcinoma 
treated with sunitinib [13] and renal cell carcinoma treated with 
sorafenib [14]. However, unlike with CT density, the MR T1 signal 
does not directly measure the tissue concentration of the administered 
contrast. The resulting necessity for scanner calibration and modeling 
to correct for the variability introduced by multiple factors, including 
scanning hardware, acquisition protocol, underlying tissue T1 signal, 
and the molecular composition of the contrast agent, represent 
intellectual challenges that still need to be solved before this 
technology can be successfully tested in a multicenter trial. 
Vascular tumor burden (VTB) is a recently developed quantitative CT 
imaging biomarker that is based on routine CT images [30, 31]. VTB 
is a size metric that quantifies the amount of vascularized tumor (cm2) 
with free form regions of interest drawn around the peripheral margin 
of target lesions on the axial CT images where the target lesions are 
the largest. Technically, VTB is the area of tumor within the region of 
interest that measures between 40 and 300 Hounsfield Units (HU) for 
contrast-enhanced CT and between 20 and 300 HU for non-enhanced 
CT images. The tumor segmentation and these thresholds are 
designed to exclude air, lung, fat, necrotic tumor, non-enhancing 
tumor, cortical bone, dense tumor calcification, hyperattenuating 
contrast within large blood vessels, and metal clips. As VTB is a size 
metric that is measured in continuous units, VTB from various target 
lesions can be summed to derive a total VTB for each time point, and 
a percent change in total VTB can be calculated, similar to percent 
change in tumor length used in RECIST 1.1. VTB is highly 
reproducible and provides a direct measure of tumor 
devascularization, allowing for early detection of tumor response in a 
population of patients with heterogeneous therapeutic efficacy. 
1.3.2 
Feasibility 
Perfusion CT is performed on multidetector CT (MDCT) scanners, 
which are widely available as the current standard for clinical exams. 
The scanning protocol is available as a standard software option on 
most scanners. This will enable enrollment of a diverse population at 
a variety of sites ranging from urban to rural, and academic to 

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community centers. Perfusion CT post-processing software is 
commercially available from multiple vendors and is in use at many 
sites for perfusion CT scanning of the brain in stroke patients and for 
tumor perfusion assessment in oncology patients. However, for the 
purposes of this trial, as with ACRIN 6695/GOG-0262, perfusion CT 
images acquired at the site will be collected by the core lab, and all 
post-processing will be performed centrally by the trial team. 
Perfusion scans in this study have been timed to coincide with 
therapy-related patient visits to minimize patient inconvenience and 
cost. In ACRIN 6695/GOG-262, the post-bevacizumab perfusion scan 
occurred on days 8-10 post first dose of bevacizumab (T2 scan in 
ACRIN6695 trial). Changes in tumor vascularity detected with 
perfusion CT seem to occur within the first 5-7 days after first dose 
anti-angiogenesis therapy, and are thought to remain unchanged for 
the first several weeks of the therapeutic response [32, 33]. Thus, the 
timing of the post-bevacizumab scan to day 13-17 on this trial is 
unlikely to significantly alter the range of perfusion CT output from that 
observed on ACRIN 6695/GOG-262. 
1.4 
Significance of the Study 
1.4.1 
Potential Value of Perfusion CT as a Non-Invasive Biomarker  
Currently, biomarkers to assess treatment response of ovarian 
carcinoma include morphologic assessment with Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 and cell surface 
glycoprotein antigen CA125. Unfortunately, these biomarkers are less 
than accurate in predicting a patient’s outcome, especially in those 
treated with newer molecular targeted agents [15]. Further, tissue 
biopsy for monitoring treatment response remains impractical, in part 
due to invasiveness. Additionally, the inherent heterogeneity of 
ovarian cancer at the tissue level results in significant inaccuracy from 
biopsy sampling. Hence, the identification of a non-invasive early 
biomarker to predict response to treatment in ovarian carcinoma 
would prove a powerful tool. Perfusion CT may serve as such a 
biomarker for evaluation of angiogenesis. As changes in tumor 
perfusion parameters have been noted to precede morphologic 
changes by weeks to months, perfusion CT represents a test that 
could accurately assess changes in tumor angiogenesis, predict long-
term efficacy, and identify candidates unlikely to incur benefit from 
bevacizumab early during the course of initial therapy [16]. 
Anti-angiogenic agents such as bevacizumab produce disease 
stabilization (cytostatic) in addition to tumor regression (cytotoxic). 
Consequently, conventional imaging strategies that rely on changes in 
tumor size, such as World Health Organization (WHO) and/or RECIST 
morphological criteria, are suboptimal for evaluating the efficacy of 
these agents [17,18]. While primary endpoints of PFS and overall 
survival (OS) remain the most valid and least ambiguous endpoints 
for clinical efficacy, the cytostatic effect of these new agents requires 
significantly more time and expense before their efficacy, or lack 
thereof, becomes evident using these parameters. Finally, response 
to these agents can be limited. Changes in the tumor 

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microenvironment (e.g., hypoxia) that result from vascular pruning and 
other consequences of VEGF inhibition can promote angiogenesis 
escape and tumor progression [8, 19]. Conventional assessment 
tools, including RECIST 1.1 or CA125, are inadequate to identify 
these patients in whom response to bevacizumab therapy will be 
short-lived. Because multiple trials have demonstrated that only a 
subset of patients respond, and the overall clinical benefit is limited, 
biomarker development resources has been directed toward finding a 
marker to predict the likelihood of anti-angiogenesis treatment failure 
[20].  
In summary, the identification of an alternative, early, non-invasive 
imaging biomarker that can be integrated into the current RECIST 1.1 
assessments, and which is proven to accurately predict long-term 
efficacy of anti-angiogenesis therapy, is of paramount importance. 
Such a biomarker has the potential to guide drug choice and dosing, 
evaluate pharmacodynamic response, and anticipate angiogenesis 
resistance and escape. This study, if successful, would provide 
necessary information toward validation of perfusion CT as an integral 
biomarker for future therapy trials. For ovarian cancer patients, such a 
biomarker would facilitate and expedite the development of drugs for 
the subgroup of patients who are at the highest risk for poor outcome. 
1.4.2 
Impact on Future Cancer Clinical Practice and Trials 
Perfusion CT has demonstrated a spectrum of potential biomarker 
applications in oncology, providing prognostic information and 
predicting therapeutic effects of various treatment regimens that target 
the tumor microvasculature. Preliminary data from metastatic colon 
cancer studies have suggested an association between progressive 
disease and a poor response to chemotherapy with perfusion 
parameters [21]. In head and neck cancers, perfusion CT has been 
able to identify tumors that are likely to have a favorable outcome 
following radiotherapy [22]. For anti-angiogenesis therapy of 
metastatic renal carcinoma with sorafenib and sunitinib [23] and 
primary hepatocellular carcinoma with bevacizumab [24], responders 
to therapy demonstrate significantly higher percentage decreases in 
tumor vascular parameters than non-responders. These observations 
indicate that perfusion CT measures the changes in the tumor 
microenvironment (e.g., hypoxia) that results from vascular pruning 
and other consequences of VEGF inhibition. 
Agents targeted for VEGF inhibition are widely used in advanced or 
recurrent colorectal, renal cell, and ovarian cancers. Patients who fail 
to respond to these conventional anti-angiogenesis agents are those 
with the poorest prognosis, and are the most likely to benefit from 
future drug development. With this in mind, extensive biomarker 
programs have been built into numerous clinical studies with 
bevacizumab [20]. In future trials, perfusion CT could be used identify 
patients who demonstrate resistance to anti-angiogenesis therapy, in 
whom novel agents should be tested. In this context, perfusion CT 
would serve as an integral biomarker in future phase II and III drug 
development trials.  In clinical practice, once successfully validated as 
a biomarker in future trials, perfusion CT has the potential to provide 

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early identification of those patients unlikely to benefit from the current 
standard anti-VEGF therapy, who could then be triaged to other 
agents more likely to succeed. 
1.4.3 
Impact on ECOG-ACRIN Scientific Objectives 
This trial fulfills multiple scientific objectives laid out by ECOG-ACRIN. 
Development and validation of advanced imaging methods to 
determine risk, identify treatment targets, monitor response to 
treatment, and establish markers for use in clinical trials and clinical 
care represent a major ECOG-ACRIN scientific objective. This trial 
furthers the development of an advanced imaging technique, 
perfusion CT, as a validated biomarker in VEGF-targeted therapy for 
early monitoring of response in clinical care and for use as an integral 
biomarker in future therapy trials. Collaboration across the NCTN in 
the development and implementation of high-impact clinical trials is 
another important ECOG-ACRIN objective. This trial has been 
designed to align with the research goals of NRG investigators who 
have identified the need for an integral biomarker in future trials of 
therapeutic agents in platinum- and bevacizumab-resistant ovarian 
cancer patients.   

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2. 
Objectives 
2.1 
Primary Aim:  
2.1.1 
To evaluate whether those patients with an increase in perfusion CT 
tumor blood flow (BF) from T0 to T1 demonstrate poorer progression-
free survival (PFS) compared to those patients with a decrease in BF 
from T0 to T1, among platinum-resistant, recurrent ovarian cancer 
patients treated with bevacizumab in combination with paclitaxel. 
2.2 
Secondary Aims 
2.2.1 
To evaluate whether change in perfusion CT tumor BF from T0 to T1, 
as a continuous variable, is associated with PFS. 
2.2.2 
To evaluate whether changes in perfusion CT tumor blood volume 
(BV) or permeability surface product area (PS) from T0 to T1 are 
associated with PFS. 
2.2.3 
To evaluate whether changes in perfusion CT tumor BF, BV, or PS 
from T0 to T1 are associated with response rate according to the 
standard anatomic response evaluation criteria (RECIST 1.1). 
2.2.4 
To identify which combination of perfusion CT parameters, including 
tumor BF, BV, and PS, can serve to optimally distinguish patients in 
terms of PFS outcome. 
2.2.5 
To evaluate whether the association between change in perfusion CT 
parameters and treatment outcome (PFS or tumor response) is stable 
when analyzed with various commercially available post-processing 
software. 
2.3 
Exploratory Aims 
2.3.1 
In the subset of patients with multiple, eligible perfusion target lesions 
within the CT imaging volume, we will describe the variability of 
perfusion CT changes across different lesions within the same patient, 
and evaluate the impact of multiple target lesions on the association 
between change in perfusion CT parameters and PFS. [8] 
2.3.2 
To evaluate the reliability of perfusion CT parameters by analyzing the 
same perfusion imaging dataset using different readers and different 
post-processing software. 
2.3.3 
To evaluate whether change in global vascular tumor burden (VTB) 
from T0 to T1 is associated with PFS, and with changes in BF, BV, or 
PS. 

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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 3 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 3 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit.  All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.ExecOfficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
3.1 
Eligibility Criteria 
3.1.1 
Registration to Step 0 
3.1.1.1 
Patient must be female ≥ 18 years of age. 
3.1.1.2 
Patient must have epithelial ovarian, fallopian tube, or 
primary peritoneal cancer. This includes high-grade serous 
ovarian cancer, endometroid, clear cell, mixed epithelial, 
undifferentiated carcinoma, transitional cell carcinoma 
histologies. 
3.1.1.2.1 
Patients with carcinosarcoma, non-
epithelial, low grade tumors, or tumors with 
low malignant potential are excluded. 
3.1.1.3 
Patient must have suspected platinum-resistant disease 
(disease progression ≤ 6 months of platinum therapy). 
3.1.1.4 
Patient must be expected to undergo therapy with 
bevacizumab in combination with paclitaxel at 
recommended standard of care doses if suspected 
recurrence is confirmed with imaging. Patient must be able 
and willing to provide written informed consent. 
3.1.1.5 
Patient must have a life expectancy of ≥ 3 months. 

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3.1.1.6 
Patient must have adequate bone marrow, coagulation, 
renal, and hepatic function; eGFR calculation ≥ 60 
mL/min/1.73 m2 (within 28 days of screening CT 
submission) 
3.1.1.7 
Patient must demonstrate an ECOG performance status of 
0-2. 
3.1.1.8 
Patient must not have undergone therapy with any VEGF 
monoclonal antibodies in the last twelve weeks. Patient 
must not have received any small molecule anti-VEGF 
drug within the previous 4 weeks. 
3.1.1.9 
Patient must not have undergone major surgery or 
radiotherapy to the pelvis or abdomen within previous 4 
weeks. 
3.1.1.10 
Patients must not have known contraindications to 
bevacizumab, including but not limited to abdominal fistula, 
GI perforation, intra-abdominal abscess, thrombotic or 
hemorrhagic disorders, uncontrolled hypertension or active 
clinically significant cardiovascular disease, non-healing 
wound, ulcer, or bone fracture within previous 4 weeks. 
3.1.1.11 
Patient must not have untreated or symptomatic CNS 
metastasis. 
3.1.1.12 
Patient must not have another active (within past 3 years) 
or concurrent malignancy. Resected basal cell skin cancer 
is allowed within past 3 years. 
3.1.1.13 Patient must not have contraindication to iodinated 
contrast. 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
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3.1.2 
Registration to Step 1 
NOTE: 
The ACR Imaging Core Lab will evaluate the potential target lesion 
once all required images are received and inform the site within five 
business days if patient is eligible and may be registered to Step 1 
and scheduled for perfusion CT imaging. The local site will receive 
notification of eligibility via RAVE. 
3.1.2.1 
Patient must be evaluable using RECIST 1.1 criteria. 
3.1.2.2 
Patient must have perfusion CT target lesion (e.g., ≥ 1 cm 
in both the long and short axis, at least one half of the 
tumor appears enhancing and solid on a contrast-
enhanced scan or has an attenuation of ≥ 10 HU on the 
unenhanced CT scan) on a contrast-enhanced 
conventional CT.  
3.1.2.3 
Conventional chest abdomen and pelvis CT images 
demonstrating recurrent tumor must be submitted within 21 
days from acquisition to the ACR Core Lab 
3.1.2.4 
Eligibility of a perfusion CT target lesion must be confirmed 
by the ACR Core Lab prior to study enrollment and the T0 
perfusion CT scan. 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 

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4. 
Registration Procedures 
4.1 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all individuals contributing to NCI-sponsored trials to register 
and to renew their registration annually.  To register, all individuals must obtain a 
Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, persons with a 
registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, 
RAVE, or TRIAD or acting as a primary site contact) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository 
(RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per 
registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required 
to access all CTEP and CTSU (Cancer Trials Support Unit) websites and 
applications.  In addition, IVRs and NPIVRs must list all clinical practice sites and 
IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in 
OPEN 
• 
Act as the site-protocol PI on the IRB approval 
Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm>. For questions, 
please contact the RCR Help Desk by email at <RCRHelpDesk@nih.gov>. 
4.2 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
4.3 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients.  
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Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled 
all regulatory criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating 
organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following 
criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for 
this study are not required to submit IRB approval documentation to the CTSU 
Regulatory Office. For sites using the CIRB, IRB approval information is received 
from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to 
the CIRB via IRB Manager to indicate their intent to open the study locally.  The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 
Office.  In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. 
4.4 
Downloading Site Registration Documents  
Site registration forms may be downloaded from the EAE161 protocol page 
located on the CTSU members’ website.   
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the ECOG-ACRIN  link to expand, then select trial protocol #EAE161 
• 
Click on LPO Documents, select the Site Registration Documents link  and 
download and complete the forms provided  
4.5 
Requirements for EAE161 Site Registration:  
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of 
Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form, or combination is accepted )  
4.6 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the 
Regulatory Submission Portal, where they will be entered and tracked in the 
CTSU RSS.  
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Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab 
 Regulatory Submission 
When applicable original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 to receive further 
instruction and support. 
4.7 
Required Protocol Specific Regulatory Documents 
1.  Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning 
risks or alternative procedures contained in the sample informed 
consent document must be justified in writing by the investigator 
and approved by the IRB. 
2.  A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
4.8 
Checking Your Site’s Registration Status 
You can verify your site registration status on the members’ section of the CTSU 
website. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
• 
Click on the Regulatory tab  
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements outlined 
by the Lead Network. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the 
enrolling investigator’s status with the NCI or their affiliated networks. 

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4.9 
Patient Enrollment 
Patient enrollment will be performed in two steps. Patients with clinically 
suspected recurrent platinum-resistant, epithelial ovarian, fallopian tube or 
peritoneal carcinoma intended for treatment with bevacizumab and paclitaxel will 
consent to a review of a standard of care chest, abdomen and pelvis CT for 
screening (Registration Step 0; for the full list of eligibility requirements at Step 0, 
see Section 3.1.1). If the standard of care imaging demonstrates evidence of 
recurrent tumor amenable to follow up with RECIST 1.1 as assessed by the site 
radiologist, the images will be submitted to the ACR Core Lab to evaluate if there 
is a lesion amenable to perfusion CT. If a perfusion CT target lesion is present as 
assessed by the trial radiologist, the site will be informed via RAVE within 5 
business days that the patient is eligible for the trial and the patient will be 
consented to enroll in the study (Registration Step 1). Patient eligibility for 
Registration Step 1 is determined centrally.  The patient will then be scheduled 
for the T0 perfusion CT scan. 
T0 perfusion CT scan should be performed 0-28 days from the standard of care 
baseline/eligibility chest, abdomen and pelvis CT. Patients must not start 
standard of care therapy (bevacizumab) prior to the T0 CT Perfusion scan. 
Bevacizumab and paclitaxel should be initiated 0-7 days from the T0 perfusion 
CT. 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at <https://ctepcore.nci.nih.gov/iam>) and a 'Registrar' role on either the 
LPO or participating organization roster. Registrars must hold a minimum of an 
AP registration type. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a 
transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval. 
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes. 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
NOTE:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for 
your records. 
Further instructional information is provided on the OPEN tab of the CTSU 
members’ side of the CTSU website at https://www.ctsu.org or at 
https://open.ctsu.org. For any additional questions contact the CTSU Help Desk 
at 1-888-823-5923 or ctsucontact@westat.com. 
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4.10 
Step 0 Registration Content Requirements 
NOTE: 
Patients must not start protocol procedures prior to Step 0 
registration. 
4.10.1 
The following information will be collected at the time of 
preregistration (Step 0).  
4.10.1.1 
Protocol Number  
4.10.1.2 
Investigator Identification  
4.10.1.2.1 
Institution and affiliate name 
4.10.1.2.2 
Investigator’s name 
4.10.1.3 
Patient Identification  
4.10.1.3.1 
Patient’s initials (first and last) 
4.10.1.3.2 
Patient’s Hospital ID and/or Social Security 
number 
4.10.1.3.3 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.10.2 
Eligibility Verification  
Patient must be consented to and be considered a viable candidate 
for registration to Step 0 of ECOG-ACRIN EAE161. 
Patients must meet all of the eligibility requirements listed in Section 
3.1.1. 
4.11 
Step 1 Registration Content Requirements 
Once the ACR Core Lab confirms the patient’s eligibility with a review of the 
standard of care chest, abdomen and pelvis CT, the patient will be permitted to 
proceed with enrollment. 
4.11.1 
The following information will be collected at the time of registration 
(Step 1).  
4.11.1.1 
Protocol Number  
4.11.1.2 
Investigator Identification  
4.11.1.2.1 
Institution and affiliate name 
4.11.1.2.2 
Investigator’s name 
4.11.1.3 
Patient Identification  
4.11.1.3.1 
Patient’s initials (first and last) 
4.11.1.3.2 
Patient’s Hospital ID and/or Social Security 
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4.11.1.3.3 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.11.2 
Eligibility Verification 
Patient must be consented to and have received ACR Imaging Core 
Lab confirmation of eligibility for registration to Step 1 of ECOG-
ACRIN EAE161. 
4.12 
Patients must meet all of the eligibility requirements listed in Section 3, including 
ACR Imaging Core Lab Confirmation of a target lesion for perfusion CT. 
4.12.1 
Data collection for this study will be done exclusively through the 
Medidata Rave clinical data management system.  Access to the trial 
in Rave is granted through the iMedidata application to all persons 
with the appropriate roles assigned in Regulatory Support System 
(RSS). To access Rave via iMedidata, the site user must have an 
active CTEP-IAM account (check at 
<https://ctepcore.nci.nih.gov/iam>) and the appropriate Rave role 
(Rave CRA, Read-Only, CRA, Lab Admin, SLA or Site Investigator) 
on either the LPO or participating organization roster at the enrolling 
site.To the hold Rave CRA role or CRA Lab Admin role, the user must 
hold a minimum of an AP registration type. To hold the Rave Site 
Investigator role, the individual must be registered as an NPIVR or 
IVR. Associates can hold read-only roles in Rave. 
Upon initial site registration approval for the study in RSS, all persons 
with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata page.  Please 
note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed.  
Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
Users that have not previously activated their iMedidata/Rave account 
at the time of initial site registration approval for the study in RSS will 
also receive a separate invitation from iMedidata to activate their 
account.  Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance).  Additional 
information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting 
the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
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4.13 
Additional Requirements  
4.13.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
4.13.2 
Data collection for this study will be done exclusively through the 
Medidata Rave clinical data management system. See Section 4.13.1 
for instructions on accessing Medidata Rave. 
4.13.3 
Digital Image Submission Using TRIAD 
TRIAD is the American College of Radiology’s (ACR) image exchange 
application.  TRIAD provides sites participating in clinical trials a 
secure method to transmit DICOM images and other objects. TRIAD 
anonymizes and validates the images as they are transferred. 
TRIAD Access Requirements: 
• 
Site physics staff who will submit images through TRIAD will need 
to be registered with the Cancer Therapy Evaluation Program 
(CTEP) and have a valid and active CTEP Identity and Access 
Management (IAM) account and be registered as an AP, NPIVR 
or IVR. Please refer to CTEP Registration Procedures of the 
protocol for instructions on how to request a CTEP-IAM account 
and complete registration in RCR. 
• 
To submit images, the site physics user must be on the site’s 
affiliate rosters and be assigned the 'TRIAD site user' role on the 
CTSU roster.  Users should contact the site’s CTSU Administrator 
or Data Administrator to request assignment of the TRIAD site 
user role.  RAs are able to submit standard of care imaging 
through the same method. 
TRIAD Installations: 
When a user applies for a CTEP-IAM account with the proper user 
role, he/she will need to have the TRIAD application installed on 
his/her workstation to be able to submit images. TRIAD installation 
documentation can be found by following this link 
https://triadinstall.acr.org/triadclient/   
This process can be done in parallel to obtaining your CTEP-IAM 
account username and password and RCR registration. 
If you have any questions regarding this information, please send an 
e-mail to the TRIAD Support mailbox at TRIAD-Support@acr.org. 
4.14 
Instructions for Patients Who Do Not Start Assigned Protocol Treatment  
If the T0 perfusion CT is not performed, the T1 perfusion CT should not be 
performed, and no further clinical data beyond baseline data will be collected for 
the study. 
Baseline and follow-up data will be collected on all patients who receive the T0 
perfusion CT, even if they do not receive the T1 perfusion CT and/or do not 
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receive bevacizumab therapy. Data must be submitted through Medidata Rave 
according to the schedule in the EAE161 Forms Completion Guidelines. 

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5. 
Treatment Plan 
5.1 
Perfusion CT with Iodinated Contrast   
Perfusion CT will be performed at participating institutions that are ACR certified 
and qualified for dynamic perfusion CT imaging. The participating institutions 
must have the appropriate multidetector CT scanner technology for the required 
scanning protocols. For an institution to be eligible, the multidetector CT scanner 
technology should have 64 or higher detector rows and should be capable of 
imaging a ≥ 2.8 cm section of the abdomen and pelvis repeatedly every 1-3 
seconds for a period up to 2 minutes. ACR Core qualification of the perfusion CT 
scanner is required for T0 and T1 perfusion CT imaging. This qualification is 
independent and separate from the ACR or ICACTL accreditation requirement. 
For the perfusion CT, the local site radiologist will assess the potential target 
lesion on the standard of care chest abdomen and pelvis CT scan using the 
following criteria: 
a) ≥ 1 cm in both the long and short axis;  
b) At least one-half of the tumor appears enhancing and solid on a contrast-
enhanced scan or an attenuation of ≥ 10 HU on an unenhanced CT scan. 
The potential target lesion will be confirmed by the ACR Imaging Core Lab to 
ascertain whether:  
a) The size of the tumor is ≥ 1 cm in both the long and short axis;  
b) At least one-half of the tumor appears enhancing and solid on a contrast-
enhanced scan or an attenuation of ≥ 10 HU on an unenhanced CT scan. 
This will determine eligibility for perfusion CT. 
Image Submission and Review Timeline 
• 
Screening Chest, Abdomen and Pelvis CT must be submitted to the ACR 
Core Lab via TRIAD within 21 days following acquisition.  
• 
The ACR Imaging Core Lab will evaluate the potential target lesion once all 
required images are received and inform the site within five business days if 
patient is eligible and may be registered to Step 1 and scheduled for 
perfusion CT imaging.  
• 
T0 perfusion CT must be submitted within 48 hours following acquisition. 
• 
T1 perfusion CT must be submitted within 48 hours following acquisition.  
5.2 
Perfusion CT Scan Timeline and Analysis 
5.2.1 
T0 Perfusion CT should be performed within 4 weeks after standard of 
care imaging to assess for a perfusion CT target lesion and within 7 
days prior to bevacizumab initiation. 
5.2.1.1 
The baseline T0 perfusion CT scan must be performed 
before initiation of bevacizumab treatment.  
5.2.2 
T1 Perfusion CT should be performed within 15 days (+/- 2 days) 
post-bevacizumab initiation and before second dose of bevacizumab.  

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5.3 
Perfusion CT Scanning Procedures  
5.3.1 
Additional information regarding the perfusion CT scan parameters 
can be found in the EAE161 Imaging ManuaI. The Imaging Manual is 
located on the CTSU EAE161 page located under the LPO tab in the 
Case Reports Forms section. The manual outlines scanner 
qualification, imaging submission, tumor eligibility etc in relation to this 
trial. 
5.3.2 
T0 Perfusion CT Scan Protocol 
5.3.2.1 
Localization scan: Refer to Imaging Manual for details. 
5.3.2.2 
Iodinated Intravenous Contrast and Perfusion CT Imaging: 
A single dose of low or isoosmolar iodinated contrast ≤ 150 
cc will be administered in two separate boluses.  The first 
bolus will be done for the CT imaging that looks at targeted 
tumor perfusion of a ≥ 4cm section of the abdomen/pelvis 
(covering the maximal cross-section of or the whole 
potential target lesion).  The second bolus will be 
administered after a delay of ten minutes for CT scanning 
of the chest, abdomen and pelvis to determine global 
tumor perfusion. The details are as follows: 
Target Tumor perfusion CT:  Dynamic perfusion CT 
imaging of the ≥ 4cm section of the abdomen/pelvis will be 
performed with 0.7 to 0.8 ml per kg of body weight low 
osmolar iodinated contrast (50-70 ml) at a concentration of 
300 – 370 mgI/ml. The contrast will be injected at a rate of 
2 to 5 ml/sec. A scanning delay of ≤ 5-15 seconds between 
scanning and injection is allowed. 
Global tumor perfusion CT: CT imaging of the chest, 
abdomen and pelvis will be performed with 0.7 to 1.0 ml 
per kg of body weight low osmolar iodinated contrast (80-
100ml) at a concentration of 300 – 370 mgI/ml. The 
contrast will be injected at a rate of 2 to 5 ml/sec. CT 
imaging of the chest, abdomen and pelvis will be 
performed in a single acquisition beginning at the apex of 
the chest and continuing through the pubic symphysis. 
Scanning will be initiated 60 seconds after the initiation of 
the intravenous contrast bolus. The volume of second 
bolus of contrast will be determined by volume of 
contrast injected for the targeted perfusion CT to 
ensure that the total volume does not exceed 150ml. 
5.3.3 
T1 Perfusion CT Scan Protocol 
5.3.3.1 
Prior to T1 scan: Site to assess kidney sufficiency per local 
institution standard. 
5.3.3.2 
Localization scan: Refer to Imaging Manual for details. 
5.3.3.3 
Iodinated Intravenous Contrast and Perfusion CT Imaging: 
A single dose of low or isoosmolar iodinated contrast ≤ 150 
cc will be administered in two separate boluses.  The first 

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bolus will be done for the CT imaging that looks at targeted 
tumor perfusion of a ≥ 4cm section of the abdomen/pelvis 
(covering the maximal cross-section of or the whole 
potential target lesion).  The second bolus will be 
administered after a delay of ten minutes for CT scanning 
of the chest, abdomen and pelvis to determine global 
tumor perfusion. 
The details are as follows: 
Target Tumor perfusion CT:  Dynamic perfusion CT 
imaging of the ≥ 4cm section of the abdomen/pelvis will be 
performed with 0.7 to 0.8 ml per kg of body weight low 
osmolar iodinated contrast (50-70 ml) at a concentration of 
300 – 370 mgI/ml. The contrast will be injected at a rate of 
2 to 5 ml/sec. A scanning delay of ≤ 5-15 seconds between 
scanning and injection is allowed. 
Global tumor perfusion CT: CT imaging of the chest, 
abdomen and pelvis will be performed with 0.7 to 1.0 ml 
per kg of body weight low osmolar iodinated contrast (80-
100ml) at a concentration of 300 – 370 mgI/ml. The 
contrast will be injected at a rate of 2 to 5 ml/sec. CT 
imaging of the chest, abdomen and pelvis will be 
performed in a single acquisition beginning at the apex of 
the chest and continuing through the pubic symphysis. 
Scanning will be initiated 60 seconds after the initiation of 
the intravenous contrast bolus. The volume of second 
bolus of contrast will be determined by volume of 
contrast injected for the targeted perfusion CT to 
ensure that the total volume does not exceed 150ml. 
5.3.3.4 
Perfusion CT scan analysis: Perfusion CT images 
submitted to the ACR core lab will then be transferred to 
the Tumor Imaging Metrics Core (TIMC) laboratory at 
Massachusetts General Hospital for post-processing and 
analysis by the trial radiologist. Post-processing of the 
dynamic CT data for analysis of perfusion characteristics 
will be performed on a dedicated CT workstation. Semi-
quantitative assessment of targeted tumor perfusion 
involves generation of perfusion maps followed by manual 
outlining of the tumor ROI by the trial radiologist (Imaging 
Manual). The acquired perfusion CT images of the outlined 
tumor will depict the rates of wash-in and wash-out of 
contrast from the tumor, which will be compared with those 
of the aorta (or its major branches) to calculate the tumor 
vascular parameters: tumor blood flow (BF), blood volume 
(BV) and permeability surface area product (PS). In order 
to study reproducibility, the same perfusion data set will be 
analyzed using the perfusion CT by two different 
radiologists. The perfusion CT data sets will be analyzed 
on different perfusion CT software platforms selected to be 
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perfusion CT to depict changes in tumor vascularity 
independent of analytical post processing software used. 
GE Healthcare software will be used for the first 
processing and MIStar software will be used for the second 
processing.  Global tumor perfusion assessment will be 
performed using eMASS software at Dr. Andrew Smith's 
Advanced Imaging Lab at the University of Alabama at 
Birmingham (UAB). Refer to protocol Section 7.4. 
5.4 
Standard of Care Systemic Therapy 
Patients will initiate standard of care systemic therapy with bevacizumab and 
paclitaxel chemotherapy 0-7 days from T0 perfusion CT. 
Paclitaxel and Bevacizumab 
• 
Paclitaxel 80mg/m2 can be delivered intravenously: 
a. Days 1, 8, 15 and 22 of a 28-day cycle OR 
b. Days 1, 8, 15 of a 28-day cycle 
• 
Bevacizumab 10mg/kg, to be delivered intravenously every two weeks 
5.5 
Adverse Event Reporting Requirements 
All toxicity grades described in this protocol and all reportable adverse 
events on this protocol will be graded using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
5.5.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done so investigators and regulatory 
agencies can detect and analyze adverse events and risk situations to 
ensure the safety of the patients enrolled, as well as those who will 
enroll in future studies using similar agents/procedures. 
5.5.2 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of an imaging agent/procedure in humans, 
whether or not considered imaging agent/procedure related. 
Therefore, an AE can be ANY unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
• 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
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ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to imaging 
agent/procedure. 
Unlikely 
The AE is doubtfully related to imaging 
agent/procedure. 
Possible 
The AE may be related to imaging 
agent/procedure. 
Probable 
The AE is likely related to imaging 
agent/procedure. 
Definite 
The AE is clearly related to imaging 
agent/procedure. 
• 
CTCAE:  The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting.  A grade (severity) is provided for each AE term.  
• 
Expectedness: Expected events are those that have been 
previously identified as resulting from administration of the 
imaging agent/procedure. An adverse event is considered 
unexpected, for expedited reporting purposes, when either the 
type of event or the severity of the event is NOT listed in the 
protocol or drug package insert. 
5.5.3 
Mechanisms for Adverse Event Reporting 
Routine reporting: Adverse events are reported in a routine manner 
at scheduled times during a trial using the Medidata Rave clinical data 
management system. Please refer to section 4 of the protocol for 
more information on how to access the Medidata Rave system and 
the EAE161 forms packet for instructions on where and when adverse 
events are to be reported routinely. 
Expedited reporting: In addition to routine reporting, certain adverse 
events must be reported in an expedited manner for timelier 
monitoring of patient safety and care. The remainder of this section 
provide information and instructions regarding expedited adverse 
event reporting. 
5.5.4 
Expedited Adverse Event Expedited Adverse Event Reporting 
Procedure 
Adverse events requiring expedited reporting will use CTEP’s Adverse 
Event Reporting System (CTEP-AERS). CTEP’s guidelines for CTEP-
AERS can be found at http://ctep.cancer.gov. 
For this study, a CTEP-AERS report must be submitted electronically 
via the CTEP-AERS Web-based application located at 
http://ctep.cancer.gov so that ECOG-ACRIN and all appropriate 
regulatory agencies will be notified of the event in an expeditious 
manner. In the rare event when Internet connectivity is disrupted a 24-
hour notification is to be made by telephone to: 
• the AE Team at ECOG-ACRIN (857-504-2900) 
• the FDA (1-800-FDA-1088) 
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An electronic report MUST be submitted via CTEP-AERS immediately 
upon re-establishment of internet connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to FDA (800-332-0178) in the same 
timeframe.  
CTEP Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.5.5 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both 
• 
the seriousness of the event 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
• 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
• 
when the adverse event occurred (within 30 days of the last 
administration of imaging agent/procedure vs. ≥ 30 days after the 
last administration of imaging agent/procedure) 
• 
the relationship to the study treatment (attribution) 
• 
the expectedness of the adverse event 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol EAE161 and outline the 
specific expedited adverse event reporting requirements for study 
EAE161. 
 

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5.5.6 
Steps to determine if an adverse event is to be reported in an 
expedited manner 
Identify the type and grade of the event 
using CTCAE v5.0. 
Determine if the event is related to the 
protocol imaging agent (attribution). 
With this information, review the chart in 
Section 5.5.7 to determine if event is 
reportable via CTEP-AERS. 
Refer to footnote b in 
Section 5.5.7 to determine 
if the event meets the 
protocol specific reporting 
requirements for this 
study. If so, report the 
event via CTEP-AERS. 
Is the event 
reportable? 
No 
Yes 
Refer to Section 5.5.7 to determine if the event meets the 
criteria as an exception to reporting on this protocol. If it 
does not, report the event via CTEP-AERS. 
Determine the expectedness of the 
event. An unexpected event is defined as 
one where the type or severity of the 
event is not listed in the investigator’s 
brochure, package insert or protocol. 
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5.5.7 
Expedited Reporting Requirements for protocol EAE161 
Expedited reporting requirements for adverse events occurring within 24 hours of the CT Perfusion and 
last dose of the iodonated contrast agent) 
Attributionc 
Grade 4 
Grade 5a 
ECOG-ACRIN 
and Protocol-
Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
Unrelated or 
Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: 
Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of 
learning of the event. 
a 
A death occurring while on study or within 24 hours of the CT Perfusion and last dose of the 
iodinated contrast agent requires both routine and expedited reporting, regardless of causality. 
Attribution to treatment or other cause must be provided. 
NOTE: Any death that occurs > 24 hours after the CT Perfusion and last dose of the 
iodinated contrast agent and is attributed possibly, probably, or definitely to the CT 
Perfusion and iodinated contrast agent treatment must be reported within 7 calendar 
days of learning of the event. 
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require 
expedited reporting for this trial: 
Serious Events: Any event following treatment that results in persistent or significant 
disabilities/incapacities, congenital anomalies, or birth defects must be reported 
via CTEP-AERS within 7 calendar days of learning of the event. For instructions 
on how to specifically report these events via CTEP-AERS, please contact the 
AEMD Help Desk at aemd@tech-res.com or 301-897-7497. This will need to be 
discussed on a case-by-case basis. 
c 
For this protocol, attribution is assessed as the relationship between the adverse event and the  
MRI/gadolimium-based contrast agent. 
• 
Other recipients of adverse event reports and supplemental data 
Adverse events determined to be required expedited reporting 
must also be reported by the institution, according to the local 
policy and procedures, to the Institutional Review Board 
responsible for oversight of the patient. 
• 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
• 
A second malignancy is a cancer that is UNRELATED to 
any prior anti-cancer treatment (including the treatment 
on this protocol).  Second malignancies require ONLY 
routine reporting as follows: 
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1. Complete a Second Primary Form in Medidata Rave within 
14 days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-
ACRIN via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior 
anti-cancer treatment (including the treatment on this 
protocol). Secondary malignancies require both routine 
and expedited reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 
14 days. 
2. Report the diagnosis via CTEP-AERS at 
http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming 
the diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-
ACRIN via Medidata Rave and submit a copy to 
NCI/CTEP. 
NOTE: 
The ECOG-ACRIN Second Primary Form and the CTEP-
AERS report should not be used to report recurrence or 
development of metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the ECOG-ACRIN Second Primary Form 
must be submitted for the most recent trial. ECOG-ACRIN 
must be provided with a copy of the form and the 
associated pathology report and cytogenetics report (if 
available) even if ECOG-ACRIN was not the patient's most 
recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the ECOG-ACRIN 
Second Primary Form. 
5.6 
Off-study Criteria 
The following are situations that would result in the patient being removed from 
the study: 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity from perfusion CT imaging. 
• 
Patient does not receive T0 CT Perfusion Scan  

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All data up until the date the patient was removed from the study are still required 
to be submitted. 
5.7 
Duration of Follow-up 
Patients will undergo medical history, physical examination, and CA-125 every 
nine weeks (+/-7 days) until death, withdrawal of consent, or up until 18 months 
of the last accrued patient. In addition, patients will undergo imaging assessment 
of the abdomen and pelvis +/- chest (chest only for patients with evidence of 
measurable disease on baseline chest imaging) every nine weeks (+/- 7 days) for 
the first year and every 12 weeks (+/- 7 days) thereafter until withdrawal of 
consent, death, or until 18 months after the last patient accrual. Follow-up data 
should be submitted quarterly for patients on study < 2 years and every 6 months 
thereafter. Data can be obtained via clinical visits, imaging visits, phone calls, 
etc. If multiple medical history, physical examination, CA-125 and imaging occur 
during the follow-up period, site should report the last test/visit occurring during 
the follow-up period on the follow-up form. 
Treatment response per RECIST 1.1, drug administration dates and treatment 
doses will be recorded for each patient. If bevacizumab is discontinued, date and 
reason should be recorded. 
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6. 
Measurement of Effect 
6.1 
Antitumor Effect – Solid Tumors  
For the purposes of this study, patients should be re-evaluated for response 
every nine weeks (+/- 7 days) in the first year and every twelve weeks (+/- 7 
days) after the first year. 
Response and progression will be evaluated in this study using the international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [10]. 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 RECIST. 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor 
burden at baseline to which subsequent measurements will be compared. All 
baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than four weeks before registration. 
2. Measurable disease is defined by the presence of at least one measurable 
lesion. 
3. All measurements should be recorded in metric notation by use of a ruler or 
calipers.  
4. The same method of assessment and the same technique must be used to 
characterize each identified lesion at baseline and during follow-up.  
6.1.1 
Definitions 
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 lesion assessment. The 
response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 
6.1.2 
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, as ≥ 10 mm with CT scan, or ≥ 10 mm 

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with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
NOTE: 
Tumor lesions that are situated in a previously irradiated 
area might or might not be considered measurable. If the 
investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered 
must be defined in the protocol. 
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 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. Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
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 

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of the 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 or absence of 
unequivocal progression of each should be noted throughout follow-
up.  
6.1.3 
Methods for Evaluation of 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 registration. 
The same method of assessment and the same technique must be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 
mm in 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 must 
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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, the PET portion of the CT 
imaging will not be included in the follow-up assessment. 
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. 
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 CA-125 response in recurrent ovarian cancer have 
been published [27]. 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 [28]. 
Cytology, Histology 
These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., 

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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. 
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. 
6.1.4 
Response Criteria 
6.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction 
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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 progression, See Section 
6.1.5.2. 
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. (Note: a change of 20% or 
more that does not increase the sum of the diameters by 5 
mm or more is coded as stable disease) 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 8 weeks (+/- 2 
days) (in general, not less than six to eight weeks).  
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (< 10 mm short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s). 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (see 
Section 6.1.4.3). Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, not a 
single lesion increase. 
When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest 
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status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy. 
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). 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
A growing lymph node that did not meet the criteria for 
reporting as a measurable or non-measurable lymph node 
at baseline should only be reported as a new lesion (and 
therefore progressive disease) if it:  
a) increases in size to ≥ 15 mm in the short axis, or  
b) there is new pathological confirmation that it is disease 
(regardless of size). 
new effusion or ascites that appears during treatment 
should only be reported as a new lesion (and therefore 
progressive disease) if it has cytological confirmation of 
malignancy. 
6.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence or non-protocol therapy (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 
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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target  
Lesions 
New 
Lesions* 
Best Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
 
CR 
Non-CR/Non-PD*** 
No 
PR 
 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not evaluated 
No 
PR 
SD 
Non-PD***/not evaluated 
No 
SD 
Documented at least once 
≥ 9 wks. from study entry 
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. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase. Please refer to the Evaluation of Non-
Target Lesions – Progressive Disease section for further explanation. 
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. 
6.1.4.5 
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.  
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 9 weeks (+/-7 
days) (in general, not less than six to eight weeks). 
 

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7. 
Study Parameters 
7.1 
Study Parameters 
7.1.1 
Scanner qualification for perfusion CT. Refer to the Imaging Manual 
on the CTSU EAE161 page for full scanner qualification parameters. 
The Imaging Manual is located under the LPO tab in the Case 
Reports Forms section on the EAE161 page. 
7.1.1.1 
A multidetector CT (64 slice or greater) scanner capable of 
imaging a 2.8 cm or wider section of the abdomen/pelvis 
repeatedly every 1-3 seconds for up to 2 minutes is 
required.  
7.1.1.2 
ACR Core Lab qualification of the perfusion CT scanner is 
required prior to enrollment of study participants. This 
qualification is independent and separate from the clinical 
imaging ACR or ICACTL accreditation requirement. 
7.1.1.3 
Sites are required to submit two (2) phantom series: one 
water section and one high contrast spatial resolution 
section. This will require the use of the quality control 
phantom supplied by the CT scanner vendor. The water 
and high contrast spatial resolution sections of the 
phantom are to be scanned according to the perfusion CT 
protocol. 
7.1.1.4 
The first imaging dataset of the first enrolled patient 
submitted within 48 hours of acquisition will serve as the 
final qualification scan. 
7.1.2 
Screening (up to -28 days from Registration to Step 0) 
• 
A signed consent form will be obtained prior to screening. 
• 
Patient undergoes SOC Chest, Abdomen, Pelvis CT. Patient 
images will be submitted to ACR Imaging Core Lab for 
confirmation of target lesion for perfusion CT within 21 days of 
acquisition. 
• 
Review of CT imaging will be completed by ACR Imaging Core 
Lab and the site will be informed whether or not the patient is 
eligible for the perfusion CT component of the trial, as well as the 
eligible target lesion if eligible, within 5 business days of the SOC 
chest, abdomen and pelvis CT image submission through 
Medidate Rave.  Patients determined to be eligible can then 
proceed with Step 1 Registration. 
NOTE: Patient needs to sign imaging consent prior to Registering 
to Step 1. 
• 
If an eligible target lesion is present, the ACR Core lab will provide 
an image annotating the lesion to the site through Medidata Rave. 
This image should be provided to the site radiologist for use in 
perfusion CT scanning. 
• 
The screening assessment will include collection of 
demographics, tumor histology, date of last platinum-based 

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chemotherapy, eGFR, calculation, CA-125 +/- 28 days (if 
available) from Step 0 Registration, and name/date of any prior 
VEGF therapy. 
7.1.3 
Visit 1 (+0 to 28 days from the SOC Chest, Abdomen, Pelvis; Prior to 
treatment) 
• 
Medical history, demographics, height, weight, and physical exam 
will be obtained.  This information does not need to be repeated if 
available in clinical records and dated within 28 days from Step 0 
registration. 
• 
Patient will undergo T0 perfusion CT. 
• 
CA-125 to be collected (+/-) 2 days of T0 perfusion CT. 
• 
An adverse event evaluation will be performed by phone at 24 
hours. 
7.1.4 
Visit 2 (+0 to 7 days from the T0 perfusion CT) 
• 
Treating physician will initiate bevacizumab plus paclitaxel 
treatment. 
7.1.5 
Visit 3 (+15 days +/- 2 days from the initiation of bevacizumab) 
• 
Prior to T1 scan: Site to assess renal function per local standard. 
• 
Patient will undergo T1 perfusion CT. T1 perfusion CT should be 
performed after the first dose of bevacizumab but before the 
second dose. 
• 
CA-125 to be collected (+/-) 2 days of T1 perfusion CT. 
• 
An adverse event evaluation will be performed by phone at 24 
hours. 
7.1.6 
Follow-up occurs until withdrawal of consent, death, or until 18 
months after the last patient accrual. Data to be submitted quarterly if 
patient is on study < 2 years, and every six months thereafter. If any 
of the visits/tests below happen more than once during the follow-up 
period, sites should report the last event occurring in the follow-up 
period on the follow-up form. 
• 
Medical history, physical exam and CA-125 every 9 weeks (+-7 
days) 
• 
For the first year patient undergoes SOC Abdomen, Pelvis CT +/- 
Chest (chest only done if patient has evidence of measurable 
disease on baseline chest imaging) every 9 weeks (+/- 7 days).  
After year one, imaging will be completed every 12 weeks. 
• 
Objective response based on standard anatomic response 
evaluation criteria (RECIST 1.1) reported very 9 weeks (+/- 7 
days) then, after year one, every 12 weeks. 
• 
Quarterly report of interval therapy since last point of follow up. 
7.1.7 
Date of progression 
• 
Report date. 
• 
Report basis for assessing progression: CA-125, imaging results, 
physical exam, etc. 
Rev. Add1 

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• 
Report interval therapy since last point of follow up. 
7.1.8 
Date of death (if applicable during follow-up) 
• 
Report date. 
• 
Report interval therapy since last point of follow up 
Rev. Add1 

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7.2 
Schedule of Procedures 
 
Screening: 
Up to 28 Days from 
Step 0 Registration 
Visit 1 (T0 Scan): 
+0 to 28 Days from SOC Chest  
Abdomen & Pelvis CT; prior to 
start of treatment 
Visit 2: 
+0 to 7 Days 
After Visit 1 
Visit 3 (T1 Scan): 
+15 +/- 2 Days After 
Visit 24 
Follow-
up8 
Consent to Screening 
X 
 
 
 
 
SOC Chest, Abdomen & Pelvis CT 
X 
 
 
 
 X1 
Consent to Study 
 
X 
 
 
 
Medical History and Physical examination 
 
X 
 
 
 X6 
Assessment of Renal Function2 
X 
 
 
 
 
CA-1253 
X 
X 
 
X 
 X6 
T0 Perfusion CT 
 
X 
 
 
 
Initiation of Bevacizumab Therapy + Paclitaxel 
 
 
X 
 
 
T1 Perfusion CT4 
 
 
 
X 
 
Assess renal function per site standard of care 
 
 
 
X 
 
Adverse Event Collection/Reporting5 
 
X 
 
X 
 
Report of therapy, progression/death7 
 
 
 
 
X 
1. Follow-up imaging can just be CT of Abdomen and Pelvis, chest only needs imaging if patient had evidence of measurable disease on baseline 
chest imaging. Patients will be imaged every 9 weeks (+/- 7 days) the first year and thereafter every 12 weeks (+/- 7 days). Follow-up will occur 
every 3 months if patient is < 2 years from study entry, and every 6 months thereafter. Study follow-up will continue until 18 months after the last 
accrued patient. Report interval therapy since last point of follow-up. 
2. Assess Creatinine and eGFR calculation within 28 days of Step 0; must be > 60 mL/min/1.73 m2. 
3. CA-125 to be submitted, if collected, within 28 days prior to Step 0 Registration; CA-125 to be collected (+/-) 2 days of T0 and T1 perfusion CT. 
4. T1 Perfusion CT should be performed after the first dose of bevacizumab but before the second dose of bevacizumab. 
5. Adverse event collection will be performed by phone 24 hours following acquisition of perfusion CT. 
6. Medical history, physical examination and CA-125 should be completed every 9 weeks (+/- 7 days) until death or until study follow-up completed 
(18 months after the last patient accrued). 
7. Report date of progression/death; report basis of assessing progression (CA125, imaging results, physical exam, etc); report interval therapy 
since last point of follow up. 
8. For tests/exams happening more than one time during a follow-up period, sites should report the last reported test/exam that occurred on the 
follow-up form. Follow-up form to be completed quarterly for the first two years and every six months thereafter. 
 
Rev. Add1 
Rev. Add1 
Rev. Add1 
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7.3 
Continuing Quality Assurance of Perfusion CT Scans  
Sites performing perfusion CT scans are required to submit images to the ACR 
Core Lab via TRIAD within 48 hours of acquisition of the T0 and T1 perfusion CT 
scans. Submissions to the ACR Imaging Core Lab must include a completed 
Image Transmittal Worksheet (ITW) and site-completed report of the dose length 
product (DLP) from each perfusion CT exam. These forms will include an ACR 
identification number and technical information for the perfusion CT scans.  
7.3.1 
Scanning Protocol 
The perfusion CT scan protocols from each site will be reviewed by 
the trial radiologist prior to scanning of the first patient to ensure that 
perfusion CT protocol of each site is congruent with the study 
protocol. Subsequently, timing of the scans (T0 and T1), kVp, mA, 
slice thickness and time interval used for the perfusion CT scans as 
noted in the DICOM header will be checked against the protocol (see 
Imaging Manual).  Discrepancies will be noted and communicated to 
the site within one week to ensure that concerns will be corrected in 
the next scan.  
7.3.2 
Radiation Dose 
From the information recorded in the ITW (T0 and T1 forms), the 
effective dose and skin dose of perfusion CT scans will be calculated 
and compared with those listed in Imaging Manual. If discrepancies 
larger than 30% from pre-specified dose limits are present, 
investigation as to the cause of the discrepancies will be initiated by 
the medical physicist immediately. These calculations will occur within 
14 days of the perfusion CT image submission. 
7.3.3 
Image Noise 
If the standard deviation of CT numbers inside a region in the 
paraspinal muscle recorded on the ITW and the technical assessment 
forms (T0, and T1 forms) is outside of the range of 17-48, 
investigation will be initiated by the medical physicist. 
7.3.4 
Image Quality 
The Imaging Co-PI will train the ACR Imaging Core Lab staff in the 
technical evaluation of the perfusion CT data. The initial technical 
analysis will be performed under the ACR Core lab and trial team 
radiologist supervision.  
All perfusion CT exams will be analyzed within 14 days of image 
submission for correct scanning procedure, selection of target lesion 
and adherence to radiation dose limits by a Core Lab technologist 
under the supervision of the ACR Medical Physicist and Radiologist. 
All problems and difficulties associated with the analysis of perfusion 
CT will be identified and resolved. 

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7.4 
Central Reader Study 
7.4.1 
Primary Aim 
For the primary aim, all perfusion CT analyses will be performed 
centrally by a single experienced reader (referred to as the primary 
reader), blinded to both the time point of the scan (T0 or T1) and 
patient data.  T0 and T1 scans will be read as a pair together and BF 
change will be available to sites within 14 days of when BOTH scans 
have been submitted to the Core Lab 
Perfusion maps will be created using a single post-processing 
platform, Body Tumor CT Perfusion Software version 4D (GE 
Healthcare, also used in ACRIN 6695). The region of interest on the 
target lesion will be drawn by the primary reader according to a pre-
defined protocol. From this, BF and BV values will be calculated.  
Direction of change in these values from T0 and T1 will be noted.  
7.4.2 
Secondary and Exploratory Aims 
For secondary aim 2.2.5, evaluating whether the association between 
change in perfusion CT parameters and patient outcome is stable 
when analyzed with different commercially-available software, image 
analysis will be performed by the primary reader in batch at or before 
the completion of cohort follow-up, where a second set of perfusion 
maps will be created using a different post-processing platform by a 
non-GE vendor, MIStar CT Perfusion Body Tumor Module (Apollo 
Medical Imaging Technology). Again, reads will be performed blinded 
to both the time point of the scan (T0 or T1) and patient data. The 
region of interest on the target lesion will be drawn according to a pre-
defined protocol. From this, BF and BV values will be calculated. 
Direction of change in these values from T0 and T1 will be noted. 
For exploratory aim 2.3.2, evaluating the reliability of perfusion CT 
parameters using different readers and different post-processing 
software, analysis will be performed by a second, independent reader 
in batch at or before the completion of cohort follow-up, where regions 
of interest will be drawn on the same target lesion according to the 
same pre-defined protocol as performed by the primary reader. This 
will be carried out on the two sets of perfusion maps from the two 
different vendors (GE Healthcare and MIStar). From this, BF and BV 
values will be calculated.  Direction of change in these values from T0 
and T1 will be noted. 
For exploratory aim 2.3.1, evaluating the impact of multiple target 
lesions on the association between change in perfusion CT 
parameters and PFS, analysis will be performed by the primary reader 
in batch at or before the completion of cohort follow-up. Analysis will 
be performed only on the subset of the cohort that demonstrate >1 
eligible target lesion within the perfusion CT image volume. Regions 
of interest will be drawn according to a pre-defined protocol on all 
eligible target lesions. From this, BF and BV values will be calculated 
for all target lesions. Direction of change in these values from T0 and 
T1 will be noted. 

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For exploratory aim 2.3.3, the analysis of vascular tumor burden 
(VTB) will be performed centrally by a single experienced reader 
blinded to clinical outcomes data. VTB analysis will be performed at 
the Advanced Imaging Lab at the University of Alabama at 
Birmingham (UAB) using eMASS software, an advanced image 
processing software platform used to quantify global tumor perfusion 
as assessed by measuring VTB. Analysis will be selected per RECIST 
1.1 guidelines. Free-form regions of interest will be drawn around the 
periphery of the target lesions. The software automatically extracts the 
VTB from the ROIs and calculates the total VTB (sum of VTB from 
individual target lesions) and percent change in total VTB. This data 
and the DICOM header information are then exported into a database. 
The software also generates a summary image, and individual key 
images are automatically archived for quality control purposes. 
 

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8. 
Statistical Considerations 
8.1 
Endpoints 
8.1.1 
Primary aim (8.2.1): The endpoint for the primary aim is progression-
free survival (PFS).  PFS will be calculated as the time to progression 
or death from the T1 scan (day 15 +/- 2 days post bevacizumab 
initiation). Patients without documented progression or death will be 
censored as of the last follow-up date. 
8.1.2 
Secondary aim #1 (8.2.2.1): The endpoint for secondary aim #1 is 
progression-free survival (PFS).  PFS will be defined as per the 
primary aim. 
8.1.3 
Secondary aim #2 (8.2.2.2): The endpoint for secondary aim #2 is 
progression-free survival (PFS).  PFS will be defined as per the 
primary aim. 
8.1.4 
Secondary aim #3 (8.2.2.3): The endpoint for secondary aim #3 is 
objective response rate, based on standard anatomic response 
evaluation criteria (RECIST 1.1). 
8.1.5 
Secondary aim #4 (8.2.2.4): The endpoint for secondary aim #4 is 
progression-free survival (PFS).  PFS will be defined as per the 
primary aim. 
8.1.6 
Secondary aim #5 (8.2.2.5): The endpoint for secondary aim #5 is 
progression-free survival (PFS).  PFS will be defined as per the 
primary aim. 
8.1.7 
Exploratory aim #1 (8.2.3.1): The endpoint for exploratory aim #1 is 
progression-free survival (PFS).  PFS will be defined as per the 
primary aim. 
8.1.8 
Exploratory aim #2 (8.2.3.2):  The endpoint for exploratory aim #2 is 
the reliability of CT perfusion measures, as assessed by the intraclass 
correlation coefficient (ICC). 
8.1.9 
Exploratory aim #3 (8.2.3.3):  The endpoint for exploratory aim #3 is 
progress-free survival (PFS).  PFS will be defined as per the primary 
aim. 
8.2 
Aims 
8.2.1 
Primary Aim 
To evaluate whether those patients with an increase in perfusion CT 
tumor blood flow (BF) from T0 to T1 demonstrate poorer progression-
free survival (PFS) compared to those patients with a decrease in BF 
from T0 to T1, among platinum-resistant, recurrent ovarian cancer 
patients treated with bevacizumab in combination with paclitaxel. 
The PFS of patients with increased (≥ 0) tumor BF from T0 to T1 will 
be compared with that of patients with decreased (< 0) tumor BF from 
T0 to T1. Kaplan-Meier survival curves will be generated, and a one-
sided log-rank test will be used to compare PFS between the two 
groups.    

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The primary aim will be analyzed from the central readings performed 
by the primary reader using the GE Healthcare Body Tumor CT 
perfusion platform (refer to Section 7.4). 
8.2.2 
Secondary Aims 
1. To evaluate whether change in perfusion CT tumor BF from T0 to 
T1, as a continuous variable, is associated with PFS. 
To examine the association between continuous change in tumor 
BF (T0 to T1) and PFS, Cox proportional hazards regression will 
be used. Both a univariable and a multivariable model will fit, with 
the multivariable model adjusting for potential confounders, 
including patient age and baseline cancer stage/histology.  Hazard 
ratios and associated 95% CIs will be reported. 
Finally, if the primary endpoint is not successful in declaring a 
statistically significant difference in PFS between those patients 
with increase (≥ 0) versus decrease (< 0) in tumor BF (T0 to T1), 
then an optimal threshold for change in tumor BF will be identified 
using recursive partitioning in a conditional inference framework 
(25).  A 95% confidence interval will be derived using the 
bootstrap technique. 
Secondary aim #1 will be analyzed from the central readings 
performed by the primary reader using the GE Healthcare Body 
Tumor CT perfusion platform (refer to Section 7.4).  
2. To evaluate whether changes in perfusion CT tumor blood volume 
(BV) or permeability surface product area (PS) from T0 to T1 are 
associated with PFS. 
The PFS of patients with increased (≥ 0) tumor BV from T0 to T1 
will be compared with that of patients with decreased (< 0) tumor 
BV from T0 to T1. Kaplan-Meier survival curves will be generated 
and a one-sided log-rank test will be used to compare PFS 
between the two groups. In addition, Cox proportional hazard 
models will be fit, similar to secondary aim #1.  
The analysis for PS will be conducted in a similar manner.  
Secondary aim #2 will be analyzed from the central readings 
performed by the primary reader using the GE Healthcare Body 
Tumor CT perfusion platform (refer to Section 7.4). 
3. To evaluate whether changes in perfusion CT tumor BF, BV, or 
PS from T0 to T1 are associated with response rate according to 
the standard anatomic response evaluation criteria (RECIST 1.1). 
Fisher’s exact test, or chi-squared test as appropriate, will be used 
to test the association between change in BF, BV, or PS from T0 
to T1 and tumor response, where tumor response is defined using 
RECIST 1.1, and each CT perfusion parameter is dichotomized 
using a change threshold of increase (≥ 0) versus decrease (< 0). 
Secondary aim #3 will be analyzed from the central readings 
performed by the primary reader using the GE Healthcare Body 
Tumor CT perfusion platform (refer to Section 7.4). 

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4. To identify which combination of perfusion CT parameters, 
including tumor BF, BV, and PS, can serve to optimally distinguish 
patients in terms of PFS outcome. 
To identify which combination of perfusion CT parameters can 
serve to optimally distinguish patients in terms of PFS outcome, a 
multivariable Cox proportional hazards regression model will be 
developed, including change in each of tumor BF, BV, and PS (T0 
to T1) as potential predictors.  A penalized regression technique 
will be considered, such as elastic net or ridge regression with 
tuning parameter selected by 10-fold cross-validation, in order to 
prevent over-fitting and to improve prediction performance.   
The estimated performance of the resulting model will be 
assessed through the C-statistic, using nested cross-validation. 
[34])   
In addition to the above multivariable Cox regression model, 
potential binary cut-offs for the combination of parameters will be 
explored using recursive binary partitioning in a conditional 
inference framework to develop a tree-structured survival model 
(25).   
Secondary aim #4 will be analyzed from the central readings 
performed by the primary reader using the GE Healthcare Body 
Tumor CT perfusion platform (refer to Section 7.4). 
5. To evaluate whether the association between change in perfusion 
CT parameters and treatment outcome (PFS or tumor response) 
is stable when analyzed with various commercially-available post-
processing software. 
Two software platforms, Body Tumor CT Perfusion Software 
version 4D (GE Healthcare, also used in ACRIN 6695) and MIStar 
CT Perfusion Body Tumor Module (Apollo Medical Imaging 
Technology), will be evaluated using the identical set of cases and 
CT images, with the same perfusion CT parameters computed at 
T0 and T1.  For the PFS outcome, we will first determine if the 
primary endpoint comparison yields the same conclusion across 
the software platforms.  Next, we will fit Cox regression models 
and report hazard ratios across platform for each CT perfusion 
parameter, as outlined in secondary aims #1 and #2. 
For the response outcome, we will report the result of Fisher’s 
exact test, or chi-square test as appropriate, across the software 
platforms, as outlined in secondary aim #3. 
Secondary aim #5 will be analyzed from the central readings 
performed by the primary reader (refer to section 7.4), where the 
MIStar readings will be done at or before the completion of cohort 
follow-up. 
8.2.3 
Exploratory Aims 
1. In the subset of patients with multiple, eligible perfusion target 
lesions within the CT imaging volume, we will describe the 
variability of perfusion CT changes across different lesions within 
the same patient, and evaluate the impact of multiple target 

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lesions on the association between change in perfusion CT 
parameters and PFS. 
The number of subjects in the study cohort with multiple, eligible 
perfusion target lesions will be reported, as well as distributional 
summary statistics of the number of lesions per patient, lesion 
size, and change in perfusion CT parameters for those subjects 
with multiple perfusion target lesions.   
We will also explore reassessing the primary endpoint and 
secondary endpoints #1 and #2, where, for subjects with multiple, 
eligible perfusion target lesions, in place of the using change in CT 
perfusion parameters (T0 to T1) corresponding to the single, 
original target lesion, we will use a summary statistic (mean, 
median, max) across the multiple lesions within a patient. 
Secondary aim #4 will be analyzed from the central readings 
performed by the primary reader using the GE Healthcare Body 
Tumor CT perfusion platform (refer to Section 7.4). 
2. To evaluate the reliability of perfusion CT parameters by analyzing 
the same perfusion imaging dataset using different readers and 
different post-processing software. 
Refer to Section 7.4.  For all enrolled patients, we will estimate the 
reliability of CT perfusion parameters by having both the T0 and 
T1 scans read by a second, independent reader, in addition to the 
primary reader, across two different software platforms, Body 
Tumor CT Perfusion Software version 4D (GE Healthcare, also 
used in ACRIN 6695) and MIStar CT Perfusion Body Tumor 
Module (Apollo Medical Imaging Technology).  The reliability 
intraclass correlation coefficient (ICC) and corresponding 95% 
confidence interval will be derived from an appropriately 
constructed random effects ANOVA model (26). Separate 
estimates of reliability will be derived and reported for each 
software platform by time point.   
In addition, method comparison and quantification of agreement of 
the software platforms will be conducted using the Bland-Altman 
approach (26). This will be done both separately by reader, and 
(assuming good reliability) using the average across the two 
readers. 
3. To evaluate whether change in global vascular tumor burden from 
T0 to T1 is associated with PFS, and with changes in BF, BV, or 
PS. 
To examine the association between vascular tumor burden (VTB) 
and PFS, Cox proportional hazards regression will be used.  VTB 
will be acquired for all enrolled patients (refer to section 7.4).  Both 
a univariable and a multivariable model will be fit for continuous 
change in VTB (T0 to T1), with the multivariable model adjusting 
for potential confounders, including patient age and baseline 
cancer stage/histology.   
In addition to evaluating association with PFS on a continuous 
scale, we will seek to identify a threshold for decrease in VTB to 

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categorize responders versus non-responders.  In previous work 
for renal cell carcinoma, a threshold of a 30% decrease in VTB 
was used to define responders [30].  We will examine this same 
pre-specified threshold for platinum-resistant, recurrent ovarian 
cancer patients treated with bevacizumab in combination with 
paclitaxel using a one-sided log rank test.  Finally, as the optimal 
threshold for VTB for recurrent ovarian cancer patients may differ 
from that of renal cell carcinoma patients, an optimal threshold for 
change in VTB will be identified using recursive partitioning in a 
conditional inference framework (25).  A 95% confidence interval 
will be derived using the bootstrap technique. 
The spearman correlation coefficient between VTB and each 
perfusion CT parameter (BF, BV, and PS), along with 
corresponding 95% confidence interval, will also be reported. 
8.3 
Sample Size Considerations 
The rate of increase versus decrease in CT perfusion tumor blood flow (BF) in 
ACRIN 6695/GOG-0262 (baseline to T2, or day 8-10 post bevacizumab initiation) 
was 14% vs. 86%, and the PFS-6 rate in the trial was 96%, with increase in BF 
being associated with worse patient outcomes.  However, unlike ACRIN 
6695/GOG-0262, the population for the proposed study will be patients with 
recurrent disease. Given this population, we expect a lower PFS-6 rate and, 
correspondingly, a larger proportion of patients with increase in BF at time point 
T1 (day 15 +/- 2 days post bevacizumab initiation). We will examine the effect on 
sample size using breakdowns of 50%/50% up to 80%/20% for BF increase 
versus decrease. 
In addition, in ACRIN 6695/GOG-0262 a difference of 4.1 months in median PFS 
was observed among patients with increase in BF versus decrease in BF.  
Further, the AURELIA trial, studying a similar cohort of recurrent disease 
patients, demonstrated a median PFS of 10.4 months (95% CI 7.9 to 11.9 
months) in the bevacizumab + paclitaxel arm [2, 35]).  As the proposed trial will 
consist of bevacizumab plus paclitaxel for all patients, we would expect roughly 
similar PFS in our cohort overall, but with the expectation that the subgroup of 
patients exhibiting an increase in BF will exhibit a lower median PFS compared 
to those with a decrease in BF.  We will thus split the difference in median PFS 
around the median of 10 months demonstrated in AURELIA, and will examine 
the effect on sample size using a difference in median PFS among the two 
groups ranging from 4 to 4.5 months. 
We assume accrual over a 24-month period, with 18 months of patient follow up. 
However, we note that a 6-month ramp-up period will likely be needed for site 
qualification before steady state accrual is achieved.  Using a one-sided log-rank 
test with an alpha level of 0.1 and power of 80%, and allowing for an inflation 
factor of 15% to account for cases with non-analyzable scans and/or cases lost-
to-follow up, results in the following sample sizes shown in the table below.  
Calculations were performed using PASS15 [29,36]. 

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Percent of 
cohort with 
increase in 
tumor BF vs. 
decrease 
Median PFS 
for patients 
with increase 
in tumor BF 
Median PFS 
for patients 
with decrease 
in tumor BF 
Difference 
in median 
PFS 
Overall 
required 
number of 
events 
Overall 
required 
sample 
size 
Final 
sample size 
allowing for 
15% 
inflation 
50% / 50% 
7.75 mos 
12.25 mos 
4.5 mos 
88 
102 
118 
50% / 50% 
7.88 mos 
12.13 mos 
4.25 mos 
98 
114 
132 
50% / 50% 
8 mos 
12 mos 
4 mos 
111 
129 
149 
 
 
 
 
 
 
 
60% / 40% 
7.75 mos 
12.25 mos 
4.5 mos 
95 
108 
125 
60% / 40% 
7.88 mos 
12.13 mos 
4.25 mos 
107 
122 
141 
60% / 40% 
8 mos 
12 mos 
4 mos 
120 
137 
158 
 
 
 
 
 
 
 
70% / 30% 
7.75 mos 
12.25 mos 
4.5 mos 
112 
126 
145 
70% / 30% 
7.88 mos 
12.13 mos 
4.25 mos 
126 
142 
164 
70% / 30% 
8 mos 
12 mos 
4 mos 
141 
160 
184 
 
 
 
 
 
 
 
75% / 25% 
7.75 mos 
12.25 mos 
4.5 mos 
128 
143 
165 
75% / 25% 
7.88 mos 
12.13 mos 
4.25 mos 
142 
160 
184 
75% / 25% 
8 mos 
12 mos 
4 mos 
160 
180 
207 
 
 
 
 
 
 
 
80% / 20% 
7.63 mos 
12.38 mos 
4.75 mos 
137 
152 
175 
80% / 20% 
7.75 mos 
12.25 mos 
4.5 mos 
152 
169 
195 
80% / 20% 
7.88 mos 
12.13 mos 
4.25 mos 
169 
189 
218 
80% / 20% 
8 mos 
12 mos 
4 mos 
190 
213 
245 
A sample size of 184 subjects (160 analyzable) would provide 80% power at 
alpha=0.1 to detect a difference in PFS among patients with increase versus 
decrease in tumor blood flow (BF) by perfusion CT (T0 to T1), where up to 70% 
of patients exhibit an increase in tumor BF, and the difference in median PFS is 4 
months or greater.  If the percentage of patients exhibiting an increase in tumor 
BF is 75%, then the study will be powered to detect a difference in median PFS 
of 4.25 months or greater; if the percentage of patients exhibiting an increase in 
tumor BF is 80%, then the study will be powered to detect a difference in median 
PFS of 4.75 months or greater. Appropriately powered scenarios correspond to 
the shaded portion of the above table.   
Regarding exploratory aim #2 (refer to Section 8.2.3.2 above), assessing the 
reliability of CT perfusion parameters, all enrolled, analyzable patients will be 
read centrally by two independent readers, blinded to both clinical and patient 
outcome data (refer to Section 7.4). A total of 160 analyzable subjects, as 
derived for the primary aim, using a two-way random effects model to estimate 
the intraclass correlation coefficient (ICC), would yield a two-sided 95% 
confidence interval for the ICC with a width no larger than 0.26 when the 
estimated ICC is as low as 0.4.  If the ICC is 0.7 or above, then the width of the 
two-sided 95% confidence interval would be no larger than 0.16. Calculations 
were performed using PASS15 [29, 37]. 

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Patients who are eligible for the EAE161 trial have been diagnosed with ovarian, 
peritoneal or fallopian tube cancer, and have platinum resistant, recurrent 
disease. We estimate that approximately 60% of patients who are screened in 
Step 0 will successfully have a target lesion identified for CT perfusion, and thus 
be eligible for enrollment onto Step 1. Therefore, we expect the need to enroll 
and screen 300 patients in Step 0 of the study in order to accrue the required 184 
eligible patients in Step 1 of the study necessary for statistical analysis. 
8.4 
Gender and Ethnicity  
Based on previous data from ACRIN 6695/GOG-0262 the anticipated accrual in 
subgroups defined by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
11 
0 
11 
Not Hispanic or Latino 
173 
0 
173 
Ethnic Category: Total of all subjects 
184 
 
184 
 
Racial Category 
American Indian or Alaskan Native 
4 
0 
4 
Asian 
4 
0 
4 
Black or African American 
14 
0 
14 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
162 
0 
162 
Racial Category: Total of all subjects 
184 
0 
184 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
8.5 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group-meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
obtained from the ECOG-ACRIN Operations Office – Boston. 

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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 by FTP burst of data.  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, 
but expedited adverse events are still required to be submitted via 
CTEP-AERS. 

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9. 
Electronic Data Capture 
Data collection will be performed exclusively in Medidata Rave. 
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 by FTP burst of data.  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). 
10. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
11. 
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24. 
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Perfusion CT to Predict Progression-free Survival and Response Rate in Bevacizumab 
Treatment of Platinum-Resistant Persistent or Recurrent Epithelial Ovarian, Fallopian 
Tube, or Peritoneal Carcinoma 
 
Appendix I 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we hope to improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and ECOG-ACRIN, we thank you again and look forward to 
helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 

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Perfusion CT to Predict Progression-free Survival and Response Rate in Bevacizumab 
Treatment of Platinum-Resistant Persistent or Recurrent Epithelial Ovarian, Fallopian 
Tube, or Peritoneal Carcinoma 
 
Appendix II 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.