A Phase III Randomized Controlled Clinical Trial of Carboplatin and Paclitaxel (or Gemcitabine) Alone or in Combination With Bevacizumab (NSC #704865) Followed by Bevacizumab and Secondary Cytoreductive Surgery in Platinum-Sensitive, Recurrent Ovarian, Peritoneal Primary and Fallopian Tube Cancer. NCI-Supplied Agents: Bevacizumab (NSC #704865)
Phase: PHASE3
Conditions: Clear Cell Adenocarcinoma, Fallopian Tube Clear Cell Adenocarcinoma, Fallopian Tube Endometrioid Adenocarcinoma, Fallopian Tube Mucinous Adenocarcinoma, Fallopian Tube Serous Adenocarcinoma, Fallopian Tube Transitional Cell Carcinoma, Fallopian Tube Undifferentiated Carcinoma, Mucinous Adenocarcinoma, Ovarian Brenner Tumor, Ovarian Clear Cell Adenocarcinofibroma, Ovarian Clear Cell Adenocarcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian Seromucinous Carcinoma, Ovarian Serous Adenocarcinoma, Ovarian Transitional Cell Carcinoma, Ovarian Undifferentiated Carcinoma, Primary Peritoneal Clear Cell Adenocarcinoma, Primary Peritoneal Endometrioid Adenocarcinoma, Primary Peritoneal Serous Adenocarcinoma, Primary Peritoneal Transitional Cell Carcinoma, Primary Peritoneal Undifferentiated Carcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma, Undifferentiated Carcinoma
Sponsor: National Cancer Institute (NCI)

i 
SUMMARY OF CHANGES 
 
For Protocol Revision # 17 to: 
 
NCI Protocol #: GOG-0213 
 
Protocol Date: November 16, 2018 
 
This amendment is being submitted in response to an RA from Dr. Helen Chen 
(helen.chen@nih.gov). 
 
# 
Section 
Page(s) 
Change 
1 
Title Page 
1 
NCI version date has been updated. 
Includes revisions #1-17. 
Revised footer has been added. 
2 
3.15 
 
Language has been updated to reflect the use of CTCAE 4.0. 
3 
4.36 
33-38 
An updated and revised CAEPR for Bevacizumab has been inserted (Version 2.5, 
May 2, 2018), and includes the following changes: 
 
• The section below utilizes CTCAE 5.0 language unless otherwise noted. 
• The SPEER grades have been updated. 
• The footnotes have been reordered.  
 
• 
Increase in Risk Attribution: 
• 
Changed to Rare but Serious from Also Reported on Bevacizumab Trials But 
With Insufficient Evidence for Attribution: Pulmonary hypertension  
 
• 
Provided Further Clarification 
• 
Blood and lymphatic system disorders - Other (renal thrombotic 
microangiopathy) is now reported as Hemolytic uremic syndrome.  
• 
Acute coronary syndrome (CTCAE 4.0 language) is now reported as Chest 
pain - cardiac.  
• 
Renal and urinary disorders - Other (nephrotic syndrome) (CTCAE 4.0 
language) is now reported as Nephrotic syndrome. 
• 
Vascular disorders - Other (arterial thromboembolic event) (CTCAE 4.0 
language) is now reported as Arterial thromboembolism.  
• 
Blood and lymphatic system disorders - Other (idiopathic thrombocytopenia 
purpura) (CTCAE 4.0 language) is now reported as Thrombotic 
thrombocytopenic purpura.  
• 
Eye disorders - Other (floaters) is now reported as Floaters. 
• 
Eye disorders - Other (vitreous hemorrhage) is now reported as Vitreous 
hemorrhage.  

ii 
# 
Section 
Page(s) 
Change 
• 
Musculoskeletal and connective tissue disorder - Other (aseptic necrotic 
bone) (CTCAE 4.0 language) is now reported as Osteonecrosis.  
• 
Renal and urinary disorders - Other (dysuria) (CTCAE 4.0 language) is now 
reported as Dysuria.  
• 
Musculoskeletal and connective tissue disorder - Other (myasthenia gravis), 
previously under the MUSCULOSKELETAL AND CONNECTIVE 
TISSUE DISORDERS SOC (CTCAE 4.0 language), is now reported as 
Myasthenia gravis under the NERVOUS SYSTEM DISORDERS SOC.  
• 
Infusion related reaction, previously under the GENERAL DISORDERS 
AND ADMINISTRATION SITE CONDITIONS SOC (CTCAE 4.0 
language), is now reported under the INJURY, POISONING AND 
PROCEDURAL COMPLICATIONS SOC. 
 
4 
4.37 
 
Language has been updated to reflect the use of CTCAE 5.0. 
5 
6.0 
 
Throughout section 6, language has been updated to reflect the use of CTCAE 
4.0. 
6 
8.19 
 
Language has been updated to reflect the use of CTCAE 4.0. 
7 
10.12 
 
Expedited Reporting via CTEP-AERS has been changed to CTCAE 5.0. 
8 
10.13 
 
Language has been added to reflect the use of CTCAE 5.0 for Expedited 
Reporting. 
9 
10.141 
 
Language has been added to reflect the use of CTCAE 5.0 for Expedited 
Reporting. 
10 
10.23 
 
Language has been added to reflect the use of CTCAE 5.0 for Expedited 
Reporting. 
11 
10.241 
 
Language has been added to reflect the use of CTCAE 5.0 for Expedited 
Reporting. 

iii 
# 
Section 
Page(s) 
Change 
12 
10.31 
 
Language has been added to reflect the use of CTCAE 5.0 for Expedited 
Reporting. 
13 
10.321 
 
Language has been modified to reflect the use of CTCAE 5.0. 
14 
11.0 
 
Throughout section 11, language has been updated to reflect the use of CTCAE 
4.0. 
15 
IC 
 
NCI Version Date has been updated. 
16 
IC 
 
An updated and revised condensed risk profile for Bevacizumab has been inserted 
(Version 2.5, May 2, 2018), and includes the following changes: 
• 
Provided Further Clarification:  
• 
Damage to the organs which may cause loss of teeth or loss of motion (under 
Occasional) is now reported as part of Damage to the jawbone which may 
cause loss of teeth (under Occasional) and Damage to organs (bone, lungs, 
others) which may cause loss of motion (under Rare). 

 
1 
 
PROTOCOL GOG-0213 
A PHASE III RANDOMIZED CONTROLLED CLINICAL TRIAL OF CARBOPLATIN AND PACLITAXEL (OR 
GEMCITABINE) ALONE OR IN COMBINATION WITH BEVACIZUMAB (NSC #704865,) FOLLOWED BY 
BEVACIZUMAB AND SECONDARY CYTOREDUCTIVE SURGERY IN PLATINUM-SENSITIVE, RECURRENT 
OVARIAN, PERITONEAL PRIMARY AND FALLOPIAN TUBE CANCER. NCI-SUPPLIED AGENTS: BEVACIZUMAB 
(NSC #704865) (12/19/2011) (10/01/12) NCT# 00565851 
NCI Version 11/16/2018 
Includes Revisions #1-17 
POINTS: 
PER CAPITA –14 
MEMBERSHIP –6 and 6 additional if surgical candidate is randomized   
TRANSLATIONAL RESEARCH PER CAPITA – Award based on specimen submission with 1 point for each FFPE tumor 
(primary, metastatic, recurrent), 1 point for frozen recurrent tumor, 0.5 point for frozen normal tissue, 0.5 point for FFPE normal 
tissue, 0.5 point for pre-op serum, 0.5 point for pre-op plasma, and 0.5 point for whole blood (MAX = 6.5 points). (03/09/15) 
TRANSLATIONAL RESEARCH MEMBERSHIP - Bonus membership point will be awarded for submission of 
satisfactory fixed primary tumor, frozen recurrent tumor, fixed recurrent tumor, frozen serum and frozen plasma.   
Lead Institution: NRG/NRG Oncology 
 
STUDY CHAIR 
STUDY CO-CHAIR 
 
STUDY CO-CHAIR 
ROBERT L. COLEMAN, MD 
NICOLA M. SPIRTOS, M.D. 
DEBORAH ARMSTRONG, M.D. 
UT MD ANDERSON CANCER CENTER 
See GOG Website Directory 
See GOG Website Directory 
DEPT OF GYN ONCOLOGY – Unit 1362 
 
 
P.O. BOX 301439 
 
 
HOUSTON, TX  77230-1439 
 
 
(713) 745-3357 
 
 
 
FAX: (713) 792-7586 
 
 
 
EMAIL: rcoleman@mdanderson.org 
 
 
 
 
STUDY CO-CHAIR 
QUALITY OF LIFE CHAIR 
QUALITY OF LIFE CO-CHAIR 
THOMAS J. HERZOG, M.D 
KAREN BASEN-ENGQUIST, PhD         JOHN K. CHAN, MD 
See GOG Website Directory  
See GOG Website Directory                      See GOG Website Directory 
STUDY CO-CHAIR 
STATISTICIAN 
PAUL SABBATINI, M.D.                                   MARK BRADY, Ph.D. 
See GOG Website Directory                               
See GOG Website Directory                         
PATHOLOGIST 
 
 
 
TRANSLATIONAL RESEARCH SCIENTIST  
RAHEELA ASHFAQ, M.D. 
Heather Lankes, PhD, MPH 
See GOG Website Directory 
See GOG Website Directory 
TRANSLATIONAL RESEARCH 
 
NURSE CONTACT 
CO-CHAIR 
 
 
 
Anne Heugel 
MICHAEL BIRRER, M.D., PhD 
 
(216) 844-8160 
See GOG Website Directory 
FAX:   (216) 844-8596 
 
 
 
 
 
EMAIL:  anne.heugel@uhhospitals.org 
 
OPEN TO PATIENT ENTRY DECEMBER 06, 2007; REVISED AUGUST 4, 2008; REVISED JUNE 22, 2009; 
REVISED MARCH 15, 2010; REVISED AUGUST 23, 2010; REVISED JANUARY 3, 2011 REVISED AUGUST 29, 2011; 
REVISED SEPTEMBER 26, 2011; REVISED DECEMBER 19, 2011, REVISED OCTOBER 1, 2012; REVISED AUGUST 19, 2013; 
REVISED SEPTEMBER 29, 2014; REVISED MARCH 9, 2015; REVISED JUNE 15, 2015; REVISED OCTOBER 13, 2015; REVISED 
OCTOBER 3, 2016; REVISED
This protocol was designed and developed by the Gynecologic Oncology Group (GOG). It is intended to be used only 
in conjunction with institution-specific IRB approval for study entry. No other use or reproduction is authorized by 
GOG nor does GOG assume any responsibility for unauthorized use of this protocol. 

 
 
2 
 
SCHEMA beginning 8/29/2011(08/29/11) (12/19/11) (10/01/12) 
 
 
 
 
 
 
The following schema was in effect between 12/6/2007 to 8/28/2011.  Once the accrual goal for 
evaluating the chemotherapy regimens was attained, that randomization was eliminated and only 
the surgical randomization remains (see the schema above) .(08/29/11)(12/19/11) 
 
SCHEMA (06/22/09) 
 
 
Patient chooses a systemic treatment with either: 
a) 
carboplatin + paclitaxel or  
b) 
carboplatin + paclitaxel + bevacizumab 
c) 
carboplatin + gemcitabine or 
d)
carboplatin + gemcitabine + bevacizumab
Begin systemic treatment with carboplatin + paclitaxel +/- bevacizumab 
or 
Begin systemic treatment with carboplatin + gemcitabine +/- bevacizumab 

 
 
3 
 
 
 
 
 
 
Post-surgical randomization treatment options now include either paclitaxel or gemcitabine in 
combination with carboplatin. Either chemotherapy doublet may be administered with 
bevacizumab at the discretion of the investigator. If chosen, bevacizumab maintenance is given 
until disease progression or unacceptable toxicity. (10/01/12) (03/09/15) 
 

 
 
4 
 
TABLE OF CONTENTS (08/04/08) (06/22/09) 
PAGE 
 
1.0 
OBJECTIVES 
7 
1.1 
Specific Hypotheses: (08/04/08) 
7 
1.2 
Primary Objectives: 
7 
1.3 
Secondary objectives: (08/04/08) 
7 
1.4 
Translational Research Hypotheses (08/04/08) 
8 
1.5 
Translational Research Objectives (08/04/08) 
8 
2.0 
BACKGROUND AND RATIONALE 
9 
2.1 
Rationale for Selected Approach and Trial Design 
9 
2.2 
Rationale for Surgery 
9 
2.3 
Rationale for Combination Chemotherapy (10/01/12) 
10 
2.4 
Rationale for Angiogenesis Targeted Therapy 
13 
2.5 
Rationale for Combination Cytotoxic and Biologic Therapy 
14 
2.6 
Gastrointestinal Perforation/Fistula 
15 
2.7 
Rationale for Clinical Trial Design  (10/01/12) 
16 
2.8 
Rationale for Evaluation of Hypersensitivity 
16 
2.9 
Rationale for Quality of Life Assessment 
17 
2.10 
Background and Rationale for Translational Research(08/04/08) 
18 
2.11 
Rationale for Banking DNA from Whole Blood for Research (06/22/09) 
20 
2.12 
Single Nucleotide Polymorphisms (SNPs) and SNP Profiling(06/22/09) 
20 
2.13 
Rationale for the inclusion of fallopian tube carcinoma (FTCA) 
20 
2.14 
Inclusion of Women and Minorities 
21 
3.0  
PATIENT ELIGIBILITY AND EXCLUSIONS 
22 
3.1 
Eligible Patients 
22 
3.2 
Ineligible Patients 
24 
4.0  
STUDY MODALITIES 
28 
4.1 
Carboplatin (Paraplatin®, NSC # 241240) 
28 
4.2 
Paclitaxel (Taxol, NSC #673089) 
29 
4.3 
Bevacizumab (NSC #704865,)(08/04/08) (12/19/11) 
31 

 
 
5 
 
4.4 
Docetaxel (Taxotere® RP-56976, NSC #628503) 
42 
4.5 Gemcitabine(10/01/12) 
43 
4.6 
Pathology Requirements (6/22/09) 
43 
5.0  
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 
44 
5.1 
Patient Entry and Registration (09/29/14) 
44 
5.2 
Treatment Plan (06/22/09) 
45 
5.3 
Secondary Cytoreduction: (06/22/09) 
51 
6.0 
TREATMENT MODIFICATIONS 
53 
6.1  
Dose Modifications: 
53 
7.0 
STUDY PARAMETERS 
63 
7.1 
Observations and Tests 
62 
7.2 
Stained Pathology Slide Requirements for Central Review… 
65 
7.3 
Translational Research 
65 
7.4 
Quality of Life: (08/04/08) 
68 
8.0  
EVALUATION CRITERIA 
70 
8.1  
Parameters of Response – GOG RECIST Criteria 
70 
9.0  
DURATION OF STUDY 
74 
9.1 
Patients will remain on the designated… 
74 
9.2 
All patients will be followed… 
74 
10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
74 
10.1 
ADVERSE EVENT REPORTING FOR A TRIAL… 
74 
10.2 
ADVERSE EVENT REPORTING FOR AN INVESTIGATIONAL AGENT… 
77 
10.3 
ADVERSE EVENT REPORTING FOR A COMMERICIAL AGENT … 
80 
10.4 
GOG DATA MANAGEMENT FORMS (08/04/08) (06/22/09) (03/15/10) 
83 
11.0 
STATISTICAL CONSIDERATIONS 
86 
11.1  Randomization(10/01/12) 
86 
11.2 
Measures of Efficacy and safety 
87 
11.3 
Treatment efficacy 
87 
11.4 
Quality of Life 
93 
11.5 
Translational Research Statistical Considerations 
95 
11.6 
The anticipated distribution … 
97 

 
 
6 
 
12.0  BIBLIOGRAPHY 
98 
APPENDIX I 
105 
APPENDIX II 
106 
APPENDIX III 
107 
APPENDIX IV 
115 
APPENDIX V 
117 
 
 
 
 
 
 
 
 

 
 
GOG-0213 
 
7 
 
1.0 
OBJECTIVES 
 
 
1.1 
Specific Hypotheses: (08/04/08) 
 
Two principle hypotheses will be directly addressed in this randomized, phase III 
clinical trial in recurrent platinum-sensitive ovarian, peritoneal primary or 
Fallopian tube cancer patients.  
 
1.11 
Surgical secondary cytoreduction prior to adjuvant chemotherapy 
increases the duration of overall survival in patients with recurrent 
platinum sensitive epithelial ovarian cancer, peritoneal primary or 
Fallopian tube cancer. 
1.12 
The addition of bevacizumab to second-line paclitaxel and carboplatin and 
maintenance phases of treatment increases the duration of overall survival 
relative to second-line chemotherapy alone in patients with recurrent 
platinum sensitive epithelial ovarian cancer, peritoneal primary, or 
Fallopian tube cancer. 
 
1.2 
Primary Objectives: 
1.21  To determine if surgical secondary cytoreduction in addition to adjuvant 
chemotherapy increases the duration of overall survival in patients with 
recurrent platinum sensitive epithelial ovarian cancer, peritoneal primary 
or Fallopian tube cancer. 
1.22 
To determine if the addition of bevacizumab to the second-line and 
maintenance phases of treatment increases the duration of overall survival 
relative to second-line paclitaxel and carboplatin alone in patients with 
recurrent platinum sensitive epithelial ovarian cancer, peritoneal primary 
or Fallopian tube cancer. 
 
1.3 
Secondary objectives: (08/04/08) 
 
1.31 
To determine if the addition of bevacizumab to the second-line and 
maintenance phase of treatment increases the duration of progression-free 
survival relative to second-line paclitaxel and carboplatin alone in patients 
with recurrent platinum sensitive epithelial ovarian cancer, peritoneal 
primary or Fallopian tube cancer. 
1.32 
To prospectively determine the incidence of carboplatin and paclitaxel 
hypersensitivity in these patients undergoing retreatment with both agents 
as first recurrence therapy. 
1.33 
To determine if surgical secondary cytoreduction in addition to adjuvant 
chemotherapy increases quality of life (QOL) in patients with recurrent 
platinum sensitive epithelial ovarian cancer, peritoneal primary or 
Fallopian tube cancer, as measured by the FACT-O trial outcome index 
and Rand SF-36 physical functioning scale. 
 
 
 

 
 
GOG-0213 
 
8 
 
1.34 
To determine if the addition of bevacizumab to the second-line and 
maintenance phases of treatment increases QOL relative to second-line 
paclitaxel and carboplatin alone in patients with recurrent platinum 
sensitive epithelial ovarian, peritoneal primary or Fallopian tube cancer. 
 
1.4 
Translational Research Hypotheses (08/04/08) 
 
The following translational research hypotheses will be tested in the tissue and 
serum specimens submitted from GOG-0213 patients undergoing secondary 
surgical cytoreduction. 
 
1.41  Molecular and biochemical profiles can be identified that are associated 
with time to first disease recurrence or death. 
 
1.42  Molecular determinants can be identified within patients with platinum-
sensitive recurrent ovarian, peritoneal primary or Fallopian tube 
carcinoma which predicts for sensitivity/resistance to combination 
chemotherapy with or without bevacizumab followed with or without 
maintenance bevacizumab therapy. 
 
1.5 
Translational Research Objectives (08/04/08) 
 
The following translational research objectives will be evaluated in the tissue and 
serum specimens submitted from GOG-0213 patients undergoing secondary 
surgical cytoreduction. 
 
Note: Testing of banked samples will not occur until an amendment to this 
treatment protocol (or separate correlative science protocol) is reviewed and 
approved in accordance with National Clinical Trials Network (NCTN) policies. 
 
1.51     To define molecular and biochemical profiles associated with the duration 
of progression-free survival in platinum-sensitive recurrent ovarian, 
peritoneal primary or Fallopian tube carcinoma treated with combination 
chemotherapy with or without bevacizumab followed with or without 
maintenance bevacizumab therapy in the presence or absence of secondary 
surgical cytoreduction. 
 
1.52      To identify molecular determinants that predict sensitivity or resistance to 
carboplatin and paclitaxel with or without bevacizumab followed with or 
without maintenance bevacizumab therapy. 
 
1.53 
To bank DNA from whole blood for research and evaluate the association 
between single nucleotide polymorphisms (SNPs) and measures of clinical 
outcome including overall survival, progression-free survival and adverse 
events.(06/22/09) 
 

 
 
GOG-0213 
 
9 
 
 
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1 
Rationale for Selected Approach and Trial Design 
 
Ovarian cancer remains the most lethal primary gynecologic malignancy in the 
United States.  This year over 16,000 women will die from their disease. The 
principle reason for this outcome is disease recurrence and the emergence of drug 
resistance.  Patients with recurrent disease frequently undergo multiple cycles of 
multiple drug regimens.  Those fortunate to achieve a response to chemotherapy 
are however, rarely cured and find that their remission cycles are short-lived.  
Even if a complete response is re-achieved it is usually of a shorter duration than 
the first disease-free interval.  Those not achieving a response to recurrence 
therapy live less than 2 years.  While effective therapy following disease 
recurrence is a major unmet need, few interventions have successfully altered the 
natural history of recurrence.  We propose to address two important interventions, 
surgery and combination chemotherapy with biologics, neither previously studied 
in a prospective randomized design, in order to determine their impact on 
survival. 
 
2.2 
Rationale for Surgery  
 
The capacity of cytoreductive surgery to improve survival for patients with 
advanced, newly diagnosed epithelial ovarian cancer is generally accepted.1  
However, the role of tumor-reductive surgery for patients with recurrent disease 
continues to evolve.2  Several series have demonstrated the importance of tumor 
reductive surgery prior to the initiation of second-line chemotherapy.1, 3, 4  
Preliminary results indicate a maximal survival benefit for patients rendered 
visibly disease-free prior to second-line therapy.1, 4, 5 The frequency of reported 
optimal operative outcomes has ranged from 37% to 83% in small series, using 
various criteria for “optimal cytoreduction”.6 The relative importance that 
differences in study cohorts, attitude, technical capability and experience have in 
accounting for variation of operative outcomes is unknown.  In a recent series, the 
largest yet published, approximately 80% of the patients had complete    
cytoreduction.5 Clinical criteria such as the median age, median disease-free 
interval, amount of prior chemotherapy, performance status, size of intra-
abdominal disease, and locations of disease suggests patients in that series to have 
disease at least as advanced as other reports.1, 3, 4, 7 That investigation 
prospectively demonstrated that secondary cytoreductive surgery, followed by 
salvage chemotherapy, allows survival that is significantly improved.  The 34.4 
month overall median survival from the time of secondary operation and the 35.9 
month overall median survival from the time of recurrence in the most recent 
series exceed what is typically reported in the salvage chemotherapy literature.  
Another noteworthy observation from this study was that the median survival 
after diagnosis of recurrence for patients who did not have salvage   

 
 
GOG-0213 
 
10 
 
chemotherapy before secondary operation (48.4 months) dramatically exceeded 
the overall median survival for those who were pretreated (24.9 months).  
Furthermore, an estimated 40% of the patients operated on before administration 
of salvage therapy survived more than five years after recurrence compared to 
only 15% in the pretreated group. Of note, patients whose disease responded to a 
recent repeat course of platinum containing agents, and patients treated with non-
platinum containing agents before secondary operation, both had poor survival, 
that did not remotely approach the overall group who had secondary 
cytoreductive operations prior to salvage chemotherapy.  Perhaps pretreatment 
with salvage chemotherapy induces drug resistance.  Regardless, limiting the role 
of surgery to palliation of symptoms for patients who failed multiple salvage 
regimens and the strategy of treating with salvage chemotherapy before an 
attempt at secondary cytoreductive surgery may greatly diminish the chances for 
subsequent survival.  Confirmation of this observation within the context of a 
multi-center randomized trial may dramatically improve the survival potential for 
women with recurrent epithelial ovarian cancer. 
 
2.3 
Rationale for Combination Chemotherapy (10/01/12) 
 
Most patients medically suitable to undergo therapy at the time of recurrence will 
be offered chemotherapy.  To date, a limited number of agents (i.e. etoposide, 
liposomal doxorubicin, topotecan, etc) have been formally approved for 
administration in this setting.  In addition, several other agents have been studied 
and are documented to have clinical activity.  Joining these novel agents are the 
taxanes and platinates commonly used as standard therapy in the front-line 
setting.  In light of this expansion of potentially active chemotherapeutics, 
physicians are administering more agents, longer to more patients.  Nonetheless, 
the degree to which this practice is benefiting patients in terms of survival is 
unclear.   
 
An additional challenge lies in how to determine when to recommend which 
agents or combinations to patients with recurrent disease.  A common determinant 
for many clinicians lies in reference to the patient’s time in remission following 
front-line therapy.  Those disease-free for more than six months are commonly 
considered to be potentially sensitive to retreatment with platinum.  Response 
characteristics with single agent platinum in this setting produce results similar to 
patients treated with novel agents.  Patients with longer disease-free interval are 
commonly treated with combination platinum and taxane therapy similar to the 
regimens received as primary therapy.  The degree to which this philosophy of 
care has affected survival is unknown but data from the limited number of 
randomized trials would suggest the following:  
• Non-platinum novel agents such as topotecan, gemcitabine, liposomal 
doxorubicin, and paclitaxel have similar response and survival characteristics 
as compared to platinum in randomized phase III trials.   

 
 
GOG-0213 
 
11 
 
•  No difference in response has been observed in these novel agents among 
platinum sensitive or resistant patients. However, treatment with liposomal 
doxorubicin demonstrated a survival benefit in comparison to topotecan in the 
absence of a response benefit among patients with platinum-sensitive disease.8 
The reasons for this are not clear but may relate to either intrinsic drug activity 
or to trial design (limited availability to liposomal doxorubicin in topotecan 
failures). 
• Platinum, and platinum combinations have favorable response characteristics 
in platinum-sensitive patients.9, 10  Platinum and taxane combination therapy 
appears to be at least as effective as single agent platinum and data from one 
large phase III trial would suggest clinical superiority.11 Although the 
randomized population in that trial was dissimilar to those commonly treated 
in the US, a second randomized phase II clinical trial in a more selective 
population essentially confirmed the observed benefit.12 Further, a randomized 
clinical trial of gemcitabine and carboplatin demonstrated superiority in 
progression-free survival over carboplatin alone in platinum-sensitive 
patients.13 Although a survival benefit was not demonstrated, the trial was 
underpowered to address this endpoint. 
• Recently, gemcitabine, carboplatin and bevacizumab was compared to 
gemcitabine and carboplatin demonstrating further enhancement in 
progression-free survival (12.4 mos vs 8.4 mos, HR 0.48, 95% CI:0.39-0.61), 
response rate (79% vs 57%, p<0.0001) and duration of response (10.4 mos vs 
7.4 mos, 95% CI: 0.41-0.70). Although immature at the time of reporting, 
there was no overall survival benefit with nearly 50% of events recorded.73 
 
From these observations, it would appear the greatest activity and potential for 
survival enhancement lies in combination, platinum-based chemotherapy 
among those deemed potentially platinum (and taxane) sensitive. As 
demonstrated above, a survival benefit is also suspected in this cohort for 
surgery. A randomized trial is needed to evaluate the addition of surgery to 
combination therapy to determine their impact on survival. 
 
2.31 
Docetaxel 
 
Taxanes are a class of anticancer agents that exert cytotoxic effects by 
their unique inhibition of microtubular assembly by stabilizing tubulin 
polymerbundles.14, 15 Both paclitaxel and docetaxel belong to the taxane 
family and have demonstrated activity in tumors that are refractory to 
conventional chemotherapy regimens. Paclitaxel is a diterpene plant 
product derived from the bark of the Western yew (Taxus brevifolia), 
while docetaxel is a semisynthetic derivative of 10-deacetylbaccatin III, a 
compound extracted from the needles of the European yew (Taxus 
baccata). While the relative efficacy of paclitaxel and docetaxel has not 
been compared clinically, docetaxel has increased activity in vitro, as well 
as clinical activity in paclitaxel resistant tumors. 

 
 
GOG-0213 
 
12 
 
 
 
 
 
In Vitro Activity. 
The cytotoxicity of docetaxel in comparison with paclitaxel was evaluated 
in several murine and human long-term cell culture lines. Docetaxel was 
found to be generally more cytotoxic (1.3-12-fold), a result that could be 
explained by its higher achievable intracellular concentration, its higher 
affinity for microtubules, and its slower cellular efflux.14-21Furthermore, 
docetaxel affects centromere organization resulting in abortive mitosis.22 
These cellular events may account for the greater cytotoxicity of docetaxel 
compared to that seen with paclitaxel. In terms of cross-resistance with 
other antitumor agents, there was cross-resistance to docetaxel in 
multidrug-resistant sublines such as  P388/DOX3, CEM/VLB 1000 and 
Chinese hamster ovary AUXB1 line.23 However, no cross-resistance to 
docetaxel was observed in CHO cells expressing a low level of 
vincristine-resistance but P-glycoprotein positive.23 This means that cross-
resistance to docetaxel was not definitively observed in sublines 
expressing the MDR phenotype.24These findings were in agreement with 
cell line studies showing that docetaxel was active in paclitaxel-resistant 
cells.16In addition, there was a lack of cross-resistance to cisplatin in 
certain cell lines.17,22 
 
 
 
 
Efficacy in Murine Tumor Models 
In a murine tumor model with B16 melanoma, docetaxel demonstrated 
clear  superiority to paclitaxel, having a 2.7 times greater log cell kill than 
paclitaxel.25 Docetaxel at a dose of 100 mg/m2 has demonstrated 
significant activity with response rates of 23-40% as second-line therapy 
in platinum  resistant ovarian carcinoma.26-28 More recently, its activity in 
paclitaxel-resistant tumors has been studied. The use of docetaxel at a dose 
of 100 mg/m2 every 21 days in paclitaxel-resistant breast cancer has 
demonstrated a 17.5% response rate in 41 evaluable patients.29 
Additionally, the use of docetaxel at this same dose in paclitaxel-resistant 
ovarian cancer has recently demonstrated a 37.5% response rate in 8 
evaluable patients.30 The in vitro, in vivo and clinical data make docetaxel 
an excellent agent to evaluate after primary platinum and  paclitaxel 
therapy. Hematologic toxicity is the dose-limiting toxicity, with 
neutropenic fever occurring in 8- 48% of patients.26-28Hematologic 
toxicity is considerably more severe with poorer hepatic function.31A 
comparative study of patients with or without liver dysfunction treated 
with docetaxel at a dose of 100 mg/m2 was recently reported. Patients with 
impaired liver function defined as an SGOT or SGPT > 1.5 x upper limit 
of normal or alkaline phosphatase > 2.5 x upper limit of normal, had a 
higher rate of neutropenic fever 23.8% vs 12.9% (p=0.06) and toxic death 
11.9% vs 1.7%, (p=0.001). For that reason strict criteria for hepatic 
function are required for this study. 
 
 
 
 
Efficacy in Humans 

 
 
GOG-0213 
 
13 
 
Several phase II and one randomized phase III trial have been conducted 
evaluating clinical efficacy of docetaxel in primary and recurrent ovarian 
cancer.  Rose et al., reporting on behalf of the GOG, demonstrated a 
22.4% overall response rate (5% CR and 17% PR) in 60 patients with 
platinum and taxane resistant recurrent disease (defined as progression on 
or within 6 months of completion of primary therapy).  Docetaxel for this 
trial was administered at 100  mg/m2.  Grade IV hematologic toxicity was 
observed in 75% of patients at this dose.32Similarly, Verschraegen et al., 
reported a 23% response rate and a median PFS of 3.5 months among 30 
assessable patients in a slightly less resistant population.  Grade IV 
granulocytopenia occurred in 72% of protocol patients and like the Rose 
trial was a reflection of higher docetaxel dosing (100 mg/m2).30  Markman, 
evaluated docetaxel (75 mg/m2) in 30 taxane-resistant ovarian cancer 
patients.  In this study, taxane-resistance was defined as progression on or 
within3 months of paclitaxel therapy.  Patients with longer intervals from 
paclitaxel were to be retreated with that agent – and progressed – prior to 
docetaxel.  In this trial, 3 patients (10%) had an objective response. 
Hematologic toxicity was reduced (30%, Grade IV), likely a reflection of 
reduced dosing.33 
 
Based on objective clinical activity in these resistant patient cohorts, a 
randomized clinical trial comparing taxane and platinum combination 
therapy in front line ovarian cancer treatment was conducted and recently 
reported.  Vasey and colleagues reported similar PFS (15.0 vs 14.8 
months, HR: 0.97 (0.83-1.13) and OS rate at 24 months (64.2% vs. 68.9%, 
HR: 1.13 (0.92-1.39) for the docetaxel/carboplatin combination compared 
with the industry standard paclitaxel/carboplatin.  In this 1077 patient trial 
toxicity was significantly different with more hematological toxicity seen 
in the docetaxel combination (Grade III/IV granulocytopenia 94% vs. 
84%, P < 0.001) but more severe and longer lasting sensory-motor 
neurotoxicity for paclitaxel/carboplatin (11% vs. 30, P < 0.001).34These 
trials establish clinical efficacy and safety for docetaxel and suggest 
possible non-cross resistance with paclitaxel. Given the lack of a clear 
dose response for this agent we propose to utilize 75 mg/m2 to initiate the 
trial. 
 
2.4 
Rationale for Angiogenesis Targeted Therapy 
 
Angiogenesis is one of the cardinal processes leading to invasion and metastasis 
of solid tumors. The angiogenic-signaling pathway may be triggered by the 
release of angiogenic promoters such as vascular endothelial growth factor 
(VEGF) from tumor cells and normal endothelial cells into the local 
microenvironment. There is accumulating evidence that angiogenesis plays a 
central role in ovarian cancer disease progression and prognosis.35-38A strong 
relationship exists between the expression of angiogenesis biomarkers and the 
behavior of epithelial ovarian cancer, suggesting pharmacological inhibitors of 

 
 
GOG-0213 
 
14 
 
angiogenesis could arrest tumor progression.39, 40Neutralizing anti-VEGF 
monoclonal antibodies have demonstrated therapeutic activity in a variety of pre-
clinical solid tumor models.41 Bevacizumab is a recombinant humanized version 
of a murine anti-human VEGF monoclonal antibody, named rhuMAb VEGF.  
Bevacizumab has been advanced into clinical development for use as  a single 
agent to induce tumor growth inhibition in patients with solid tumors and for use 
in combination with cytotoxic chemotherapy to delay the time to disease 
progression in patients with metastatic solid tumors.42 A recent phase II trial of 
single agent bevacizumab for patients with recurrent, platinum/taxane refractory 
epithelial ovarian and peritoneal primary cancer has been reported in the GOG 
(GOG-0170D). Sixty-two women were enrolled in the phase II trial, and objective 
responses were observed in 17.7%.43Response duration was 10.3 months. This 
was an extremely unusual observation for a compound presumed to be at best 
cytostatic when administered as a single agent.  Further exploration in 
combination with chemotherapy is warranted in ovarian cancer patients given the 
survival benefits observed for bevacizumab-combinations in other solid tumors 
such as breast, renal, lung and colon cancers.  
 
2.5 
Rationale for Combination Cytotoxic and Biologic Therapy  
 
Evidence from pre-clinical studies and recent phase II and III clinical trials in 
other solid tumors has demonstrated enhanced anti-tumor activity of 
traditional cytotoxic regimens, when combined with bevacizumab. For example, 
Devore and colleagues reported on a three-arm phase II randomized trial of 
carboplatin/paclitaxel with or without bevacizumab (7.5 mg/kg or 15 mg/kg dose 
levels) every 21 days until disease progression, in 99 patients with stages IIIB and 
IV non-small cell lung cancer. Response rates were 21.9 percent (7/32 patients) in 
the low dose and 42.9 percent (14/35 patients) in the high dose bevacizumab 
combination arms, compared to a response rate of 31.3 percent (10/32 patients) in 
the chemotherapy alone arm. A phase II/III trial in this patient population has 
been conducted by ECOG; the final analysis of this study is pending. 
 
More importantly, a recently reported phase III trial, AVF2107, of over 800 
previously untreated patients with metastatic colorectal cancer randomized to 
receive either bevacizumab for one year plus the Saltz chemotherapy regimen  
(5-FU/Leucovorin/CPT-11, IFL) or the Saltz regimen plus placebo for one year 
met its primary endpoint of improving overall survival. The magnitude of benefit 
observed far exceeded what the study was designed to demonstrate. The trial also 
met the secondary endpoints of progression-free survival, response rate, and 
duration of response (see following table).   
 
 
IFL/Bevacizumab 
(n = 403) 
IFL/Placebo 
(n = 412) 
Hazard Ratio 
(p-value) 
Response Rate 
44.9% 
34.7% 
(0.0029) 
Median TTP 
10.6 mos 
6.2 mos 
(0.00001) 
Median Survival 
20.3 mos 
15.6 mos 
0.65 

 
 
GOG-0213 
 
15 
 
(0.00003) 
 
Bleeding, thrombosis, asymptomatic proteinuria and hypertension were identified 
in phase II studies as possible safety events, but only Grade 3 hypertension and 
arterial thrombosis events were clearly increased in this phase III study.   
 
Preliminary results from a more recent, large, randomized phase III trial for 
patients with advanced colorectal cancer who had previously received treatment 
show that those who received bevacizumab in combination with an oxaliplatin 
regimen known as FOLFOX4 (oxaliplatin, 5-fluorouracil and leucovorin) had a 
significantly prolonged survival over patients who received FOLFOX4 
alone.  The Data Monitoring Committee overseeing the trial, known as E3200, 
recommended that the results of a recent interim analysis be made public because 
the study had met its primary endpoint of demonstrating improved overall 
survival, which was 17% longer in the bevacizumab arm. Specifically, the median 
overall survival in the bevacizumab plus FOLFOX4 arm was 12.5 months 
compared to 10.7 months for patients treated with FOLFOX4 alone.  There was a 
26 percent reduction in the risk of death (hazard ratio of 0.74) for patients in this 
study who received bevacizumab plus FOLFOX4 compared to those who 
received FOLFOX4 alone. Treatment toxicities observed in this study were 
consistent with those adverse effects observed in other clinical trials in which 
bevacizumab was combined with chemotherapy. These included hypertension and 
bleeding as more predominant in the bevacizumab arm. 
 
Multiple phase I-III trials, such as those cited above, have demonstrated the safety 
and tolerability of bevacizumab with traditional schedules and dosing of 
carboplatin and paclitaxel. 
 
2.6 
Gastrointestinal Perforation/Fistula 
 
 
GI perforations/fistulas were rare but occurred at an increased rate in 
bevacizumab-containing therapies. The majority of such events required surgical 
intervention and some were associated with a fatal outcome. In the pivotal phase 
III trial in CRC (AVF2107), the incidence of bowel perforation was 2% in 
patients receiving IFL/bevacizumab and 4% in patients receiving 5-
FU/bevacizumab compared to 0.3% in patients receiving IFL alone. In various 
phase II series of bevacizumab in recurrent ovarian cancer the rate of GI 
perforation has ranged from 0-14%.  No phase III randomized trials of 
bevacizumab alone or in combination with chemotherapy have been conduct 
heretofore.  Review of cases reported to CTEP in an open-label phase II ovarian 
cancer trial of bevacizumab did not specifically isolate risk factors for this 
complication; however, most patients were heavily pretreated and had abdominal 
tumor burden (CTEP IND Action Letter, October 4, 2005).  GI perforation has 
also been reported in patients with gastric/esophageal cancer, pancreatic cancer, 
or co-morbid GI conditions such as diverticulitis and gastric ulcer. GI 
perforation should be included in the differential diagnosis of patients on 

 
 
GOG-0213 
 
16 
 
bevacizumab therapy presenting with abdominal pain, fever of unclear 
source, or rectal/abdominal abscess. 
 
2.7 
Rationale for Clinical Trial Design  (10/01/12) 
 
Bevacizumab was selected for evaluation in combination with standard 
chemotherapy based on preliminary phase II single agent data obtained in patients 
with recurrent epithelial ovarian and peritoneal primary cancers and results from a 
phase III clinical trial in patients with metastatic colorectal cancer demonstrating 
a survival benefit to patients receiving bevacizumab with standard 
cytotoxic chemotherapy compared with patients receiving standard chemotherapy 
alone. Recently, evidence of enhanced progression-free survival was observed for 
combination bevacizumab with gemcitabine and carboplatin followed by 
bevacizumab maintenance to progression in women with platinum-sensitive 
recurrent ovarian cancer.73Based on the mechanism of action of bevacizumab, 
there may be benefit to extended therapy until disease progression, in extending 
PFS or OS in this patient population. Therefore, combination chemotherapy is 
compared against combination carboplatin/paclitaxel/bevacizumab or 
carboplatin/gemcitabine/bevacizumab with bevacizumab maintenance therapy. 
 
2.8 
Rationale for Evaluation of Hypersensitivity 
 
Expansion of the use of platinum and taxane compounds for the treatment of 
recurrent disease has ushered in an increasing awareness of problematic drug-
specific hypersensitivity reactions (HSRs).44-48The syndrome is manifested by 
flushing, dyspnea/bronchospasm, back pain, chest discomfort, pruritus, erythema, 
nausea, hypotension and occasionally bradycardia/tachycardia.  They are 
profound experiences for patients.  Although reported as early as the 1970’s for 
platinum and the 1980’s for paclitaxel, prophylaxis has been unable to completely 
eradicate these reactions often considered by investigators as severe enough to 
warrant agent discontinuation. Markman, reporting on 205 patients treated with 
carboplatin, documented 24 (12%) with HSR occurring after a median of 8 
courses.  He noted that without prophylaxis, only 1 of 3 patients retreated with the 
agent were able to undergo infusion.49Recently, however, several investigators 
have reported in small single institution studies the success of retreatment 
programs for those patients suffering hypersensitivity reactions to either or both 
carboplatin and paclitaxel.  These regimens, which include slower infusion, 
prolonged and repeated premedication prophylaxis and accelerated dosing over 
time, have been largely successful.  Brown and colleagues reported on 32 patients 
demonstrating hypersensitivity reactions while undergoing treatment for 
gynecological malignancies.  Twenty-three patients had recurrent ovarian or 
peritoneal cancer.  Reactions to platinum (cisplatin and carboplatin) and paclitaxel 
were observed.  Seventeen patients underwent a desensitization protocol and had 
re-treatment attempted. Seven out of 8 platinum HSRs and 8 out of 10 paclitaxel 
HSRs were successfully re-treated following desensitization. Lee and colleagues 
also reported successful reinfusion of paclitaxel, carboplatin or both in 57 patients 

 
 
GOG-0213 
 
17 
 
(255 courses) using a desensitization protocol.  Twelve percent of patients had 
breakthrough symptoms described as of lower severity than the index event – 
these were also successfully controlled and enabled subsequent retreatment.48 
 
The incidence of hypersensitivity is largely unknown particularly in this era of 
nearly universal paclitaxel and platinum re-treatment. Estimates range from 2-
16% for paclitaxel and 5-20% for cisplatin and carboplatin with the latter being 
reported with increasing frequency.  No prospective trials to date have evaluated 
this incidence in the recurrent setting.  Information will be useful in developing 
strategies to predict or modify re-treatment to avoid these dramatic complications 
of infusion.  
 
2.9 
Rationale for Quality of Life Assessment 
 
The quality of life (QOL) component of this trial has two foci: evaluating the 
effects of the cytoreductive surgery and assessing the impact of adding 
bevacizumab to second-line paclitaxel and carboplatin for second-line and 
maintenance therapy. 
 
The primary QOL question with regard to the surgery randomization is whether 
cytoreductive surgery is associated with improved quality of life due to its anti-
tumor effect.  The evaluation of this question is critical because, although 
cytoreductive surgery has the potential to increase survival and improve QOL 
through reducing tumor burden, potential surgical complications and recovery 
from surgery may adversely affect QOL.  Thus, secondary cytoreductive surgery 
may initially produce a decline in quality of life, while patients recover from 
surgery and complications, followed by an improvement in quality of life due to 
reduced tumor burden.  
 
With regard to the chemotherapy, the principle QOL question is whether the 
addition of bevacizumab to second-line carboplatin and paclitaxel, followed by 
maintenance therapy with bevacizumab is associated with better quality of life 
than carboplatin and paclitaxel combination therapy. The addition of maintenance 
treatment may present additional toxicities such as fatigue, rash, and diarrhea.50-
52These toxicities could affect a range of quality of life areas. 
 
Quality of life will be assessed using the Functional Assessment of Cancer 
Therapy-Ovarian (FACT-O) a 37-item questionnaire that measures physical, 
functional, social, and emotional well-being, along with a subscale that measures 
concerns specific to women with ovarian cancer.  The physical, functional, social, 
and emotional well-being subscales comprise the FACT-G (General), which is 
considered appropriate for use with patients with any form of cancer.  Version 4 
of the FACT-G is widely used and has undergone psychometric testing and 
demonstrates good reliability and validity consistent with previously published 
data on earlier versions. In a validation study of the FACT-O (FACT-G subscales 
plus ovarian-specific subscales), the total scale and subscales demonstrated very 

 
 
GOG-0213 
 
18 
 
good to excellent internal consistency reliability (0.74-0.92) and test-retest 
reliability (0.72-0.88).53 Validity of the FACT-O was demonstrated by correlation 
with other quality of life measures, and by its relationship to performance status, 
treatment status, and disease stage.  The FACT-O, particularly the physical well-
being, functional well-being, and ovarian subscales were sensitive to changes in 
performance status over a two-three month period. To assess the effects of 
bevacizumab-related side effects on QOL, questions from the FACIT 
measurement system have been added related to rash, concerns about appearance, 
diarrhea, fatigue, and appetite (labeled “Additional Concerns (TSE)”.    
 
 
In order to evaluate the effect of surgery on quality of life, patients will complete 
the Physical Functioning Subscale of the Rand 36-Item Short Form Health Survey 
(Rand SF-36).  The Physical Functioning (PF) Subscale is a 10-item subscale of 
the Rand SF-36a global quality of life questionnaire, designed to assess quality of 
life of patients across all medical conditions 54-56. 
 
 
The PF Subscale consists of items concerning activities of daily living: walking, 
climbing stairs, bathing, dressing, and performance of physical activities, with 
each item rated on a three-point scale of limitation of activity due to the patients' 
health, from "not limited" to "limited a lot." Internal consistency of the PF 
subscale is excellent, with an alpha co-efficient ranging from 0.89 to 0.92.56 The 
PF subscale has been found to significantly correlate with other physical 
functioning measures (Sickness Impact Profile [SIP], r=.67-.78; shortened 
Arthritis Impact Measurement Scale (sAIMS, r=.60). Further evidence of validity 
was provided by the PF subscale distinguishing between patients with serious and 
mild medical conditions.57Furthermore, the PF subscale has been found to be 
responsive to changes in functioning after surgical procedures (thoracic surgery 
for treatment of non-small-cell lung cancer, abdominal aortic aneurysm repair, 
and total hip arthroplasty 58), and sensitive to differences in quality of life between 
laparoscopic and open surgical procedures 59,60  and between epidural and patient-
controlled analgesia after colonic surgery.57 Norms have been developed for all 
subscales of the SF-36, by gender and age groups, based upon 2,474 respondents, 
as well as for patients with physical limitations.58, 59 
 
 
Eight questions will be included to measure specific quality of life problems after 
surgery (labeled “Additional Concerns (S)” in).  These questions will address 
issues such as pain, fatigue, problems with the surgical incision, and ostomy 
appliances.  Similar questions have been used in GOG-0152 (A Phase III 
Randomized Study of Cisplatin And Taxol® with Interval Secondary 
Cytoreduction versus Cisplatin and Paclitaxel in Patients with Suboptimal Stage 
III Epithelial Ovarian Carcinoma).  Several of the questions were taken from 
questionnaires in the FACIT quality of life measurement system.61 others were 
drafted to be similar in format to FACIT questions.   
 
2.10 
Background and Rationale for Translational Research(08/04/08) 
 

 
 
GOG-0213 
 
19 
 
The translational research component of this protocol will focus on the molecular 
and biochemical phenotype of recurrent ovarian cancer.  It is well known that the 
vast majority of patients with advanced ovarian cancer who respond to initial 
therapy will recur.  However, these recurrent tumors remain essentially a 
molecular enigma because of their general unavailability for analysis.  A brief 
review of the GOG Tissue Bank demonstrated that less than 5% of ovarian cancer 
specimens are from sources other than the primary tumor.  Further, only 22 
specimens of recurrent ovarian cancer with attached clinical data have been 
banked. 
 
This protocol provides an extraordinary opportunity to study these tumors, 
characterize them on a molecular basis, compare them to the original primary 
tumor, and determine the basis for disease recurrence and altered drug 
sensitivities. In the past five years, over 600 manuscripts on expression profiling 
of cancers using microarray technology have been published, illustrating the 
recognized utility of this approach in exploring questions of tumor biology and 
clinical correlates. The principles of class prediction and class discovery as they 
apply to the molecular classification of human cancers were exemplified by 
Golub et al., who used oligonucleotide microarrays to monitor gene expression in 
acute leukemias as a test case.62 Class prediction identified and validated a subset 
of informative genes whose expression was highly correlated with previously 
defined classes. Further, subsequent studies have utilized these approaches to  
provide proof of the "molecular profiling principle" as well as to gain novel 
insights into clinical cancer problems. Using a specialized, lymphoid cell-specific 
cDNA microarray, Alizadeh et al. performed expression profiling of diffuse large 
B-cell lymphomas and identified two molecularly distinct forms of this 
malignancy that correlated with overall survival.63 
 
Further, recent work on the problem of drug resistance has detailed multiple 
potential biochemical mechanisms, which may be critical for the development of 
drug resistance in ovarian cancer.  For instance the expression level of DNA 
repair enzymes and membrane transporters have been implicated in cisplatin 
resistance while microtubule mutations have been shown to affect paclitaxel 
sensitivity.64, 65 These in vitro determined mechanisms require testing and 
validation on in vivo derived tumor specimens. 
 
GOG-0213 patients with platinum-sensitive, recurrent epithelial ovarian, 
peritoneal primary or Fallopian tube carcinoma undergoing secondary 
cytoreduction will be able to provide archival formalin-fixed and paraffin-
embedded primary or metastatic tumor, a pre-op serum specimen, a pre-op plasma 
specimen, formalin-fixed recurrent tumor, frozen recurrent tumor, formalin-fixed 
normal tissue and/or frozen normal tissue to establish an enduring resource for 
defining the molecular and biochemical phenotype of recurrent ovarian cancer. 
The pre-op serum and plasma will be prepared from blood drawn prior to 
secondary cytoreductive surgery. The exact choice of the biomarkers and profiles 
to be evaluated and the assays to be performed in the tissue, serum and plasma 

 
 
GOG-0213 
 
20 
 
specimens submitted for the GOG-0213 patients undergoing secondary 
cytoreduction will be reevaluated based on evolving data in the field.   
 
2.11 
Rationale for Banking DNA from Whole Blood for Research (06/22/09) 
 
The National Cancer Institute is encouraging Cooperative Clinical Trial Groups 
including the Gynecologic Oncology Group to bank whole blood from women 
participating in clinical trials such that the blood specimens will be linked to 
clinical outcome data (progression-free survival, overall survival, response and 
adverse effects) and information regarding treatment.  The purpose of this effort is 
to support research including pharmacogenomic and pharmacogenetic research.   
 
Women who are candidates for this clinical trial or who have already been 
enrolled on GOG-0213 will be asked to give permission for 10 ml of their blood 
to be collected for this research study and for future research.  No matter what the 
women decide to do, it will not affect their care. The women can still participate 
in this GOG study even if they do not allow their blood to be collected and used 
for this research study and/or for future research. Women already enrolled on 
GOG-0213 will need to be re-consented for this collection. 
 
2.12 
Single Nucleotide Polymorphisms (SNPs) and SNP Profiling(06/22/09) 
 
It is well known that individual single nucleotide polymorphisms (SNPs) and SNP 
profiles are associated with many clinical aspects of cancer.  This includes risk of 
developing invasive cancer, risk of recurrence of cancer, patient survival and 
chemotherapy toxicity.  We propose to use genome wide SNP-association studies 
and individual SNP analyses to identify SNPs which correlate with a variety of 
clinical measures including but not limited to patient survival, recurrence of 
disease, response, and toxicity 
 
2.13 
Rationale for the inclusion of fallopian tube carcinoma (FTCA) 
 
Primary carcinoma of the fallopian tube is among the rarest malignancies of the 
female genital tract accounting for approximately 3.3/1,000,000 women annually.  
Despite its rarity, the disease shares many features of ovarian and primary 
peritoneal cancer including, risk factors (age and nulliparity), genomic alterations 
(LOH 3q and 8q, 1q, 5p, 7q, 12p and 20q), genetic abnormalities (Her 2-neu, P53, 
and k-ras mutations), natural history (local followed peritoneal metastases), 
response to chemotherapy, and anticipated survival by stage.66-68   The latter 
feature is modeled after primary ovarian cancer as well.  Most strikingly though is 
the relationship between BRCA mutation and the attendant increased risk of 
fallopian tube cancer over baseline.  A life-time risk increase of 120 fold over 
background has been reported for women who harbor BRCA mutation.  In fact, 
women diagnosed with FTCA may be at greater risk for harboring a BRCA 
mutation than women diagnosed with ovarian cancer.  As such, women 
undergoing risk-reducing bilateral salpingo-oophorectomy (RRBSO) are 

 
 
GOG-0213 
 
21 
 
recommended to have as much of the fallopian tube resected as possible and 
undergo step-sectioning as is performed for the ovary.   
 
Since there appears to be a common set of environmental and genetic risk factors 
for FTCA and ovarian cancer, it is not surprising that the clinical approach for 
these two neoplasms is similar including primary surgical resection and debulking 
or staging, adjuvant platinum- and taxane-based chemotherapy and surveillance 
protocols (including CA-125). Based on these features and the lack of consensus 
as to the precise diagnostic criteria separating primary entities of the ovary, 
fallopian tube and peritoneum it is appropriate to consider FTCA within this 
spectrum of disease. 
 
2.14 
Inclusion of Women and Minorities 
 
The Gynecologic Oncology Group and GOG participating institutions will not 
exclude potential subjects from participating in this or any study solely on the 
basis of ethnic origin or socioeconomic status.  Every attempt will be made to 
enter all eligible patients into this protocol and therefore address the study 
objectives in a patient population representative of the entire ovarian, fallopian 
tube and peritoneal primary cancer population treated by participating institutions. 
 
 

 
 
GOG-0213 
 
22 
 
 
3.0  
PATIENT ELIGIBILITY AND EXCLUSIONS 
 
3.1 
Eligible Patients 
 
3.10 
Patients enrolled after August 28, 2011 must be candidates for 
cytoreductive surgery and consent to have their surgical treatment 
determined by randomization.(08/29/11)(12/19/11) 
 
3.11 
Patients must have histologic diagnosis of epithelial ovarian carcinoma, 
peritoneal primary or Fallopian tube carcinoma, which is now recurrent.  
 
3.12 
Patients with the following histologic epithelial cell types are eligible: 
Serous adenocarcinoma, endometrioid adenocarcinoma, mucinous 
adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, 
mixed epithelial carcinoma, transitional cell carcinoma, malignant 
Brenner's Tumor, or adenocarcinoma not otherwise specified (N.O.S.). 
 
3.13 
Patients must have had a complete response to front-line platinum-taxane 
therapy (at least three cycles).(08/04/08)  
 
3.131 A complete response to front-line chemotherapy must include: 
negative physical exam, negative pelvic exam and normalization of 
CA125, if elevated at baseline. Although not required, any 
radiographic assessment of disease status (e.g. CT, MRI, PET/CT, 
etc) obtained following the completion of primary therapy (defined 
in 3.133) should be considered   negative for disease.  
 
3.132 All patients must have also had a treatment-free interval without 
clinical evidence of progressive disease of at least 6 months from 
completion of front-line chemotherapy (both platinum and taxane). 
Front-line therapy may have included a biologic agent (i.e. 
bevacizumab). 
 
3.133    Front-line treatment may include maintenance therapy following 
complete clinical or pathological response. However, maintenance 
cytotoxic chemotherapy must be discontinued for a minimum of 6 
months prior to documentation of recurrent disease.  Patients 
receiving maintenance biological therapy or hormonal therapy 
are ELIGIBLE provided their recurrence is documented more 
than 6 months from primary cytotoxic chemotherapy completion 
(includes maintenance chemotherapy) AND a minimum 4 weeks 
has elapsed since their last infusion of biological 
therapy.(06/22/09) 
 

 
 
GOG-0213 
 
23 
 
3.14 
Patients must have clinically evident recurrent disease for the purpose of 
this study,(08/29/11) 
 
3.142Measurable disease(RECIST) is defined as at least one lesion that 
can be accurately measured in at least one dimension (longest 
dimension to be recorded). Each lesion must be more than or equal 
to 20 mm when measured by conventional techniques, MRI or CT, 
or more than or equal to 10 mm when measured by spiral CT.  
 
 
 
3.15 
Patients must have adequate: 
 
3.151 Bone marrow function: Absolute neutrophil count (ANC) greater 
than or equal to 1,500/mm3, equivalent to Common Toxicity 
Criteria for Adverse Events v4.0 (CTCAE) Grade 1.  
 
3.152 Platelets greater than or equal to 100,000/mm3. (CTCAE Grade 0-
1). 
 
3.153 Renal function: Creatinine (non-IDMS) ≤ 1.5 x institutional upper 
limit normal (ULN), CTCAE Grade 1 (03/15/10) (08/23/10) 
 
3.154 Hepatic function:  
 
 
3.1541 Total bilirubin ≤ 1.5 ULN (CTCAE Grade 1). 
 
3.1542 SGOT/AST and Alkaline Phosphatase ≤ 2.5 times the 
upper limit of normal in the absence of liver metastasis.  
SGOT/AST and Alkaline Phosphatase <5.0 times ULN in the 
presence of liver metastasis. 
 
3.155 This criterion applies only to the patients enrolled before 
August 29, 2011 and those enrolled after this date electing to 
receive Bevacizumab. 
 
Patients must have a urine protein-to-creatinine ratio (UPCR) < 1.0 
mg/dL.  The UPCR has been found to correlate directly with the 
amount of protein excreted in a 24 hr urine collection.  
Specifically, a UPCR of 1.0 is equivalent to 1.0 gram of protein in 
a 24-hour urine collection.  Obtain at least 4 ml of a random urine 
sample in a sterile container (does not have to be a 24 hour urine).  
Send the sample to the lab with a request for urine protein and 
creatinine levels [separate requests].  The lab will measure protein 
concentration (mg/dL) and creatinine concentration (mg/dL).  The 
UPCR is derived as: protein concentration (mg/dL) / creatinine 
concentration (mg/dL).   
 

 
 
GOG-0213 
 
24 
 
3.16 
(This eligibility criterion does not apply to patients enrolled after August 
28, 2011).(08/29/11)(12/19/11)Patients who are not candidates for surgical 
cytoreduction are eligible for the chemotherapy randomization. Patients 
are not considered candidates for surgical cytoreduction if complete 
cytoreduction in the estimation of the investigator is impossible or a 
medical infirmity precludes exploration and debulking. 
 
3.17 
Patients must have met the pre-entry requirements specified in Section 7.0. 
 
3.18 
Patients must have signed an approved informed consent and authorization 
permitting release of personal health information. 
 
3.19 
Patients must have a GOG Performance Status of 0, 1, or 2. 
 
3.110 Patients must be at least 18 years old. 
 
3.2 
Ineligible Patients 
 
3.21  Patients who have received more than one previous regimen of 
chemotherapy (maintenance is not considered a second regimen). 
 
3.22 
Patients receiving concurrent immunotherapy, or radiotherapy. 
 
3.23 
Patients who have received prior radiotherapy to any portion of the 
abdominal cavity or pelvis are excluded. 
 
3.24 
Patients whom have already undergone secondary cytoreduction for 
recurrent disease are excluded.(08/29/11) 
 
3.25 
Patients with a prior histologic diagnosis of borderline, low malignant 
potential (grade 0) epithelial carcinoma that was surgically resected and 
who subsequently developed an unrelated, new invasive epithelial ovarian 
or peritoneal primary cancer are eligible provided that they meet the 
criteria listed in Section 3.12. 
 
3.26 
Patients who require parenteral hydration or nutrition and have evidence 
of partial bowel obstruction or perforation. 
 
3.27 
Patients who have received prior chemotherapy for any abdominal or 
pelvic tumor (other than ovarian, fallopian tube, and primary peritoneal) 
are excluded. (06/22/09) (03/15/10) 
 
3.28 
Patients with synchronous primary endometrial cancer, or a past history of 
primary endometrial cancer, are excluded, unless all of the following 
conditions are met: Stage not greater than I-B; no more than superficial 
myometrial invasion, without vascular or lymphatic invasion; no poorly 

 
 
GOG-0213 
 
25 
 
differentiated subtypes, including papillary serous, clear cell or other 
FIGO Grade 3 lesions. 
 
3.29 
Patients with uncontrolled infection. 
 
3.30 
Patients with concurrent severe medical problems unrelated to the 
malignancy that would significantly limit full compliance with the study 
or expose the patient to extreme risk or decreased life expectancy. 
 
3.31 
Patients with ≥ grade 2 peripheral neuropathy 
 
3.32 
Patients with a history of allergic reactions to carboplatin and/or paclitaxel 
or chemically similar compounds. Patients with allergic (hypersensitivity) 
reactions to these chemotherapeutic agents are NOT excluded IF they 
were successfully retreated following a desensitization program or 
protocol. 
 
3.33 
This criterion applies only to the patients enrolled before August 29, 
2011 and those enrolled after this date electing to receive 
Bevacizumab.(10/01/12) 
 
Patients with known hypersensitivity to Chinese hamster ovary cell 
products or other recombinant human or humanized antibodies. 
 
3.34 
Patients of childbearing potential, not practicing adequate contraception, 
patients who are pregnant or patients who are nursing are not eligible for 
this trial.  To date, no fetal studies in animal or humans have been 
performed.  The possibility of harm to a fetus is likely.  Bevacizumab 
specifically inhibits VEGF, which is responsible for the formation of new 
blood vessels during development, and antibodies can cross the placenta. 
Therefore, bevacizumab should not be administered to pregnant women. 
In addition, there are unknown immediate and long-term consequences of 
chemotherapy administration to these women.  In addition, surgical 
exploration as mandated by randomization during pregnancy may cause 
imminent mortal consequences. Further, it is not known whether 
bevacizumab is excreted in human milk. Because many drugs are excreted 
in human milk, bevacizumab should not be administered to nursing 
women.  Subjects will be apprised of the large potential risk to a 
developing fetus. 
 
3.35 
Patients with other invasive malignancies, with the exception of non-
melanoma skin cancer, who had (or have) any evidence of the other cancer 
present within the last 5 years or whose previous cancer treatment 
contraindicates this protocol  therapy. 
 

 
 
GOG-0213 
 
26 
 
3.36 
This criterion applies only to the patients enrolled before August 29, 
2011 and those enrolled after this date electing to receive 
Bevacizumab.(10/01/12) 
 
Patients with active bleeding or pathologic conditions that carry high risk 
of bleeding such as a known bleeding disorder, coagulopathy, or tumor 
involving major vessels. 
 
3.37 
This criterion applies only to the patients enrolled before August 29, 
2011 and those enrolled after this date electing to receive 
Bevacizumab.(10/01/12) 
 
 
Patients with a history or evidence upon physical examination of CNS 
disease, including primary brain tumor, seizures not controlled with 
standard medical therapy, any brain metastases or a history of stroke 
within 5 years of the first date of treatment on this study. 
 
3.38 
This criterion applies only to the patients enrolled before August 29, 
2011 and those enrolled after this date electing to receive 
Bevacizumab. (10/01/12) 
 
Patients with clinically significant cardiovascular disease. This includes:  
 
3.381 Patients with significant cardiac conduction abnormalities, i.e. PR 
 
interval > 0.24 sec or 2nd or 3rd degree AV block. 
 
3.382 Uncontrolled hypertension, defined as systolic > 150 mm Hg or 
diastolic > 90 mm Hg. 
 
3.383 Myocardial infarction, cardiac arrhythmia or unstable angina < 6 
months prior to registration. 
 
3.384 New York Heart Association (NYHA) Grade II or greater 
congestive heart failure. 
 
3.385 Serious cardiac arrhythmia requiring medication. 
 
3.386 Grade II or greater peripheral vascular disease (exception: episodes 
of ischemia < 24 hrs in duration, that are managed non-surgically 
and without permanent deficit).(03/15/10) 
 
3.387 History of CVA within six months. 
 
3.39 
This criterion applies only to the patients enrolled before August 29, 
2011 and those enrolled after this date electing to receive 
Bevacizumab.(10/01/12) 
 

 
 
GOG-0213 
 
27 
 
Patients who have had a major surgical procedure, open biopsy, dental 
extractions or other dental surgery/procedure that results in an open 
wound, or significant traumatic injury within 28 days prior to the first date 
of treatment on this study, or anticipation of need for major surgical 
procedure during the course of the study; patients with placement of 
vascular access device or core biopsy within 7 days prior to the first date 
of treatment on this study. 
 
3.391 Patients undergoing pre-treatment secondary cytoreduction will 
undergo therapy with bevacizumab on cycle #2 (See Section 5.234). 
 
3.392 Patients undergoing pre-treatment surgery for purposes other than 
cytoreduction may also participate provided they meet eligibility in 
Section 3.1.  Patients randomized to arms containing bevacizumab 
must wait a minimum of 28 days since that procedure to begin 
protocol treatment. Patients who undergo an uncomplicated port 
placement must wait a minimum of 7 days to begin protocol 
treatment. (03/15/10) 
 

 
 
GOG-0213 
 
28 
 
4.0  
STUDY MODALITIES 
 
4.1 
Carboplatin (Paraplatin®, NSC # 241240)  
 
4.11   Formulation: Carboplatin is supplied as a sterile lyophilized powder 
available in single-dose vials containing 50 mg, 150 mg and 450 mg of 
carboplatin for administration by intravenous infusion. Each vial contains 
equal parts by weight of carboplatin and mannitol.  
 
 
4.12   Solution Preparation: Immediately before use, the content of each vial 
must be reconstituted with either sterile water for injection, USP, 5% 
dextrose in water, or 0.9% sodium chloride injection, USP, according to 
the following schedule:  
 
Vial Strength 
Diluent Volume 
50 mg 
5 ml 
150 mg 
15 ml 
450 mg 
45 ml 
 
These dilutions all produce a carboplatin concentration of 10 mg/ml.  
 
NOTE: Aluminum reacts with carboplatin causing precipitate formation 
and loss of potency. Therefore, needles or intravenous sets containing 
aluminum parts that may come in contact with the drug must not be used 
for the preparation or administration of carboplatin.  
 
 
4.13   Storage: Unopened vials of carboplatin are stable for the life indicated on 
the package when stored at controlled room temperature and protected 
from light. 
 
 
4.14   Stability:  When prepared as directed, carboplatin solutions are stable for 
eight hours at room temperature. Since no antibacterial preservative is 
contained in the formulation, it is recommended that carboplatin solutions 
be discarded eight hours after dilution.  
 
 
4.15   
Supplier: Commercially available from Bristol-Myers Squibb Company.  
 
4.16  
Administration: See Section 5.2.  
 
4.17   
Adverse effects:  
 
 
Hematologic: Myelosuppression 
 
 
Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain, constipation 
Neurologic: Peripheral neuropathy, ototoxicity, visual disturbances, 
change in taste, central nervous system symptoms 
Renal: Abnormal renal function test results including serum creatinine, 
blood urea nitrogen, and creatinine clearance 

 
 
GOG-0213 
 
29 
 
Hepatic: Abnormal liver function tests including bilirubin, SGOT, and 
alkaline phosphatase 
Electrolyte Changes: Abnormally decreased serum electrolyte values 
reported for sodium, potassium, calcium, and magnesium. 
Allergic Reactions: Rash, urticaria, erythema, pruritus, and rarely 
bronchospasm and hypotension. 
 
Injection Site Reactions: Redness, swelling, pain; necrosis associated with 
extravasation has been reported. 
Other: Pain, asthenia, alopecia. Cardiovascular, respiratory, genitourinary, 
and mucosal side effects have occurred in 6% or less of the patients. 
Cardiovascular events (cardiac failure, embolism, cerebrovascular 
accidents) were fatal in less than 1% of patients and did not appear to be 
related to chemotherapy. Cancer-associated hemolytic-uremic syndrome 
has been reported rarely. Malaise, anorexia, and hypertension have been 
reported as part of post-marketing surveillance.  
 
*See FDA-approved package insert for a comprehensive list of adverse 
events associated with carboplatin.  
 
4.2 
Paclitaxel (Taxol, NSC #673089)  
 
4.21  Formulation: Paclitaxel is a poorly soluble plant product from the western 
yew, Taxus brevifolia. Improved solubility requires a mixed solvent 
system with further dilutions of either 0.9% sodium chloride or 5% 
dextrose in water.  
 
Paclitaxel is supplied as a sterile solution concentrate, 6 mg/ml in 5 ml 
vials (30 mg/vial) in polyoxyethylated castor oil (Cremophor EL) 50% and 
dehydrated alcohol, USP, 50%. The contents of the vial must be diluted 
just prior to clinical use. It is also available in 100 and 300 mg vials. 
 
4.22   Solution Preparation: Paclitaxel, at the appropriate dose, will be diluted in 
500-1000 ml of 0.9% Sodium Chloride injection, USP or 5% Dextrose 
injection, USP (D5W) (500 ml is adequate if paclitaxel is a single agent). 
Paclitaxel must be prepared in glass or polyolefin containers due to 
leaching of diethylhexlphthalate (DEHP) plasticizer from polyvinyl 
chloride (PVC) bags and intravenous tubing by the Cremophor vehicle in 
which paclitaxel is solubilized.  
 
NOTE: Formation of a small number of fibers in solution (within 
acceptable limits established by the USP Particulate Matter Test for LVPs) 
has been observed after preparation of paclitaxel. Therefore, in-line 
filtration is necessary for administration of paclitaxel solutions. In-line 
filtration should be accomplished by incorporating a hydrophilic, 
microporous filter of pore size not greater than 0.22 microns (e.g.: IVEX-

 
 
GOG-0213 
 
30 
 
II, IVEX-HP or equivalent) into the IV fluid pathway distal to the infusion 
pump. Although particulate formation does not indicate loss of drug 
potency, solutions exhibiting excessive particulate matter formation 
should not be used.  
 
4.23   Storage: The intact vials can be stored in a temperature range between 2-
25° C (36-77°F).  
 
4.24   Stability: Commercially available paclitaxel will be labeled with an 
expiration date. All solutions of paclitaxel exhibit a slight haziness directly 
proportional to the concentration of drug and the time elapsed after 
preparation, although when prepared as described above, solutions of 
paclitaxel (0.3-1.2 mg/ml) are physically and chemically stable for 27 
hours. 
 
 
4.25  Supplier: Commercially available from Bristol-Myers Squibb Company.  
 
4.26   Administration:  Paclitaxel, at the appropriate dose and dilution, will be 
given as a 3-hour continuous IV infusion. Paclitaxel will be administered 
via an infusion control device (pump) using non-PVC tubing and 
connectors, such as the IV administration sets (polyethylene or polyolefin) 
that are used to infuse parenteral Nitroglycerin. Nothing else is to be 
infused through the line where paclitaxel is being administered. See 
section 5.2. 
 
4.27   Adverse Effects: Hematologic: Myelosuppression 
Gastrointestinal: Nausea and vomiting, diarrhea, stomatitis, mucositis, 
pharyngitis, typhlitis, ischemic colitis, neutropenic enterocolitis 
Heart: Arrhythmia, heart block, ventricular tachycardia, myocardial 
infarction (MI), bradycardia, atrial arrhythmia 
Pulmonary: Pneumonitis 
Blood Pressure: Hypotension, hypertension (possibly related to 
concomitant medication--Dexamethasone) 
Neurologic: Sensory (taste), peripheral neuropathy, seizures, mood 
swings, hepatic encephalopathy, encephalopathy 
Skin: Infiltration: erythema, induration, tenderness, rarely ulceration, 
injection-recall reactions, erythema multiforme (e.g., Stevens-Johnson 
syndrome, toxic epidermal necrolysis) 
Allergy: Anaphylactoid and urticarial reactions (acute), flushing, rash, 
pruritus 
Liver: Increased SGOT, SGPT, bilirubin, alkaline phosphatase and 
triglycerides, hepatic failure, hepatic necrosis 
Other:  Alopecia, fatigue, arthralgia, myalgia, light-headedness, myopathy, 
headaches 

 
 
GOG-0213 
 
31 
 
Other, Vision:  Sensation of flashing lights, blurred vision, scintillating 
scotomata 
*See FDA- approved package insert for a comprehensive list of adverse 
events associated with paclitaxel. 
 
4.3 
Bevacizumab (NSC #704865) (08/04/08) (12/19/11) 
 
All investigators who receive a copy of the protocol should also obtain a copy of 
the Investigator’s Brochure (IB).  IB’s are available from the Pharmaceutical 
Management Branch, CTEP, DCTD, NCI and may be obtained by emailing the 
IB Coordinator (ibcoordinator@mail.nih.gov) or by calling the IB Coordinator at 
301-496-5725. 
 
4.31 
Description:  Bevacizumab is a recombinant humanized anti-VEGF 
monoclonal antibody, consisting of 93% human and 7% murine amino 
acid sequences.  The agent is composed of human IgG framework and 
murine antigen-binding complementarity-determining regions.  
Bevacizumab blocks the binding of vascular endothelial growth factor 
(VEGF) to its receptors resulting in inhibition of angiogenesis. 
 
4.32 
How Supplied:  Bevacizumab is supplied as a clear to slightly opalescent, 
sterile liquid ready for parenteral administration in a 400 mg (25mg/ml – 
16 mL) fill glass vial containing bevacizumab with phosphate, trehalose, 
polysorbate 20, and Sterile Water for Injection, USP. Japanese institutions 
may use 400 mg or 100 mg vials of commercially available Avastin. 
 
4.33 
Storage and Stability:  Bevacizumab is shipped on blue ice for next day 
delivery.  On receipt, bevacizumab should be stored in the refrigerator (2o 
to 8oC) and should remain refrigerated until just prior to use.  Do not 
freeze.  Do not shake.  Shelf-life studies of bevacizumab are continuing.  
Investigators will be notified when lots have expired.  The sterile single 
use vials contain no antibacterial preservatives; therefore, vials should be 
discarded eight hours after initial entry. 
 
4.34 
Preparation:  Vials contain no preservative and are intended for single use 
only.  Place the calculated dose in 100 mL of 0.9% Sodium Chloride for 
injection. Once diluted in 0.9% Sodium Chloride for injection, the 
bevacizumab solution must be administered within 8 hours. 
 
4.35 
Administration:  Bevacizumab is administered intravenously as a 
continuous infusion.  The initial dose should be administered over a 
minimum of 90 minutes.  If no adverse reactions occur after the initial 
dose, the second dose should be administered over a minimum of 60 
minutes.  If no adverse reactions occur after the second dose, all 
subsequent doses should be administered over a minimum of 30 minutes.  

 
 
GOG-0213 
 
32 
 
If infusion-related adverse reactions occur, all subsequent infusions should 
be administered over the shortest period that was well tolerated. 
To insure complete delivery of bevacizumab, flush the IV infusion line 
with 0.9% sodium chloride. The following are two recommended methods 
for flushing the bevacizumab IV infusion line: 
1.  When the bevacizumab infusion is complete, add an additional 50mL 
of 0.9% sodium chloride for injection to the bevacizumab infusion bag. 
Continue the infusion until a volume equal to that of the volume contained 
in the tubing has been administered. 
2.  Replace the empty bevacizumab infusion bag with a 50mL bag of 0.9% 
sodium chloride for injection and infuse a volume equal to the volume 
contained in the tubing.  
Please note: the flush is not included in the total recommended infusion 
times. 
 
4.36 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Bevacizumab (NSC #704865) (08/23/10) (12/19/11) (09/29/14) (10/03/16) 
 
Revised Bevacizumab CAEPR – Version 2.5, May 2, 2018 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Bevacizumab (rhuMAb VEGF, NSC 704865) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for further clarification. 
Frequency is provided based on 3540 patients. Below is the CAEPR for Bevacizumab (rhuMAb VEGF). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
Version 2.5, May 2, 20181 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
Anemia (Gr 3) 
 
Febrile neutropenia 
Febrile neutropenia (Gr 3) 
 
Hemolytic uremic syndrome 
CARDIAC DISORDERS 
 
Cardiac disorders - Other 
(supraventricular arrhythmias)2  
Cardiac disorders - Other (supraventricular 
arrhythmias)2 (Gr 3) 

 
 
GOG-0213 
 
33 
 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Chest pain - cardiac3 
 
Heart failure 
 
Left ventricular systolic 
dysfunction 
 
Myocardial infarction3 
 
Ventricular arrhythmia 
 
Ventricular fibrillation 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
Abdominal pain (Gr 3)  
 
Colitis 
Colitis (Gr 3) 
 
Constipation 
Constipation (Gr 3) 
 
Diarrhea 
Diarrhea (Gr 3) 
 
Dyspepsia 
Dyspepsia (Gr 2) 
 
Gastrointestinal fistula4 
 
Gastrointestinal hemorrhage5 
Gastrointestinal hemorrhage5 (Gr 2) 
 
Gastrointestinal obstruction6 
 
Gastrointestinal perforation7 
 
Gastrointestinal ulcer8 
 
Ileus 
 
Mucositis oral 
Mucositis oral (Gr 3) 
 
Nausea 
Nausea (Gr 3) 
 
Vomiting 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Fatigue 
Fatigue (Gr 3) 
 
Non-cardiac chest pain 
Non-cardiac chest pain (Gr 3) 
 
Pain 
Pain (Gr 3) 
HEPATOBILIARY DISORDERS 
 
Gallbladder perforation 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction 
Allergic reaction (Gr 2) 
 
Anaphylaxis 
INFECTIONS AND INFESTATIONS 
 
Infection9 
Infection9 (Gr 3) 
 
Infections and infestations - 
Other (necrotizing fascitis) 
 
Infections and infestations - Other 
(peri-rectal abscess) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
Infusion related reaction 
Infusion related reaction (Gr 2) 
 
Injury, poisoning and procedural 
complications - Other 
(anastomotic leak)10 
 
Wound complication 
Wound complication (Gr 2) 
 
Wound dehiscence 
Wound dehiscence (Gr 2) 
INVESTIGATIONS 
 
Alanine aminotransferase increased 
Alanine aminotransferase increased (Gr 3) 
 
Alkaline phosphatase increased 
Alkaline phosphatase increased (Gr 3) 
 
Aspartate aminotransferase increased 
Aspartate aminotransferase increased (Gr 3) 

 
 
GOG-0213 
 
34 
 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Blood bilirubin increased 
Blood bilirubin increased  
(Gr 2) 
 
Creatinine increased 
Neutrophil count decreased 
Neutrophil count decreased (Gr 3) 
 
Platelet count decreased 
Platelet count decreased  
(Gr 4) 
 
Weight loss 
Weight loss (Gr 3) 
 
White blood cell decreased 
White blood cell decreased (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
Anorexia (Gr 3) 
 
Dehydration 
Dehydration (Gr 3) 
 
Hyperglycemia 
 
Hypokalemia 
 
Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
Arthralgia (Gr 3) 
 
Avascular necrosis11 
 
Generalized muscle weakness 
 
Musculoskeletal and connective 
tissue disorder - Other (bone 
metaphyseal dysplasia)12 
 
Myalgia 
Myalgia (Gr 3) 
 
Osteonecrosis of jaw13 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
Dizziness (Gr 2) 
 
Headache 
Headache (Gr 3) 
 
Intracranial hemorrhage 
 
Ischemia cerebrovascular 
 
Peripheral sensory neuropathy14 
 
Reversible posterior 
leukoencephalopathy syndrome 
 
Syncope 
RENAL AND URINARY DISORDERS 
 
Acute kidney injury 
 
Hematuria 
Hematuria (Gr 3) 
 
Nephrotic syndrome 
 
Proteinuria 
Proteinuria (Gr 2) 
 
Urinary fistula 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
Reproductive system and breast 
disorders - Other (ovarian 
failure)15 
 
Vaginal fistula 
 
Vaginal hemorrhage 
Vaginal hemorrhage (Gr 3) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Allergic rhinitis 
Allergic rhinitis (Gr 2) 
 
Bronchopleural fistula 
 
Bronchopulmonary hemorrhage 

 
 
GOG-0213 
 
35 
 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Cough 
Cough (Gr 3) 
 
Dyspnea 
Dyspnea (Gr 2) 
 
Epistaxis 
Epistaxis (Gr 3) 
 
Hoarseness 
Hoarseness (Gr 3) 
 
Pulmonary hypertension 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(nasal-septal perforation) 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(tracheo-esophageal fistula) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Dry skin 
 
Erythroderma 
 
Palmar-plantar 
erythrodysesthesia syndrome 
 
Pruritus 
Pruritus (Gr 2) 
 
Rash maculo-papular 
Rash maculo-papular (Gr 2) 
 
Urticaria 
Urticaria (Gr 2) 
VASCULAR DISORDERS 
 
Arterial thromboembolism3,16 
Hypertension 
Hypertension (Gr 3) 
 
Thromboembolic event 
Thromboembolic event (Gr 3) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Supraventricular arrhythmias may include supraventricular tachycardia, atrial fibrillation, and atrial flutter. 
 
3The risks of arterial thrombosis such as cardiac or CNS ischemia are increased in elderly patients and in patients 
with a history of diabetes. 
 
4Gastrointestinal fistula may include: Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, Gastric 
fistula, Gastrointestinal fistula, Rectal fistula, and other sites under the GASTROINTESTINAL DISORDERS SOC. 
 
5Gastrointestinal hemorrhage may include: Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, 
Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Oral 
hemorrhage, Rectal hemorrhage, and other sites under the GASTROINTESTINAL DISORDERS SOC. 
 
6Gastrointestinal obstruction may include: Colonic obstruction, Duodenal obstruction, Esophageal obstruction, Ileal 
obstruction, Jejunal obstruction, Rectal obstruction, Small intestinal obstruction, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
7Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation. 
 

 
 
GOG-0213 
 
36 
 
8Gastrointestinal ulcer may include: Duodenal ulcer, Esophageal ulcer, Gastric ulcer, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
9Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
10Anastomotic leak may include Gastric anastomotic leak; Gastrointestinal anastomotic leak; Large intestinal 
anastomotic leak; Rectal anastomotic leak; Small intestinal anastomotic leak; Urostomy leak; Vaginal anastomotic 
leak. 
 
11There have been reports of non-mandibular osteonecrosis (avascular necrosis) in patients under the age of 18 
treated with bevacizumab. 
 
12Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth plates. 
 
13Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients in association with bevacizumab 
treatment, the majority of whom had received prior or concomitant treatment with i.v. bisphosphonates. 
 
14Increased rate of peripheral sensory neuropathy has been observed in trials combining bevacizumab and 
chemotherapy compared to chemotherapy alone.  
 
15Ovarian failure, defined as amenorrhea lasting 3 or more months with follicle-stimulating hormone (FSH) 
elevation (≥30 mIU/mL), was increased in patients receiving adjuvant bevacizumab plus mFOLFOX compared to 
mFOLFOX alone (34% vs. 2%).  After discontinuation of bevacizumab, resumption of menses and an FSH level 
<30 mIU/mL was demonstrated in 22% (7/32) of these women.  Long term effects of bevacizumab exposure on 
fertility are unknown. 
 
16Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, heart attack, and 
stroke. 
 
 
Adverse events reported on bevacizumab (rhuMAb VEGF) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that bevacizumab (rhuMAb VEGF) caused the adverse 
event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Disseminated intravascular 
coagulation; Hemolysis; Thrombotic thrombocytopenic purpura 
CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block first degree; Cardiac arrest; 
Myocarditis; Pericardial effusion; Restrictive cardiomyopathy; Right ventricular dysfunction 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (tympanic membrane perforation); 
Hearing impaired; Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye disorders - Other 
(blindness); Eye disorders - Other (conjunctival hemorrhage); Eye disorders - Other (corneal epithelial defect); Eye 
disorders - Other (ischemic CRVO); Eye disorders - Other (macular pucker); Eye disorders - Other (transient 
increased IOP > or =30 mm Hg); Eye pain; Floaters; Keratitis; Optic nerve disorder; Photophobia; Retinal 
detachment; Retinal tear; Retinopathy; Vitreous hemorrhage; Watering eyes 
GASTROINTESTINAL DISORDERS - Ascites; Cheilitis; Colonic stenosis; Dry mouth; Dysphagia; 
Enterocolitis; Esophageal pain; Esophageal stenosis; Flatulence; Gastrointestinal disorders - Other (peritonitis); Oral 
pain; Pancreatitis; Proctitis; Rectal mucositis; Rectal stenosis; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema face; Edema 
limbs; Edema trunk; Facial pain; Fever; Flu like symptoms; Gait disturbance; Injection site reaction; Localized 
edema; Multi-organ failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder necrosis; Gallbladder obstruction; Hepatic failure; 
Hepatic necrosis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Bruising; Burn; Dermatitis 
radiation; Fracture 

 
 
GOG-0213 
 
37 
 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood antidiuretic hormone abnormal; 
CD4 lymphocytes decreased; CPK increased; Carbon monoxide diffusing capacity decreased; Electrocardiogram 
QT corrected interval prolonged; Forced expiratory volume decreased; GGT increased; INR increased; Lipase 
increased; Lymphocyte count decreased; Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; 
Hypomagnesemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone pain; Chest 
wall pain; Fibrosis deep connective tissue; Head soft tissue necrosis; Joint effusion; Muscle weakness lower limb; 
Muscle weakness upper limb; Musculoskeletal and connective tissue disorder - Other (polymyalgia rheumatica); 
Neck pain; Osteonecrosis; Pain in extremity; Pelvic soft tissue necrosis; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Arachnoiditis; Ataxia; Central nervous system necrosis; Cerebrospinal fluid 
leakage; Cognitive disturbance; Depressed level of consciousness; Dysesthesia; Dysgeusia; Dysphasia; 
Encephalopathy; Extrapyramidal disorder; Facial nerve disorder; Hydrocephalus; Leukoencephalopathy; Memory 
impairment; Myasthenia gravis; Nervous system disorders - Other (increased intracranial pressure); Paresthesia; 
Peripheral motor neuropathy; Pyramidal tract syndrome; Seizure; Somnolence; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Libido decreased; 
Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis noninfective; Dysuria; 
Renal and urinary disorders - Other (ureterolithiasis); Renal hemorrhage; Urinary frequency; Urinary incontinence; 
Urinary retention; Urinary tract obstruction; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Erectile dysfunction; Irregular 
menstruation; Pelvic pain; Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Atelectasis; Hypoxia; Nasal congestion; Pulmonary fibrosis; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (dry nares); Respiratory, thoracic and mediastinal disorders - Other (pulmonary 
infarction) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; Nail loss; Pain of skin; 
Photosensitivity; Purpura; Rash acneiform; Skin and subcutaneous tissue disorders - Other (diabetic foot ulcer); Skin 
and subcutaneous tissue disorders - Other (skin breakdown/ decubitus ulcer); Skin hyperpigmentation; Skin 
induration; Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Lymphocele; Phlebitis; Vasculitis 
 
Note: Bevacizumab (rhuMAb VEGF) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
  
 
4.37 
General Information on Adverse Effects of Bevacizumab (06/22/09) 
Based on clinical trials with bevacizumab as monotherapy or in 
combination with chemotherapy, the most common adverse events of any 
severity include asthenia, pain, headache, hypertension, diarrhea, 
stomatitis, constipation, epistaxis, dyspnea, dermatitis and proteinuria.  
The most common grade 3-4 adverse events were asthenia, pain, 
hypertension, diarrhea and leukopenia.  The most serious AEs include life-
threatening or fatal hemorrhage, arterial thromboembolic events, 
gastrointestinal perforation and wound dehiscence; these events were 
uncommon but occurred at an increased frequency compared to placebo or 
chemotherapy controls in randomized studies.    
 

 
 
GOG-0213 
 
38 
 
 
The following is a description of major adverse events associated with 
bevacizumab therapy.  A list of Comprehensive Adverse Events and 
Potential Risks (CAEPR)in NCI-CTCAE v5.0 terms is included above. 
Reference may also be made to the Investigators’ Brochure and the FDA 
package insert (www.fda.gov/cder/foi/label/2004/125085lbl.pdf).  
 
Infusion-Related Reactions: Infusion reactions with bevacizumab were 
uncommon (<3%) and rarely severe (0.2%).  Infusion reactions may 
include rash, urticaria, fever, rigors, hypertension, hypotension, wheezing, 
or hypoxia.  Currently, there is no adequate information on the safety of 
retreatment with bevacizumab in patients who have experienced severe 
infusion-related reactions.  
 
Hypertension: Hypertension is common in patients treated with 
bevacizumab, with an incidence of 20-30% across trials.  Initiation or 
increase of anti-hypertensive medications may be required, but in most 
cases, blood pressure (BP) can be controlled with routine oral drugs.  
However, incidents of hypertensive crisis with encephalopathy or 
cardiovascular sequelae have been rarely reported.  BP should be closely 
monitored during bevacizumab therapy and the goal of BP control should 
be consistent with general medical practice.  Bevacizumab therapy should 
be suspended in the event of uncontrolled hypertension. 
 
Proteinuria: Proteinuria has been seen in all bevacizumab studies to date, 
ranging in severity from an asymptomatic increase in urine protein 
(incidence of about 20%) to rare instances of nephrotic syndrome (0.5% 
incidence).  Pathologic findings on renal biopsies in two patients showed 
proliferative glomerulonephritis.  NCI-CTCAE grade 3 proteinuria (> 
3.5gm/24 hour urine) is uncommon, but the risk may be higher in patients 
with advanced RCC.  In the phase 2 randomized study in RCC, 24-hour 
urine was collected in a subset of patients enrolled, and grade 3 proteinuria 
was found in 4 patients in the 10 mg/kg-arm (n=37), 2 patients in the 
3mg/kg arm (n=35) and none in the placebo arm (n=38).  The safety of 
continuing bevacizumab in patients with moderate or severe proteinuria 
has not been adequately tested.   
 
Hemorrhage: The incidence of hemorrhage is increased with bevacizumab 
therapy.  Epistaxis is common, occurring in 20-40% of patients, but it is 
generally mild and rarely requires medical intervention.  Life-threatening 
and fatal hemorrhagic events have been observed in bevacizumab studies 
and included pulmonary hemorrhage, CNS bleeding and gastrointestinal 
(GI) bleeding.  In a phase 2 study in non-small cell lung cancer, 6 cases of 
life-threatening hemoptysis or hematemesis were reported among 66 
patients treated with bevacizumab and chemotherapy; 4 of these events 
were fatal.97 In the pivotal phase 3 trial in advanced colorectal cancer, the 
rate of GI hemorrhage (all grades) was 24% in the IFL/bevacizumab arm 

 
 
GOG-0213 
 
39 
 
compared to 6% in the IFL arm; grade 3-4 hemorrhage was 3.1% for 
IFL/bevacizumab and 2.5% for IFL.  Serious GI hemorrhage has also been 
observed in clinical trials with bevacizumab in patients with pancreatic 
cancer or varices treated with bevacizumab.  
 
Arterial Thromboembolic Events:  The risk of arterial thromboembolic 
events is increased with bevacizumab therapy, and such events included 
cerebral infarction, transient ischemic attack (TIA), myocardial infarction 
and other peripheral or visceral arterial thrombosis.  In the pivotal trial in 
CRC  
 
(AVF2107), the incidence of arterial thromboembolic events was 1% in 
the IFL/placebo arm compared to 3% in the IFL/ bevacizumab arm.  A 
pooled analysis of five randomized studies showed a two-fold increase in 
these events (4.4% vs 1.9%).  Certain baseline characteristics, such as age 
and prior arterial ischemic events, appear to confer additional risk.98In 
patients > 65 years treated with bevacizumab and chemotherapy, the rate 
of arterial thromboembolic events was approximately 8.5%.  
 
 
Gastrointestinal Perforation/Fistula: GI perforations/fistulas were rare but 
occurred at an increased rate in bevacizumab-containing therapies.  The 
majority of such events required surgical intervention and some were 
associated with a fatal outcome.  In the pivotal phase 3 trial in CRC 
(AVF2107), the incidence of bowel perforation was 2% in patients 
receiving IFL/bevacizumab and 4% in patients receiving 5-
FU/bevacizumab compared to 0.3% in patients receiving IFL alone.  GI 
perforation has also been reported in patients with gastric/esophageal 
cancer, pancreatic cancer, ovarian cancer or co-morbid GI conditions such 
as diverticulitis and gastric ulcer.  GI perforation should be included in 
the differential diagnosis of patients on bevacizumab therapy 
presenting with abdominal pain, fever of unclear source, or 
rectal/abdominal abscess. 
 
Wound Healing Complications:  Bevacizumab delays wound healing in 
rabbits, and it may also compromise or delay wound healing in patients. 
Bowel anastomotic dehiscence and skin wound dehiscence have been 
reported in clinical trials with bevacizumab.  The appropriate interval 
between surgery and initiation of bevacizumab required to avoid the risk 
of impaired wound healing has not been determined.  However, all clinical 
trials with bevacizumab have required a minimum of 28 days from prior 
major surgery; experience in the pivotal trial in advanced CRC suggests 
that initiation of bevacizumab 29-50 days following surgery should be 
associated with a very low incidence of wound dehiscence.  The optimal 
interval between termination of bevacizumab and subsequent elective 

 
 
GOG-0213 
 
40 
 
surgery has not been determined either.  In the pivotal study in CRC, 40 
patients on the IFL/bevacizumab arm and 25 patients on the ILF/placebo 
arm underwent major surgery while on study; among them, significant 
post-operative bleeding or wound healing complications occurred in 4 of 
the 40 patients from the IFL/bevacizumab arm and none of the 25 patients 
from the IFL alone arm.  Decisions on the timing of elective surgery 
should take into consideration the half-life of bevacizumab (average 21 
days, with a range of 11-50 days). 
 
Congestive Heart Failure: The risk of left ventricular dysfunction may be 
increased in patients with prior or concurrent anthracycline treatment.  In 
phase 3 controlled clinical trials in metastatic breast cancer (AVF 2119g) 
in which all patients had received prior anthracyclines, congestive heart 
failure (CHF) or cardiomyopathy were reported in 7 patients (3%) in the 
bevacizumab/capecitabine arm compared to 2 (1%) in the capecitabine-
only arm.  No increase in CHF was observed in CRC trials with 
bevacizumab in combination with IFL or 5-FU.   
 
Venous Thrombosis:  Venous thromboembolic events reported in 
bevacizumab trials included lower extremity deep vein thrombosis (DVT), 
pulmonary embolism and rarely, mesenteric or portal vein thrombosis.  In 
the pivotal phase 3 trial of IFL + bevacizumab (given at 5 mg/kg q2w), the 
overall incidences of G3-4 venous thromboembolic events were 
comparable in the two arms (15.1 vs 13.6%).    
 
Fertility and Pregnancy:  Clinical data are lacking regarding the immediate 
or long-term effect of bevacizumab on fertility and pregnancy.  However, 
bevacizumab is known to be teratogenic and detrimental to fetal 
development in animal models.  In addition, bevacizumab may alter 
corpus luteum development and endometrial proliferation, thereby having 
a negative effect on fertility.  As an IgG1, it may also be secreted in 
human milk.  Therefore, fertile men and women on bevacizumab studies 
must use adequate contraceptive measures and women should avoid breast 
feeding.  The duration of such precautions after discontinuation of 
bevacizumab should take into consideration the half-life of the agent 
(average 21 days, with a range of 11 to 50 days). 
 
Immunogenicity:  As a therapeutic protein, there is a potential for 
immunogenicity with bevacizumab.  With the currently available assay 
with limited sensitivity, high titer human anti-bevacizumab antibodies 
have not been detected in approximately 500 patients treated with 
bevacizumab. 
 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), or similar 
leukoencephalopathy syndrome: RPLS/PRES are clinical syndromes 
related to vasogenic edema of the white matter and have rarely been 

 
 
GOG-0213 
 
41 
 
reported in association with bevacizumab therapy (<1%). Clinical 
presentations may include altered mental status, seizure, and cortical 
blindness. MRI scans are required for diagnosis: typical finding are 
vasogenic edema in the white matter of the posterior parietal and occipital 
lobes, and less frequently in the anterior distributions and the gray matter. 
In RPLS associated with bevacizumab mild or significant BP elevations 
were seen in some but not all cases. RPLS/ PRES should be in the 
differential diagnosis in patients presented with unexplained mental status 
change, visual disturbance, seizure or other CNS finding. MRI is the key 
to diagnosis. This syndrome is potentially reversible, but timely correction 
of the underlying causes, including control of BP and interruption of the 
offending drug, is important in order to prevent irreversible tissue damage. 
(06/22/09) 
 
Neutropenia: when combined with chemotherapy, bevacizumab increased 
the risk of neutropenia compared to chemotherapy alone. In a phase 3 trial 
with IFL +/- bevacizumab in colorectal cancer, grade 3-4 neutropenia was 
21% in the bevacizumab arm + IFL vs 14% in the IFL arm (grade 4 
neutropenia was 3% vs 2%). In a phase 3 trial with carboplatin and 
paclitaxel +/- bevacizumab in NSCLC, the bevacizumab-containing arm 
was associated with an increased rate of grade 4 neutropenia (27% vs 
17%), febrile neutropenia (5.4% vs 1.8%), and an increased risk of 
infection with neutropenia (4.4% vs 2.0%) with three fatal cases in the 
bevacizumab + chemotherapy arm vs none in the chemotherapy control 
arm .(06/22/09) 
 
4.38 
Agent Ordering and Agent Accountability (08/04/08) 
 
NCI supplied agents may be requested by the Principal Investigator (or 
their authorized designee) at each participating institution.  Pharmaceutical 
Management Branch (PMB) policy requires that agent be shipped directly 
to the institution where the patient is to be treated.  PMB does not permit 
the transfer of agents between institutions (unless prior approval from 
PMB is obtained.) The CTEP assigned protocol number must be used for 
ordering all CTEP supplied investigational agents.  The responsible 
investigator at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form 
(IDF), and Financial Disclosure Form (FDF).  If there are several 
participating investigators at one institution, CTEP supplied 
investigational agents for the study should be ordered under the name of 
one lead investigator at that institution. 
 
 
 
4.39 
Agent may be requested by completing a Clinical Drug Request (NIH-
986) and mailing it to the Drug Management and Authorization Section, 
PMB, DCTD, NCI, 9000 Rockville Pike, EPN Room 7149, Bethesda, MD 

 
 
GOG-0213 
 
42 
 
20892-7422 or faxing it to (301) 480-4612.  For questions call (301) 496-
5725. 
 
 
 
4.40 
Agent Inventory Records - The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of the 
inventory and disposition of all agents received from DCTD using the NCI 
Drug Accountability Record (DAR) Form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.)(6/22/09) 
 
 
 
4.41 
Under Japanese regulation, because bevacizumab is commercially 
available and approved by the PMDA for this indication, it can no longer 
be supplied free of charge.  As of (03/09/15), Japanese sites enrolling 
and/or treating patients on this study must use commercially available 
bevacizumab. Japanse institutional pharmacies will handle drug 
accountability (03/09/15) 
 
4.4 
Docetaxel (Taxotere® RP-56976, NSC #628503)  
 
4.41 
Formulation:  Docetaxel is supplied as a sterile, non-pyrogenic, non-
aqueous viscous solution in single dose vials containing 20mg/0.5mL or 
80mg/2mL of docetaxel.  Each mL contains 40mg docetaxel (anhydrous) 
and 1040mg polysorbate 80. 
 
4.42 
Docetaxel requires dilution prior to use.  A sterile, non-pyrogenic, single 
dose diluent is supplied for this purpose.  The diluent for docetaxel 
contains 13% (w/w) ethanol in water for injection and is supplied in vials. 
 
4.43 
Storage:  Unopened vials of docetaxel are stable to the date indicated on 
the package when stored between 2 and 25°C (36 and 77°F).  Protect from 
light. 
 
4.44 
Preparation:  Docetaxel must be combined with its supplied diluent (final 
concentration = 10mg/mL) and then further diluted prior to infusion.  
Docetaxel should be diluted in 0.9% Sodium Chloride for Injection, USP 
or 5% Dextrose Injection, USP to produce a final concentration of 0.3 to 
0.74mg/mL.  The fully prepared docetaxel infusion solution should be 
used within 4 hours (including the infusion duration). 
 
NOTE:  In order to minimize patient exposure to the plasticizer DEHP, 
which may be leached from PVC infusion bags or sets, the final docetaxel 
dilution for infusion should be stored in bottles (glass, polypropylene) or 
plastic (polypropylene, polyolefin) bags and administered through 
polyethylene-lined administration sets. 
 
All patients should be premedicated with oral corticosteroids for 3 days 
starting 1 day prior to docetaxel administration in order to reduce the 

 
 
GOG-0213 
 
43 
 
incidence and severity of fluid retention as well as the severity of 
hypersensitivity reactions. 
 
4.45 
Adverse Effects:  Consult the package insert for the most current and 
complete information. 
 
4.46 
Supplier:  Commercially available from Aventis.  Consult the American 
Hospital Formulary Service Drug Information guide, Facts and 
Comparisons, or the package insert for additional information. 
 
4.5 Gemcitabine(10/01/12) 
 
4.51 
Formulation: Gemcitabine is supplied as a lyophilized powder in sterile 
vials containing 200 mg or 1 gram of gemcitabine as the hydrochloride 
salt (expressed as the free base), mannitol and sodium acetate. 
 
4.52 
Gemcitabine requires dilution prior to use.  The lyophilized product will 
be reconstituted with normal saline added to the vial in order to make a 
solution ideally containing 10 mg/ml or </= 40 mg/ml for 200 mg and 1 
gram vials. 
 
4.53 
Storage:  Unopened vials of gemcitabine are stable to the date indicated on 
the package when stored between 2 and 25°C (36 and 77°F).  Once the 
drug has been reconstituted, it should be stored at controlled room 
temperature (range, 20 to 25oC) and used within 24 hours. 
 
4.54 
Preparation: An appropriate amount of drug will be administered as 
prepared or diluted with an additional 100 ml of normal saline. Once the 
drug has been reconstituted, it should be stored at controlled room 
temperature (range, 20 to 25oC) and used within 24 hours. 
 
4.55 
Administration: Gemcitabine will be infused over 1 hour 
 
4.56 
Adverse Effects:  Consult the package insert for the most current and 
complete information. 
 
4.57 
Supplier:  Commercially available from Eli Lilly Pharmaceuticals.  
Consult the American Hospital Formulary Service Drug Information 
guide, Facts and Comparisons, or the package insert for additional 
information. 
 
4.6 
Pathology Requirements (6/22/09) 
 
4.61 
Eligible Patients: Patients must have histologic diagnosis of epithelial 
ovarian carcinoma, peritoneal primary or Fallopian tube carcinoma, which 
is now recurrent.  Patients with the following histologic epithelial cell 

 
 
GOG-0213 
 
44 
 
types are eligible: Serous adenocarcinoma, endometrioid adenocarcinoma, 
mucinous adenocarcinoma, undifferentiated carcinoma, clear cell 
adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, 
malignant Brenner's Tumor, or adenocarcinoma not otherwise specified 
(N.O.S.). 
 
4.62 
Ineligible Patients: Patients with a gynecologic malignancy other then 
epithelial ovarian carcinoma, peritoneal primary or Fallopian tube 
carcinoma. 
 
4.63 
Requirements and Instructions: Stained pathology slides are required for 
central review by the GOG Pathology Committee to confirm eligibility for 
the protocol.  See section 7.2 and 10.2 for specific requirements and 
instructions for the stained pathology slides, pathology reports and forms. 
 
5.0  
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 
 
Before patient entries will be accepted, an official signed CTSU IRB Certification Form 
and a CTSU IRB/Regulatory Approval Transmittal Sheet (forms can be downloaded at 
www.ctsu.org) must be received by the CTSU Regulatory Office.  These forms can be 
faxed or mailed to: 
CTSU Regulatory Office 
Coalition of National Cancer Cooperative Groups 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
1-888-823-5923 
  FAX 215-569-0206  
 
5.1 
Patient Entry and Registration (09/29/14) 
 
All site staff will use OPEN to enroll patients to this study.  OPEN can be 
accessed at on the GOG web menu page and clicking on the OPEN link.  
  
Prior to accessing OPEN site staff should verify the following: 
  
• 
All eligibility criteria have been met within the protocol stated 
timeframes. Site staff should use the registration forms provided on the 
group web site as a tool to verify eligibility. 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
  
 
Access requirements for OPEN: 
  

 
 
GOG-0213 
 
45 
 
• 
Site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account. This is the same account (user id and password) used 
for the CTSU members' web site.  
• 
To perform registrations, the site user must have been assigned the 
'Registrar' role on the GOG or CTSU roster.  
• 
To perform registrations you must have an equivalent 'Registrar' role on 
the Lead Group roster.  Role assignments are handled through the Groups 
in which you are a member.  
  
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 CTSU members' web site 
OPEN tab or within the OPEN URL. For any additional questions contact 
the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
5.2 
Treatment Plan (06/22/09) 
 
5.21 
Patients meeting eligibility requirements will be considered first for the 
surgical randomization aspect of the trial.  Suitability for secondary 
cytoreduction will be made by the individual patient’s Attending 
Physician.  Guidelines for consideration in assessing candidacy for 
secondary cytoreduction are listed in Section 5.211. If the patient is 
considered to be a suitable surgical candidate she will undergo 
randomization as outlined in Section 5.22.   
 
(The following two sentences do not apply to patients enrolled onto the 
study after August 28, 2011): If the patient is considered not to be a 
suitable surgical candidate she will be allowed to participate in the 
chemotherapy randomization aspect of the trial as outlined in Section 5.23. 
Patients undergoing surgical randomization will also be randomized to a 
chemotherapy regimen at the same time. (08/29/11)(12/19/11) 
 
5.211 Guidelines for Secondary Cytoreduction:  The goal of secondary 
cytoreduction is COMPLETE REMOVAL OF ALL VISIBLE 
DISEASE.  While no specific eligibility can be globally provided, 
patients with recurrent disease which will not be addressed at 
surgery should not undergo surgical randomization. In general, 
women with carcinomatosis and/or ascites make poor surgical 
candidates as the diffusion of disease usually precludes complete 
cytoreduction.  Similarly, women with parenchymal organ disease 
(e.g. lung, liver, pancreas, kidney, bone, etc) are poor candidates, if 
the disease is felt unresectable by preoperative evaluation. 
Assessment of candidacy will be made by physical exam, 
laboratory and imaging (MRI, PET/CT and/or CT).  Although it is 

 
 
GOG-0213 
 
46 
 
recognized that patients with longer treatment-free intervals may 
be considered better surgical candidates (providing some 
expansion of the preoperative tumor volume characteristics) than 
those with shorter treatment-free intervals, the primary tenet of 
surgery for this study in all women enrolled in this arm is complete 
surgical resection (no visible residual).  
 
5.22 
Randomization I:  Surgery:  Patients entered onto the surgical arm of the 
trial will undergo abdominal exploration with cytoreduction as outlined in  
(Appendix II) within 4 weeks of registration.  Chemotherapy will be 
administered following recovery up to 6 weeks after surgery. A discussion 
with the study chair is required if study treatment is not initiated within 6 
weeks of surgery.(6/22/09) (03/15/10) 
 
 
5.23 
Randomization II: Chemotherapy. (Between Dec 6, 2007 and August 28, 
2011 the following 4 treatment arms were randomly assigned to 
patients enrolled into this study.  Beginning August 29, 2011 all 
patients are required to be surgical candidates, and only the surgical 
component of treatment is randomized.  For these later patients the 
systemic treatment, which consists of either paclitaxel+carboplatin (as 
described for arms I and III) or gemcitabine+carboplatin (as 
described for arms V and VII) or 
paclitaxel+carboplatin+bevacizumab (as described for arms II and 
IV) or gemcitabine+carboplatin+bevacizumab (as described for arms 
VI and VIII) is selected and declared prior to enrolling onto the study.  
(08/29/11)(12/19/11) (10/01/12) 
 
 
 
 
 
5.231 Regimens: (06/22/09) (03/15/10) (10/01/12) 
 
Arm Surgery Chemotherapy* 
Schedule 
Maintenance Regimen 
I 
No 
Paclitaxel 175 mg/m2 ** 
Carboplatin AUC 5 
Every 21 days 
(Section 5.24) 
None 
II  
No 
Paclitaxel 175 mg/m2 ** 
Bevacizumab 15 mg/kg 
Carboplatin AUC 5 
  
Every 21 days  
(Section 5.25) 
Bevacizumab 15 mg/kg 
every 21 days until 
progression or toxicity 
precludes further treatment. 
Patient chooses systemic treatment with either: 
    a) carboplatin + paclitaxel or gemcitabine or 
    b) carboplatin + paclitaxel or gemcitabine + bevacizumab 

 
 
GOG-0213 
 
47 
 
 
*All chemotherapy doses on day one unless otherwise indicated.  For those patients randomized 
to cytoreductive surgery, bevacizumab is to be started at the 2nd cycle of therapy. 
** Note:  docetaxel 75mg/m2 IV over 1 hour may be substituted for paclitaxel (see Sections 
5.233and 6.161). 
 
5.232 Patients continue to receive maintenance treatment until disease 
progression or until adverse events prohibit further therapy. 
 
5.233 Sequence and timing of drug administration: (08/04/08) 
(03/15/10)(08/29/11)(12/19/11)(10/01/12) 
• Paclitaxel will be infused over 3 hours.  (Note, for 
circumstances in which docetaxel should be substituted for 
paclitaxel: Docetaxel will be administered as a 1 hour IV 
infusion at a starting dose of 75 mg/m2 see Sections 6.161 and 
6.167). 
• Bevacizumab administration will be as a short intravenous 
infusion following paclitaxel infusion.  Anaphylaxis 
precautions should be observed during bevacizumab 
V 
No 
Gemcitabine 1000 
mg/m2  d1 & d8 
Carboplatin AUC 4 day 
1 
Every 21 days  
(Section 5.24) 
  
None 
VI 
No 
Gemcitabine 1000 
mg/m2  d1 & d8 
Bevacizumab 15 mg/kg 
Carboplatin AUC 4 day 
1 
Every 21 days  
(Section 5.25) 
Bevacizumab 15 mg/kg 
every 21 days until 
progression or toxicity 
precludes further treatment. 
III 
Yes 
Paclitaxel 175 mg/m2 ** 
Carboplatin AUC 5 
Every 21 days 
(Section 5.24) 
None 
IV 
Yes 
Paclitaxel 175 mg/m2 ** 
Bevacizumab 15 mg/kg 
Carboplatin AUC 5 
  
Every 21 days  
(Section 5.25) 
Bevacizumab 15 mg/kg 
every 21 days until 
progression or toxicity 
precludes further treatment. 
VII 
Yes 
Gemcitabine 1000 
mg/m2  d1 & d8 
Carboplatin AUC 4 day 
1 
Every 21 days  
(Section 5.24) 
  
None 
VIII 
Yes 
Gemcitabine 1000 
mg/m2  d1 & d8 
Bevacizumab 15 mg/kg 
Carboplatin AUC 4 day 
1 
Every 21 days  
(Section 5.25) 
Bevacizumab 15 mg/kg 
every 21 days until 
progression or toxicity 
precludes further treatment. 

 
 
GOG-0213 
 
48 
 
administration. The initial dose would be administered over 90 
± 15 minutes.  If no adverse reactions (including fever and or 
chill) occur, the second dose should be administered over a 
minimum of 60 ± 10 minutes.  If no adverse reactions occur 
after the second dose, all subsequent doses should be 
administered over a minimum of 30 minutes. 
• Bevacizumab has been associated with an increase in 
wound complications and bowel perforations in post-
operative patients.  Thus, patients in Randomization I who 
undergo surgery and are to receive bevacizumab after 
Randomization II will have the first  
cycle of therapy without bevacizumab.  They will receive it 
in cycle #2. 
• Gemcitabine will be administered over 60 minutes on days 
1 and 8 of each 21-day cycle. Patients will be monitored 
prior to each dose with a complete blood count, including 
differential counts. 
• Carboplatin will be administered as a 60-minute infusion.  
When administered in conjunction with other medications, 
carboplatin will be infused after the other agents. Carboplatin, 
either alone or in combination should be premedicated with 
dexamethasone (either IV or PO), anti-histamine H1 (such as 
diphenhydramine) and anti-histamine H2 (such as cimetidine, 
ranitidine, or famotidine). 
 
5.234 Pre-Medication:(10/01/12) 
 
For all courses where paclitaxel is to be administered, it is 
recommended that a preparative regimen be employed one hour 
prior to the treatment regimen on that day to reduce the risk 
associated with hypersensitivity reactions.  This regimen should 
include dexamethasone (either IV or PO), anti-histamine H1 (such 
as diphenhydramine) and anti-histamine H2 (such as cimetidine, 
ranitidine, or famotidine). 
 
When carboplatin and paclitaxel are administered with 
bevacizumab, it is recommended that the preparatory regimen as 
outlined above should be given 30 minutes if IV or 60 minutes if 
PO before infusion to reduce the risk of hypersensitivity associated 
with these agents. 
 
In the event of a prior bevacizumab hypersensitivity reaction the 
prophylactic regimen should be repeated prior to subsequent doses 
of bevacizumab (Section 5.2551).  Thus, the patient will be 
premedicated prior to paclitaxel AND prior to bevacizumab. 
 

 
 
GOG-0213 
 
49 
 
For all courses where docetaxel is to be administered, (see Sections 
6.161 and 6.167) it is recommended that patients be premedicated 
with dexamethasone 8 mg orally taken the night before, morning 
of, and evening after each treatment (total dose, 24 mg/wk), and an 
anti-histamine H1 (diphenhydramine 25-50 mg IVP or orally, or an 
equivalent dose of an alternate H1 blocker such as loratadine or 
fexofenadine) one hour prior to docetaxel. 
 
5.235 Antiemetic Regimens(10/01/12) 
It is anticipated that nausea and vomiting may be a significant side 
effect of each regimen.  The following representative antiemetic 
regimens are suggested: 
 
• Ondansetron 8-32 mg IV 30 minutes prior to administration 
of chemotherapy and dexamethasone 10-20 mg IV 30 
minutes prior to drug administration or, 
• Granisetron 1 mg IV (or 2 mg PO) 30 minutes prior to 
chemotherapy plus dexamethasone 10 mg IV, with or 
without lorazepam 0.5 – 2.0 mg IV 30 minutes prior to 
chemotherapy. 
• Be sure to give prescription(s) for prevention of delayed 
nausea/vomiting as per institutional guidelines/standards. 
 
5.236Dosing of Paclitaxel(06/22/09) 
 
The initial dose of paclitaxel will be 175 mg/m2. Alterations in this 
dose are presented in Section 6.1612.  As such, patients whose body 
weight changes by 10% or more should undergo recalculation based 
on the adjusted body surface area. 
 
 
5.237Dosing of bevacizumab(06/22/09)(08/29/11) 
 
Bevacizumab will be administered at 15 mg/kg IV. For patients 
randomized to the chemotherapy arm, the weight at screening 
will be used to determine the bevacizumab dose to be used for the 
duration of the study.  For patients undergoing the second surgical 
procedure the baseline weight for calculating the bevacizumab 
dose should be post-op.  If a patient’s weight changes by ≥ 10% 
during the course of the study, the bevacizumab dose will be 
recalculated. 
 
5.2371 Supportive Care Guidelines for Bevacizumab 
If an infusion-related adverse reaction occurs, the patient 
should be pre-medicated prior to subsequent doses of 
bevacizumab (Section 5.234); however, the infusion time 

 
 
GOG-0213 
 
50 
 
for bevacizumab may not be decreased for the next 
infusion. If a patient experiences an infusion-associated 
averse event with the 60-minute infusion, all subsequent 
doses should be given over 90 minutes ± 15 minutes. 
 
5.238 Dosing of Carboplatin (03/15/10) (08/23/10) (1/3/11)  
 
See Appendix V for current Carboplatin dose calculation instructions 
 
5.239 Dosing of Gemcitabine (10/01/12) 
 
See Section 5.233 
 
 
5.24 
Duration of treatment – Paclitaxel or Gemcitabine and Carboplatin (Arm I,  
Arm III, Arm V, and Arm VII): (06/22/09) 
 
5.241 Patients with measurable disease achieving clinical complete 
response (negative physical exam, negative CT scan or MRI and 
normal CA-125) (CR; Section 8.131) during the chemotherapy 
phase will be treated with a minimum of 6 cycles of therapy or for 
2 additional cycles following the CR designation (maximum of 8 
cycles), whichever is greater.   
 
5.242 If stable or partial regression is the maximum documented 
response, patients will continue their chemotherapy to a maximum 
of 8 cycles (see Section 8.15) or adverse effects (see Section 6.0).  
Patients will then be  
 
 
followed off therapy until documented progression occurs. (See 
Section 8.14) (08/04/08)(6/22/09) 
 
5.243 If progressive disease is observed while on therapy, patients will 
have study therapy discontinued and will be treated with 
appropriate alternative chemotherapy.  
 
5.244 Patients without measurable lesions as determined by a CT scan 
prior to initiating study treatment will continue therapy for 6 cycles 
or if CA-125  
 
normalizes for 2 cycles beyond CA-125 normalization, whichever 
is greater as long as: the criteria for progression (See Section 8.14); 
and the criteria for study termination by drug toxicity (See Section 
6.0) have not been met.  Patients with normal CA-125 at the start 
of therapy (without measurable lesions) will have chemotherapy 
stopped after six cycles. . 
 
5.25   Duration of treatment – Carboplatin, Bevacizumab and Paclitaxel or  

 
 
GOG-0213 
 
51 
 
Gemcitabine (Arm II  Arm IV, Arm VI, and Arm VIII) (06/22/09) 
(03/15/10)(10/01/12) 
 
5.251 Patients with measurable disease achieving clinical complete 
response (CR; Section 8.131) during the chemotherapy phase will 
be treated for a minimum of 6 cycles of therapy or for 2 additional 
cycles following the CR designation (maximum of 8 cycles) and 
then begin the maintenance regimen. The maintenance phase will 
be continued until progression or adverse effects preclude 
additional treatment.  
 
5.252 If stable or partial regression is the maximum documented 
response, patients will receive up to 8 cycles (minimum of 6 
cycles) of therapy and then begin the maintenance regimen. The 
maintenance phase will be continued until progression or adverse 
effects preclude additional treatment.(08/04/08) 
 
5.253 If progressive disease is observed while on therapy, patients in all 
arms will have study therapy discontinued and will be treated with 
appropriate alternative chemotherapy. 
 
5.254 Patients without measurable lesions as determined by a CT scan 
prior to initiating study treatment will continue chemotherapy and 
the biologic agent for 6 cycles or if CA-125 normalizes for 2 
cycles beyond CA-125 normalization, whichever is greater as long 
as: the criteria for progression (See Section 8.15); and the criteria 
for study termination by drug toxicity (See Section 6.0) have not 
been met.  Patients with normal CA-125 at the start of therapy 
(without measurable disease) will have chemotherapy stopped after 
six cycles. The maintenance regimen will begin after completing 
chemotherapy and continue until progression or adverse effects 
preclude additional treatment.  
 
5.26 
Biometric considerations in dose calculation 
 
Maximum body surface area used for dose calculations will be 2.0 m2 as 
per GOG Chemotherapy Procedures Manual 
 
5.3 
Secondary Cytoreduction: (06/22/09) 
 
The value of secondary surgical cytoreduction is being evaluated in this trial 
through a randomization of surgical candidates deemed appropriate by their 
treating physicians. Participation in the surgical randomization arm of this trial is 
NOT required for entry on this study. Patients with recurrent disease, meeting 
entry criteria but deemed not appropriate for surgical exploration are eligible to 
participate in the chemotherapy randomization. Those patients for whom their 

 
 
GOG-0213 
 
52 
 
treating physicians consider appropriate for surgery will be randomized to either 
secondary cytoreduction or no surgery prior to a second randomization of 
chemotherapy. Surgical exploration should be undertaken within 28 days of 
registration onto this study. 
 
5.31 
Procedures and goals of secondary cytoreduction are outlined in Appendix 
II. 
 
5.32 
Please see Section 7.3 for a summary of the specimen requirements and 
laboratory testing for this protocol. In addition, please carefully review 
Appendix III for a detailed description of the Specimen Procedures for 
GOG-0213.  

 
 
GOG-0213 
 
53 
 
6.0 
TREATMENT MODIFICATIONS 
 
6.1  
Dose Modifications: 
Since chemotherapy in the recurrent setting is largely palliative, infusion without 
routine use of growth factor support will be attempted.  Certain chemotherapy 
combinations have additive hematologic toxicity and other combinations are 
characterized by differing hematologic toxicity.  Therefore, dose modification 
will be based on dose-limiting toxicity (DLT) for either or both neutropenia 
(ANC) or thrombocytopenia (PLT) and conducted as outlined in the following 
table below. 
 
If a dose reduction is indicated, recalculate chemotherapy dosages using the 
baseline weight and serum creatinine. (03/15/10) 
 
6.11 
Dose-limiting neutropenia (DLT-ANC) is defined as: 
• Febrile neutropenia:  febrile is defined as fever ≥ 38.5°C, with or 
without documented infection in the presence of an ANC of 1000 
cells/mm3 or less 
• Prolonged Grade IV ANC persisting ≥ 7 days. 
• Uncomplicated Grade IV ANC, < 7 days, is NOT a DLT. 
 
6.12 
Dose-limiting thrombocytopenia (DLT-PLT) is defined as: 
• Grade IV thrombocytopenia (< 25,000/mm3) 
• Grade III thrombocytopenia (25,000 to 50,000/mm3) complicated by 
bleeding, easy bruising, petechiae or requiring platelet transfusion (see 
Section 6.141) 
• Uncomplicated Grade III thrombocytopenia is NOT a DLT 
 
6.13 
Guidelines for dose modification based on dose-limiting neutropenia and 
thrombocytopenia: (nadirs) 
 
Table A 
DLT 
ANC‡ 
DLT 
PLT§ 
First Occurrence 
Second Occurrence 
Third 
Occurrence 
Yes 
No 
Reduce the REGIMEN drug 
doses by one level as in Table 
B-1   * 
Add myeloid growth 
factor AND maintain all 
drug doses 
Off Study 
Treatment, 
Follow-up 
Continued 
Yes 
Yes 
Reduce the REGIMEN drug 
doses by one level as in Table 
B-1   * 
Off Study Treatment, 
Follow-up Continued 
 
No 
Yes 
Decrease one AUC unit AND 
maintain other drug doses 
*  
Off Study Treatment, 
Follow-up Continued 
 
‡ 
DLT-ANC: Neutropenic Dose-Limiting Toxicity (Section 6.11) 
 

 
 
GOG-0213 
 
54 
 
§ 
DLT-PLT: Thrombocytopenic Dose-Limiting Toxicity (Section 6.12) 
 
* 
For patients in whom docetaxel has been substituted for paclitaxel according to 
guidelines in Sections 6.161 and 6.167, dose modifications can be found in Table 
B-2. 
 
6.14 
Adjustments for Hematologic Toxicity (03/15/10) 
 
6.141 Hemorrhage:  Patients receiving bevacizumab who develop a 
CTCAE V4.0 Grade 3 hemorrhage and receiving full-dose 
anticoagulation will be taken off study treatment.  For all other 
patients with CTCAE V4.0  
 
Grade 3 hemorrhage, bevacizumab should be held until ALL of the 
following criteria are met (continue carboplatin and paclitaxel): 
 
• 
bleeding has resolved 
• 
blood hemoglobin level is stable (serial measures with less 
than 10% change) 
• 
there is no bleeding diathesis that would increase the risk of 
therapy 
• 
there is no anatomical or pathologic condition that can 
increase the risk of hemorrhage recurrence.   
 
 
Patients who experience delay of resolution according to the above 
criteria for greater than 3 weeks, recurrence of Grade 3 
hemorrhage, or any CTCAE V4.0 Grade 4 hemorrhage will be 
taken off study treatment. 
 
6.142 Thrombosis:(03/15/10) 
 
 
 
Arterial Thrombosis 
Patients will be taken off study treatment for ≥ CTCAE Grade 3 
arterial thrombotic events (including cerebrovascular ischemia, 
transient ischemic attack, cardiac ischemia/infarction, peripheral or 
visceral arterial ischemia) or CTCAE Grade 2 arterial thrombotic 
events new or worsened since beginning bevacizumab therapy. 
 
 
Venous Thrombosis 
All therapy (carboplatin, paclitaxel, and bevacizumab)will be held 
for CTCAE Grade 3 or asymptomatic CTCAE Grade 4 venous 
thrombosis.  For patients on therapeutic anticoagulation, PT INR 
or PTT (whichever appropriate) should be monitored closely 
during bevacizumab therapy.  If the planned duration of full-dose 
anticoagulation is ≤ 3 weeks, treatment should be held until the 
full-dose anticoagulation period is over.  If the planned duration of 
full-dose anticoagulation is > 3 weeks, treatment may be resumed 

 
 
GOG-0213 
 
55 
 
during the period of full dose anticoagulation if ALL of the 
following criteria are met (otherwise the patient will be taken off 
study treatment): 
 
• The patient must have an in-range INR (usually between 2 and 
3) on a stable dose of warfarin (or other anticoagulant) or on 
stable dose of heparin prior to restarting treatment.  
• The subject must not have pathological conditions that carry 
high risk of bleeding (e.g. tumor involving major vessels). 
• The subject must not have had hemorrhagic events while on 
study. 
• The patient is benefiting from treatment (no evidence of 
disease progression). 
 
Patients with symptomatic CTCAE Grade 4, or 
recurrent/worsening thromboembolic events after resumption of 
bevacizumab, will be taken off study treatment. 
 
6.143 Coagulopathy:  For CTCAE V4.0 Grade 3 or 4 coagulopathy: 
hold all therapy (carboplatin, paclitaxel, and bevacizumab), until 
PT resolves to Grade 1.  For patients with PT/INR > therapeutic 
range while on therapeutic warfarin, hold treatment until PT/INR 
within therapeutic range.  Patients experiencing treatment delay >3 
weeks because of failure to meet the above criteria will be taken 
off study. (06/22/09) (03/15/10) 
 
Table B-1 
Regimen modifications for DLTs (6.11-613), hematologic 
toxicities (6.141-6.143) and delayed hematologic toxicity 
(6.153)(03/15/10) 
 
Arm 
Drug 
Level –1 
Starting Dose 
I and 
III 
Paclitaxel * 
135 mg/m2 
175 mg/m2 
Carboplatin 
AUC 4 
AUC 5 
II and 
IV 
Paclitaxel * 
135 mg/m2 
175 mg/m2 
Bevacizumab 
15 mg/kg  
15 mg/kg 
Carboplatin 
AUC 4 
AUC 5 
* See Table B-2 below, for patients in whom docetaxel has been 
substituted for paclitaxel according to guidelines in Sections 6.161 and 
6.167. 
 
Table B-2 
Dose Levels for Docetaxel* 
 
Arm 
Drug 
Level –1 
Starting Dose 
I-IV 
Docetaxel 
65 mg/m2 
75 mg/m2 
 
* For patients in whom docetaxel has been substituted for paclitaxel 
according  
 
to guidelines in Sections 6.161 and 6.167. 

 
 
GOG-0213 
 
56 
 
 
6.15 
General Guidelines for Delayed Hematologic Toxicity 
 
6.151 No subsequent chemotherapy cycle shall begin until the absolute 
neutrophil count (ANC) ≥ 1,500/mcl and platelets ≥ 100,000/mcl. 
No subsequent cycle of maintenance bevacizumab shall begin until 
the ANC is ≥ 1000/mcl and platelets are ≥ 75,000/mcl. (03/15/10) 
 
6.152 Failure of the counts to recover appropriately by day 21 will 
require delay of the subsequent treatment until adequate count 
recovery. 
 
6.153 Patients who require a delay of greater than 1 but < 2 weeks for 
adequate count recovery (with or without growth factors) will have 
subsequent treatment with a one level dose reduction.  Patients 
who have a second delay of greater than 7 days will require the use 
of myeloid growth factors in all subsequent cycles. Patients who 
have a delay of > 2 weeks will have a one level dose reduction and 
the addition of myeloid growth factors in all subsequent cycles. 
(03/15/10) 
 
6.154 Patients who require a delay of greater than 3 weeks for adequate 
count recovery (with or without growth factors) will be removed 
from study treatment, but follow-up will continue. 
 
6.155 There will be no dose modification on the basis of uncomplicated 
WBC or ANC nadirs.   
 
6.156 Patients will NOT receive prophylactic thrombopoietic agents on 
this study.   
 
6.1561 Patients may receive erythropoietin (EPO), iron 
supplements, and/or transfusions as clinically indicated for 
management of anemia.   
 
6.1562 Patients may not receive amifostine or other protective 
reagents, unless indicated in the study design. 
 
 
6.16 
Adjustments for Non-hematologic Toxicity 
 
Individual agents may be associated with specific non-hematological 
toxicity which warrants dose modification.  Allowable dosing 
modifications are presented in the following table: 
 
Table C Regimen modifications for non-hematologic toxicities (see 
dose adjustments per toxicity type as outlined below 

 
 
GOG-0213 
 
57 
 
 
 
 
* For patients in whom docetaxel has been substituted for paclitaxel 
according  
 
to guidelines in Sections 6.161 and 6.167. 
 
 
6.161 Neurologic toxicity: Grade 2 (or greater) peripheral neuropathy 
requires reduction of one dose level in paclitaxel and delay in 
subsequent therapy (all agents) for a maximum of 3 weeks until 
recovered to grade 1.  If peripheral neuropathy fails to recover to 
Grade 1 by a maximum delay of three weeks from time therapy is 
due then paclitaxel should be withheld from all subsequent 
chemotherapy cycles. For patients with persistent Grade 2 
neurotoxicity, substitute docetaxel, unless medically 
contraindicated, according to Section 5.233.(03/15/10)  Patients 
with persistent Grade 3-4 neurotoxicity should be removed from 
study. 
 
In such cases where docetaxel has been substituted for paclitaxel, 
if CTCAE Grade 3 or 4 peripheral neuropathy occurs during or 
after the first cycle of docetaxel substitution then subsequent doses 
of docetaxel will be delayed for a maximum of three weeks until 
recovered to CTCAE Grade ≤ 2. If peripheral neuropathy fails to 
recover to Grade ≤ 2 by a maximum delay of three weeks from 
time therapy is due, then the patient is removed from study. 
(08/23/10) 
 
6.162    Gastrointestinal toxicity: There will be no dose modifications for 
nausea, diarrhea, or constipation.  It is recommended that routine 
medical measures be employed to manage nausea and constipation. 
 
6.163   Renal toxicity: If renal function worsens on therapy, an 
investigation for underlying causes should be undertaken.  
Calculated or measured creatinine clearance under 40 ml/min or 
significant worsening of the renal function (50% reduction in 
calculated CrCl) requires withholding treatment until a cause is 
identified or renal function improves.  In particular, disease 
progression should be ruled out.  In these patients creatinine 
clearance should be evaluated weekly. If calculated or measured 
CrCl is less than 40 ml/min after a two-week delay, the Study 
Chair must be notified.  No treatment is to be given to a patient 
with a calculated or measured CrCl less than 40 ml/min.  
 
Agent 
-2 Level 
-1 Level 
Starting Dose Level 
Carboplatin 
Off study treatment 
AUC 4 
AUC 5 
Paclitaxel 
110 mg/m2 
135 mg/m2 
175 mg/m2 
Bevacizumab 
Off study treatment 
15 mg/kg 
15 mg/kg 
Docetaxel * 
55  mg/m2 
65  mg/m2 
75  mg/m2 

 
 
GOG-0213 
 
58 
 
6.164 
Proteinuria:(06/22/09) Patients receiving bevacizumab should be 
monitored by  urine analysis for urine protein: creatinine (UPC) 
ratio prior to every other dose of bevacizumab. 
 
 
UPC ratio ≤ 3.5 (CTCAE, v4.0 Grade 0-2) Continue bevacizumab. 
 
UPC ratio > 3.5 hold bevacizumab until UPC ratio recovers to 
≤3.5.  If bevacizumab is held for > 3 weeks, the patient is removed 
from study. Grade 4 or nephrotic syndrome: Patient is removed 
from study. 
 
* Please note chemotherapy may be administered if 
bevacizumab is held for Grade 3 proteinuria. 
 
6.165   Hepatic toxicity: Hepatic toxicity is not expected as a direct 
complication of chemotherapy in this population using the 
prescribed dose and schedule for each regimen.  However, the 
development of grade 3 (or greater) elevations in SGOT (AST), 
alkaline phosphatase or bilirubin requires reduction of one dose 
level in all study drugs with the exception of carboplatin and delay 
in subsequent therapy for a maximum of 3 weeks until recovered 
to grade 1.  If therapy is held for > 3 weeks the patient is removed 
from study. 
 
6.166   There will be no dose modifications for alopecia.  
 
6.167 Hypersensitivity reaction to paclitaxel or bevacizumab: The 
occurrence of a hypersensitivity reaction to paclitaxel or 
bevacizumab is not considered a dose-limiting toxicity.  Patients 
may be retreated at full doses after administration of medication 
(such as decadron 20 mg IV and diphenhydramine 50 mg IV 30 
minutes prior to reinfusion) to prevent hypersensitivity reaction 
and may utilize a slow initial infusion rate of the suspected agent 
which is gradually increased to the standard infusion rate in the 
absence of reaction (such as 1 cc of the original IV solution diluted 
in 100 ml over 10 minutes, then 5 cc in 100 ml over 10 minutes 
then 10 cc in 100 ml over 10 minutes and finally, the original 
solution at the original speed).  However, if despite these safety 
measures repeat attempt at infusion of the inciting drug results in a 
recurrent hypersensitivity reaction, the inciting drug should be 
discontinued for the remainder of the study. In the event of any 
CTCAE Grade 3 or 4 allergic or infusional reactions to 
bevacizumab, the patient is removed from study. In the event of 
recurrent hypersensitivity reaction to paclitaxel, docetaxel should 
be substituted for paclitaxel, according to guidelines in Sections 
5.233 and 6.161. 
 

 
 
GOG-0213 
 
59 
 
Hypersensitivity reaction to carboplatin: The occurrence of a 
hypersensitivity reaction to carboplatin may occur in this 
previously treated population.  Successful retreatment has been 
reported with a modified dilution and infusion schedule.45,46 A 
suggested desensitization protocol that may be used in patients 
with a carboplatin hypersensitivity is reduced infusion dose of 
1:1000 dilution (0.1cc in 100 ml) over 1 hour, followed by a 1:100 
dilution (1.0 cc in 100 ml) over 1 hour, followed by a 1:10 dilution 
(10 cc in 100 ml) over 1 hour, followed by 1:1 concentration for 
the remaining infusion. Patients experiencing a significant 
hypersensitivity reaction to carboplatin may be removed at the 
discretion of the treating physician if it is felt to be unsafe to offer 
a desensitization program.(08/29/11) 
 
6.168 Hypertension:  Patients receiving bevacizumab should be 
monitored prior to each dose with measurement of blood pressure.  
Medication classes used for management of patients with Grade 3 
hypertension receiving bevacizumab included ACE inhibitors, 
Beta blockers, diuretics, and calcium channel blockers.   
 
• For controlled hypertension, defined as systolic ≤ 150 mm Hg 
and diastolic ≤ 90 mmHg, continue therapy; 
 
• For uncontrolled hypertension (systolic > 150 mm Hg or 
diastolic > 90) or symptomatic hypertension less than CTCAE 
V4.0 Grade 4, hold all therapy (carboplatin, paclitaxel, and 
bevacizumab) for one week with anti-hypertensive therapy 
initiated or continued. (03/15/10) 
 
• If hypertension is controlled and symptomatic hypertension has 
resolved by three weeks after holding treatment, continue all 
therapy.   
 
• If hypertension remains uncontrolled or symptomatic 
hypertension, less than CTCAE V4.0 Grade 4, persists after 
three weeks after holding treatment, the patient is removed 
from study. 
 
• Any patient developing CTCAE V4.0 Grade 4 hypertension 
will be removed from study. 
 
 
6.169 Wound disruption: Patients will be removed from study in the 
event of a wound disruption requiring medical or surgical 
intervention.   

 
 
GOG-0213 
 
60 
 
 
 
 
 
6.1610Bowel perforation/obstruction/fistula/GI leak: For new 
development of bowel perforation, bowel obstruction (partial or 
complete), fistula, or GI leak (any grade); the patient will be taken 
off study treatment. 
 
6.1611 Potential modifications for other non-hematologic toxicities with 
an impact on organ function of Grade 2 (or greater) require 
discussion with one of the study co-chairs. 
 
           6.1612 Weight loss: If a patient’s weight changes by ≥ 10% during the 
course of the study, the doses of paclitaxel (or docetaxel) and 
bevacizumab will be recalculated.  For patients undergoing the 
second surgical procedure the baseline weight for calculating the 
carboplatin and bevacizumab should be the patient’s postoperative 
weight. (08/04/08) 
 
6.1613  RPLS (Reversible Posterior Leukoencephalopathy Syndrome) 
or PRES (Posterior Reversible Encephalopathy Syndrome): 
Hold bevacizumab in patients with symptoms/ signs suggestion of 
RPLS/ PRES; subsequent management should include MRI scans 
and control of HTN. Discontinue bevacizumab upon diagnosis of 
RPLS/ PRES unless the patient meets the criteria below. 
(03/15/10) 
 
Note:  (06/22/09) 
• Resumption of bevacizumab may be considered in patients 
who have documented benefit from the agent, provided that 
RPLS was mild and has completely resolved clinically and 
radiographically within 2-4 weeks; decision to resume 
bevacizumab in these patients must be discussed with the 
study chair and approved by the sponsor.  
• Chemotherapy may continue if the patient is considered 
medically stable for infusion. 
 
6.17 
No dose-escalations are allowed on this study. 
 
6.18 
Dose modifications for Gemcitabine/carboplatin (Arms V, VI, VII, 
VIII) (10/01/12) 
 
 
 
6.181Carboplatin and Gemcitabine (Day1) 
Carboplatin and gemcitabine dosing on Day 1 of each cycle should 

 
 
GOG-0213 
 
61 
 
be held if ANC is <1500/μL, Hgb is <8.5 g/dL, or platelets are 
<100,000/μL within 24 hours of the scheduled treatment. The 
chemotherapy can be delayed for a maximum of 3 weeks until 
these values are achieved. Patients who fail to recover adequate 
counts(with or without growth factors) within the 3 weeks will no 
longer receive protocol- defined chemotherapy but will enter into 
the maintenance phase to receive the study drug (bevacizumab or 
observation) alone. Study drug can be held for up to 3 weeks if 
carboplatin and gemcitabine are held in order to allow for same-
day administration of carboplatin and gemcitabine and study drug 
(if chosen). 
Dose adjustment for gemcitabine in combination with carboplatin 
for subsequent cycles is based on toxicity observed during the 
preceding cycle. The dose of gemcitabine should be permanently 
reduced to the 800 mg/m2 on Days 1 and 8, in case of any of the 
following hematologic toxicities: 
• 
Absolute granulocyte count <500 x 106/L for more than 5 
days  
• 
Absolute granulocyte count <100 x 106/L for more than 3 
days  
• 
Febrile neutropenia  
• 
Platelets <25,000 x 106/L  
• 
Cycle delay of more than one week due to toxicity  If any 
of the above toxicities recur after the initial dose reduction 
for the subsequent cycles, gemcitabine should be given 
only on day 1 at 800 mg/m2 (omit gemcitabine on Day 8).  
6.182 Gemcitabine Dose Modification within a Treatment Cycle (Day 
8)   
Gemcitabine dosage adjustments for hematologic toxicity within a 
cycle of treatment is based on the granulocyte and platelet counts 
taken on Day 8 of therapy, as shown in the Table. 
TABLE: Day 8, Gemcitabine Dose Modification for Hematological Toxicity   
 
Absolute granulocyte count (/mm3) 
 
Platelet count (/mm3) 
Gemcitabine Dose 
≥ 1500 
and 
≥100,000 
100% D1 dose 

 
 
GOG-0213 
 
62 
 
1000−1499 
and/or 
75,000−99,999 
50% D1 dose 
<1000 
and/or 
<75,000 
Omit D8 dose 
If a patient experiences an HSR, platinum desensitization may be 
allowed after discussion with the Study Chair. For any other dose 
modifications for non-hematologic toxicity, please follow 
institutional practice and prescribing information (also outlined in 
Section 6.16). In general, for severe (Grade 3 or 4) non-
hematological toxicities, except nausea/vomiting, therapy with 
gemcitabine should be held or decreased by 50% depending on the 
judgment of the treating physician.  Patients who require 
discontinuation of either carboplatin or gemcitabine due to toxicity 
should continue receiving study drug with the non-discontinued 
chemotherapy to complete 6 cycles (7−10 cycles if deemed 
necessary by the investigator and approved by the Study Chair). 
Patients requiring discontinuation of both carboplatin and 
gemcitabine prior to disease progression should continue single-
agent study drug until disease progression or unacceptable toxicity, 
as determined by the investigator. 
 

 
 
GOG-0213 
 
63 
 
7.0 
STUDY PARAMETERS 
 
7.1 
Observations and Tests(08/04/08) (06/22/09)(03/15/10)(10/01/12) 
 
The following observations and tests are to be performed and recorded on the 
appropriate form(s). See Section 7.2 for the stained pathology slide 
requirements to confirm eligibility for GOG-0213 and Section 7.31 for the 
specimen requirements for translational research.     
 
 
Pre-Treatment 
During Chemotherapy Phase During Maintenance/Surveillance  
Phase (Patients on Arm II, IV, 
VI, and VIII only) 
 
 
Observations and Tests 
 
Prior to 
Surgery 
 
 
Prior to 
chemo- 
therapy  
 
 
Weekly 
Prior to 
Each 
Course 
(q 3 wks) 
Prior to 
Every 
Other 
Course 
(q 6 weeks) 
Prior to 
Every 
Course 
(q 3 wks) 
Prior to Every 
Other Course  
(q 6 weeks) 
Q 3 
Months x 
8 then q 6 
Months 
All 
Patients 
History & Physical 
1 
1 
 
X 
 
 
X 
 
Blood pressure* 
1 
1 
2 
X 
 
X 
X 
 
Toxicity Assessment 
 
 
 
X 
 
 
X 
 
CBC/Differential/ 
Platelets 
3 
3 
X 
4 
 
4 
 
 
Urine pregnancy test in 
women of child-bearing 
potential 
3 
 
 
 
 
 
 
 
Urine Protein-Creatinine 
Ratio (UPCR)* 
3,5 
3, 5 
 
 
6 
 
6 
 
Serum Creatinine 
3 
3 
 
4 
 
 
4 
 
Bilirubin, SGOT/AST,  
Alkaline Phosphatase 
3 
3 
 
4 
 
 
4 
 
Ca/PO4/Mg 
 
3 
 
7 
 
 
7 
 
Serum CA-125 Level 
1 
1 
 
4,13 
 
 
4,13 
13 
PT/PT INR/PTT* 
3 
3 
 
8 
 
 
8 
 
Audiogram 
 
9 
 
 
 
 
 
 
EKG 
1 
1 
 
 
 
 
 
 
Radiographic Tumor 
Measurement 
1,10 
1, 10 
 
 
See 
footnote 
11c),d) 
 
 
11 
Chest X-Ray 
1,12 
1, 12 
 
 
 
 
 
 
QOL Survey 
X,14 
X, 14 
 
 
14 
 
14 
14 
Incision Check* 
 
X 
15 
 
 
 
 
 
 
 
* Required only for patients who were enrolled prior to August 29, 2011 as well as those enrolled after 
this date electing to receive bevacizumab. 
 
1.  Must be obtained within 28 days of first treatment.  For those patients randomized to cytoreductive surgery, these 
observations are repeated prior to initiating chemotherapy.  

 
 
GOG-0213 
 
64 
 
2.  Blood pressure should be assessed at least weekly during the first cycle of bevacizumab therapy. During the time 
between treatments, blood pressure assessment may be done at home by the patient at the investigator’s discretion. 
3.  Must be obtained within 14 days prior to registration. For patients randomized to cytoreductive surgery, these 
observations are repeated within 14 days prior to initiating chemotherapy. (06/22/09) 
4. Must be obtained within 4 days of re-treatment with protocol therapy. 
5.  Urine protein should be assessed by UPCR (see Section 3.37 for details). Patients must have a UPCR < 1.0 to allow 
participation in the study. 
6. Patients receiving bevacizumab should be monitored by urine analysis for urine protein: creatinine (UPC) ratio 
prior to every other dose of bevacizumab. 
7.  When clinically indicated. 
8.  For patients on prophylactic or therapeutic anticoagulation, PT INR should be monitored before each treatment.  
Treatment should be held for PT INR of > 1.5 on prophylactic warfarin or > therapeutic range if on full-dose warfarin. 
9.  For patients with a history of hearing loss; repeat as clinically indicated. 
10.  An initial CT scan (with intravenous and oral contrast, unless contraindicated) or MRI (with gadolinium, unless 
contraindicated and fat suppression sequence) of at least the abdomen and pelvis is required to establish post-surgical 
baseline for the extent of residual disease within28 days prior to initiating chemotherapy.(06/22/09) PET-CT imaging 
alone cannot be used to establish extent of post-operative disease residuum unless also performed with CT or MRI as 
described. 
11. Follow-Up Radiographic Assessment of Disease (in patients with measurable and non-measurable disease). Imaging 
should use the same modality and encompass the same fields as in the initial pre-treatment evaluation should be 
repeated with the following schedule:  
 
a) Within 28 days of first treatment. 
 
b) If the patient was randomized to cytoreductive surgery, then repeat radiographic assessment within 14 days of 
initiating chemotherapy. 
 
c) After cycle 3 (before cycle 4) of study treatment(06/22/09) 
 
d) After cycle 6 of study treatment (06/22/09) 
 
e) After cycle 8 of study treatment (03/15/10) 
 
f) Every three months for two years and then every 6 months after completion of chemotherapy during the 
maintenance/surveillance phase.  
 
Imaging assessments as part of this protocol can be discontinued if disease progression is confirmed according to 
guidelines in section 8.14 and 8.15..  However, if disease progression is based only on rising CA-125 criteria, then 
radiographic imaging must be obtained within two weeks following the date CA-125 based progression was 
documented.(08/29/11) 
12.  Not required if CT or MRI of chest already performed at pre-treatment baseline. 
13.  Progression can be based upon serum CA-125, if one of the three conditions are met: 1. Patients with elevated CA-125 
pretreatment and normalization of CA-125 must show evidence of CA-125 greater than or equal to two times the 
upper normal limit on two occasions at least one week apart or 2. Patients with elevated CA-125 pretreatment, which 
never normalizes must show evidence of CA-125 greater than or equal to two times the nadir value on two occasions 
at least one week apart or 3. Patients with CA-125 in the normal range pretreatment must show evidence of CA-125 
greater than or equal to two times the upper normal limit on two occasions at least one week apart. When disease 
progression is defined by CA-125 criteria alone, imaging using the same modality and encompassing the same field as 
in the initial pre-treatment evaluation should be obtained within 2 weeks that such progression is documented (see 
Section 7.1).If the patient does not meet criteria for disease progression on the basis of CA-125 elevations, then CA-
125 monitoring should be continued according to schedule.  (06/22/09) 
14.  See Section 7.3.  QOL surveys are to be assessed for at most 6 time points: 
 
 
a) prior to surgery (for those randomized to cytoreductive surgery). 
 
 
b) prior to initiating chemotherapy. 
 
 
c) prior to cycle 3 (6 weeks after starting chemotherapy). 
 
 
d) prior to cycle 6 (15 weeks after staring chemotherapy). 
 
 
e) 6 months after starting chemotherapy. 
 
 
f) 12 months after starting chemotherapy.  
15. Patients with granulating incisions healing by secondary intention with no evidence of fascial dehiscence or 
infection may initiate therapy, but require weekly wound examinations until complete closure.  Any occurrence 
of fascial dehiscence or deterioration related to the incision should be addressed according to guidelines for 
treatment modification in Section 6.1512 and Adverse Events reporting in Section 10.3. 
 

 
 
GOG-0213 
 
65 
 
 
7.2 
Stained Pathology Slide Requirements for Central Review to Confirm Protocol 
Eligibility (06/22/09) 
 
Stained pathology slides are required for central review by the GOG Pathology 
Committee to confirm eligibility for the protocol.  At least one representative 
H&E stained slide (or slides) demonstrating primary site, histologic cell type, and 
grade, and one H&E stained slide showing the most advanced stage of disease 
will be required.  If the most advanced stage of disease is not documented by 
histology, the method of stage documentation needs to be stated (e.g. CT, MRI, 
etc.).  If this protocol allows patients with recurrent or persistent disease, slides 
from recurrence and/or persistent disease will be required only if 
recurrence/persistent disease is confirmed by histology or cytology. 
 
When submitting pathology material to the GOG Statistical and Data Center 
individual slides must be labeled with GOG Patient ID, patient initials and the 
surgical / pathology accession number (e.g., S08-2355) and block identifier (e.g., 
A6).  Do not label the slides with disease site (e.g., right ovary) or procedure 
date.   
 
Pack the labeled slides into plastic slide cassette(s).  Tape plastic slide cassettes 
shut and wrap in bubble wrap or another type of padded material prior to 
shipping.  Please include the GOG Patient ID, patient initials, and protocol 
number on all pages of the pathology report and black out the patient’s 
name.  Ship pathology slides, three copies of both the Pathology Form F (if 
required for the protocol) and the official pathology report in your own shipping 
containing using postal mail at your own expense directly to the Pathology 
Materials Coordinator at the GOG Statistical and Data Center, Roswell Park 
Cancer Institute, Research Studies Center, Carlton and Elm Streets, Buffalo, 
New York, 14263; phone (716) 845-5702.  The GOG Upload Application in 
SEDES is an alternative method for submitting stained slides, pathology reports 
and Form F to the GOG Statistical and Data Center.  Please see section 4.6 and 
10.2 for additional requirements and instructions.   
 
7.3 
Translational Research  
 
Note: Testing of banked samples will not occur until an amendment to this 
treatment protocol (or separate correlative science protocol) is reviewed and 
approved in accordance with National Clinical Trials Network (NCTN) policies. 
 
7.31 
Specimen Requirements (08/04/08) (06/22/09) (03/09/15) 
 
If the patient gives permission for her specimens to be collected and used 
for this optional translational research component, then participating 
institutions within the United States are required to submit the patient’s 
specimens as outlined below (unless otherwise specified). 

 
 
GOG-0213 
 
66 
 
 
Required Specimen (Specimen Code) 
Collection Time Point 
Sites Ship Specimens to 
ALL PATIENTS 
Whole Blood (WB01) 
7-10mL drawn into purple top (EDTA) tube(s) 
Prior to or after starting study 
treatment 
GOG Tissue Bank within 
26 weeks of registration2 
SURGICAL ARM PATIENTS ONLY 
FFPE Primary or Metastatic Tumor (FT01)* 
1st Choice: Block 
2nd Choice: 16 unstained slides (charged, 5µm) 
Prior to all treatment 
GOG Tissue Bank within 8 
weeks of registration2 
Pre-Op Serum (SB01) 
Prepared from 7-10mL of blood drawn into 
plain red top tube(s) 
Optional - Prior to secondary 
cytoreductive surgery 
GOG Tissue Bank within 1 
week of surgery2 
Pre-Op Plasma (PB01) 
Prepared from 7-10mL of blood drawn into 
purple top (EDTA) tube(s) 
FFPE Recurrent Tumor (FR01)* 
1st Choice: Block 
2nd Choice: 16 unstained slides (charged, 5µm) 
At time of secondary 
cytoreductive surgery 
Snap Frozen Recurrent Tumor (RR01)* 
At least 0.2g in foil 
FFPE Normal Tissue (FN01)* 
1st Choice: Block 
2nd Choice: 16 unstained slides 5um thick 
Optional - At time of secondary 
cytoreductive surgery 
Snap Frozen Normal Tissue (RN01)* 
At least 0.2g in foil 
* 
A copy of the corresponding pathology report must be shipped with all tissue specimens (tumor and normal) sent to the 
GOG Tissue Bank. 
2 
GOG Tissue Bank / Protocol GOG-0213 Nationwide Children’s Hospital, 700 Children’s Drive, WA1340, Columbus, 
OH 43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: GOGBank@nationwidechildrens.org 
 
 
7.3.2 
Laboratory Testing (03/09/15) 
 
7.3.2.1 Creation of Tissue Microarrays (TMAs) 
 
A series of TMAs to study biomarkers of recurrence, survival, 
and/or treatment response/resistance will be created.  The specific 
types of TMAs that will be created will depend on FFPE block 
submissions and the clinical outcomes observed for these cases. 
 
Unstained sections from TMAs (or conventional blocks for cases 
not represented on the TMAs) will be distributed to Dr. Michael 
Birrer and/or other investigators approved by the GOG Committee 
on Experimental Medicine (CEM) for biomarker, genomic, 
proteomic, and/or SNP analyses.   
 
7.3.2.2 Light Microscopy 
 
Light microscopy will be done to characterize the histopathologic 
features of tissue specimens undergoing molecular and 
biochemical profiling and to satisfy some of the specimen selection 

 
 
GOG-0213 
 
67 
 
criteria for gene expression profiling. Stained sections will be 
reviewed by Dr. William Rodgers, chair of the GOG Pathology 
Committee, and other members of the committee. 
 
7.3.2.3 Biomarker Analysis 
 
Multiple types of biomarker analyses (e.g., immunohistochemistry 
(IHC), reverse phase array, conventional immunoblot assays, 
quantitative RT-PCR) will be done to expand the current 
understanding of the biology, progression, metastasis, and 
responsiveness of recurrent ovarian and peritoneal primary cancer. 
 
IHC will be done using sections from conventional blocks and/or 
TMAs by Dr. Michael Birrer, the GOG Receptors and Targets 
Core Laboratory, and/or other CEM-approved investigators.  
 
Reverse phase array and conventional immunoblot analyses will be 
done using lysates from frozen recurrent tumor, microdissected 
recurrent tumor cells, and normal tissue. 
 
Quantitative RT-PCR will be done to identify and/or validate 
prognostic or predictive markers of recurrence, survival, and 
treatment response/resistance. In addition, these assays will be 
used to validate individual markers identified in gene expression 
microarray studies.  
 
7.3.2.4 Genomic Profiling 
 
Gene expression microarray analysis will be done using RNA 
isolated from frozen recurrent tumor and normal tissue and an 
appropriate platform to define gene expression patterns associated 
with disease progression, spread of disease, response to treatment, 
and/or patient outcome. These studies will be done by Dr. Michael 
Birrer and/or other CEM-approved investigators.   
 
7.3.2.5 Proteomic Profiling 
 
Proteomic profiling will be done using pre-op serum to define 
protein/peptide fragment patterns that are associated with disease 
progression, spread of disease, and response to treatment or patient 
outcome. Proteomic studies will be done by CEM-approved 
investigators.  
 
7.3.2.6 SNP Analysis 
 

 
 
GOG-0213 
 
68 
 
Whole blood will be shipped to the GOG Tissue Bank for 
immediate processing, extraction of DNA, and Q/C. DNA will be 
shipped to Dr. Michael Birrer and/or other CEM-approved 
investigators for whole genome SNP association studies and/or 
evaluation of individual SNPs.  
 
7.3.3 Future Research (03/09/15) 
 
Details regarding the banking and use of translational research specimens 
for future research can be found in Appendix III.   
 
7.4 
Quality of Life: (08/04/08) 
 
7.41 
Patients in the secondary cytoreduction arm will complete the quality of 
life questionnaire packet (which includes the FACT-O and the RAND SF-
36 physical functioning questionnaire) before surgery and before the first 
cycle of chemotherapy.  The FACT-O is available in Spanish and French.  
Requests should be submitted to the GOG Statistical and Data Center. 
Patients in the no surgery arm will complete the quality of life 
questionnaire packet before the first cycle of chemotherapy.  Follow-up 
questionnaires will be completed prior to beginning of the third cycle 
(approximately six weeks from the start of treatment) and prior to 
beginning of the sixth cycle (or approximately 15 weeks from the start of 
treatment).   Additional quality of life assessments will be done at six and 
twelve months after initiating chemotherapy.   If a patient progresses or is 
removed from the study treatment, continue to follow the schedule of 
QOL assessments when possible regardless of subsequent treatments.  
Whenever possible, QOL questionnaires should be administered at the 
clinic visit before the patient is seen by the physician and before 
evaluations (e.g., results of CA-125 or scans) are shared with her.  In the 
event that the questionnaires are not administered at the clinic visit, the 
QOL data can be collected by telephone or mail as back-up methods, with 
telephone data collection being the preferred back-up method.  
 
7.42 
The Quality of Life Liaison (Nurse\Data Manager) at each institution has 
overall responsibility for the administration of the study questionnaire. 
 
7.43 
The Nurse\Data Manager should read the instructions printed on the 
questionnaire to the patient and ensure the patient understands the 
instructions. It is important to assure the patient that all material on the 
questionnaire is confidential and will not be shared with the health care 
team and that it will not become part of the medical record.  
 
7.44 
Assistance in reading the questionnaire is permitted if the patient is unable 
to complete the questionnaire on her own (e.g., difficulty in reading, 

 
 
GOG-0213 
 
69 
 
elderly). It is important not to influence the response of the patient. Note 
why the patient required assistance and what assistance was given.  
 
7.45 
Patients should be instructed to answer all the questions regardless of 
whether the symptoms or conditions asked about are related to cancer or 
cancer treatment. Discourage family members from being present during 
questionnaire completion or from influencing patient’s response.  
 
7.46 
Review the questionnaire for completeness before the patient leaves.  
 
7.47 
If the patient has marked more than one answer per question, ask the 
patient which answer best reflects how she is feeling.  
 
7.48 
If the patient has skipped a question or questions, assure that she noted in 
the space provided that she has chosen not to answer those questions.  
 
7.49 
It is essential that questionnaires be completed according to the schedule 
described in Section 7.1.  
 
7.410 If the patient refuses or cannot complete the questionnaire at any time 
point, she should be asked to do so at the next scheduled administration 
time.  
 
7.411 The patient may withdraw from the quality of life section of the protocol 
for any reason. The reason must be documented on the form.  
 
7.412 The Quality of Life Liaison may attend a training session held at a 
biannual GOG meeting. 
 
 

 
 
GOG-0213 
 
70 
 
8.0  
EVALUATION CRITERIA 
 
8.1  
Parameters of Response – GOG RECIST Criteria 
 
8.11  Measurable disease is defined as at least one lesion that can be accurately 
measured in at least one dimension (longest dimension to be recorded).  
Each lesion must be ≥ 20 mm when measured by conventional techniques, 
including palpation, plain x-ray, CT, and MRI, or ≥ 10 mm when 
measured by spiral CT.   
 
8.12  Baseline documentation of “Target” and “Non-Target” lesions 
 
All measurable lesions up to a maximum of 5 lesions per organ and 10 
lesions in total representative of all involved organs should be identified as 
target lesions and will be recorded and measured at baseline.  Target 
lesions should be selected on the basis of their size (lesions with the 
longest dimension) and their suitability for accurate repetitive 
measurements by one consistent method of assessment (either by imaging 
techniques or clinically).  A sum of the longest dimension (LD) for all 
target lesions will be calculated and reported as the baseline sum LD.  The 
baseline sum LD will be used as reference to further characterize the 
objective tumor response of the measurable dimension of the disease. 
 
All other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not 
required and these lesions should be followed as “present” or “absent”. 
 
All baseline evaluations of disease status should be performed as close as 
possible to the start of treatment and never more than 4 weeks before the 
beginning of treatment. 
 
8.13  Best Response 
 
Measurement of the longest dimension of each lesion size is required for 
follow-up.  Change in the sum of these dimensions affords some estimate 
of change in tumor size and hence therapeutic efficacy.  All disease must 
be assessed using the same technique as baseline. Reporting of these 
changes in an individual case should be in terms of the best response 
achieved by that case since entering the study.    
 
8.131 Complete Response (CR) is disappearance of all target and non-
target lesions and no evidence of new lesions documented by two 
disease assessments at least 4 weeks apart.  Normalization of 
CA125, if elevated at baseline, is required for ovarian carcinoma 
studies. 
 

 
 
GOG-0213 
 
71 
 
8.132 Partial Response (PR) is at least a 30% decrease in the sum of 
longest dimensions (LD) of all target measurable lesions taking as 
reference the baseline sum of LD.  There can be no unequivocal 
progression of non-target lesions and no new lesions.  
Documentation by two disease assessments at least 4 weeks apart 
is required.  In the case where the ONLY target lesion is a solitary 
pelvic mass measured by physical exam, which is not 
radiographically measurable, a 50% decrease in the LD is required. 
 
8.133  Increasing Disease is at least a 20% increase in the sum of LD of 
target lesions taking as references the smallest sum LD or the 
appearance of new lesions within 8 weeks of study entry.  
Unequivocal progression of existing non-target lesions, other than 
pleural effusions without cytological proof of neoplastic origin, in 
the opinion of the treating physician within 8 weeks of study entry 
is also considered increasing disease (in this circumstance an 
explanation must be provided).  In the case where the ONLY target 
lesion is a solitary pelvic mass measured by physical exam, which 
is not radiographically measurable, a 50% increase in the LD is 
required. 
 
8.134  Symptomatic deterioration is defined as a global deterioration in 
health status attributable to the disease requiring a change in 
therapy without objective evidence of progression. 
 
8.135  Stable Disease is any condition not meeting the above criteria. 
 
8.136 Inevaluable for response is defined as having no repeat tumor 
assessments following initiation of study therapy for reasons 
unrelated to symptoms or signs of disease.   
 
8.14  Progression (measurable disease studies) is defined as ANY of the 
following: 
• 
At least a 20% increase in the sum of LD target lesions taking as 
reference the smallest sum LD recorded since study entry  
• 
In the case where the ONLY target lesion is a solitary pelvic mass 
measured by physical exam which is not radiographically measurable, 
a 50% increase in the LD is required taking as reference the smallest 
LD recorded since study entry 
• 
The appearance of one or more new lesions   
• 
Death due to disease without prior objective documentation of 
progression 
• 
Global deterioration in health status attributable to the disease 
requiring a change in therapy without objective evidence of 
progression  

 
 
GOG-0213 
 
72 
 
• 
Unequivocal progression of existing non-target lesions, other than 
pleural effusions without cytological proof of neoplastic origin, in the 
opinion of the treating physician (in this circumstance an explanation 
must be provided) (06/22/09) 
• 
Progression based on serum CA-125:  
° 
Patients with elevated CA-125 pretreatment with normalization 
of CA-125 must show evidence of CA-125 during study 
treatment greater than or equal to two times the upper normal 
limit on two occasions at least one week apart  
 - or - 
° 
Patients with elevated CA-125 pretreatment, which never 
normalized during study treatment must show evidence of CA-
125 greater than or equal to two times the nadir value on two 
occasions at least one week apart  
 
 
 
 
 
-  or - 
° 
Patients with CA-125 in the normal range must show evidence 
of CA-125 greater than or equal to two times the upper normal 
limit on two occasions at least one week apart 
 
 
When disease progression is defined by CA-125 criteria alone, 
imaging using the same modality and encompassing the same 
field as in the initial pretreatment evaluation should be 
obtained within 2 weeks that such progression is documented 
(see Section 7.1).  If the disease progression is noted on 
imaging, then the date of progression will be the date of the 
imaging studies.  Otherwise, the date of progression will be the 
date of the first CA-125 level that indicates 
progression.(08/23/10) 
 
Progression (non-measurable disease) is defined as ANY of the following: 
• Appearance of any new clinical, radiological or histological evidence 
of disease since study entry  
• Global deterioration in health status attributable to the disease 
requiring a change in therapy without objective evidence of recurrence 
• Death due to disease without prior objective documentation of 
recurrence 
• 
Progression based on serum CA-125:  
° 
Patients with elevated CA-125 pretreatment with normalization 
of CA-125 must show evidence of CA-125 during study 
treatment greater than or equal to two times the upper normal 
limit on two occasions at least one week apart  
 - or - 
° 
Patients with elevated CA-125 pretreatment, which never 
normalized during study treatment must show evidence of CA-
125 greater than or equal to two times the nadir value on two 
occasions at least one week apart  

 
 
GOG-0213 
 
73 
 
 
 
 
 
 
-  or - 
° 
Patients with CA-125 in the normal range must show evidence 
of CA-125 greater than or equal to two times the upper normal 
limit on two occasions at least one week apart 
 
 
When disease progression is defined by CA-125 criteria alone, 
imaging using the same modality and encompassing the same 
field as in the initial pretreatment evaluation should be 
obtained within 2 weeks that such progression is documented 
(see Section 7.1).  If the disease progression is noted on 
imaging, then the date of progression will be the date of the 
imaging studies.  Otherwise, the date of progression will be the 
date of the first CA-125 level that indicates 
progression.(08/23/10) 
 
8.15 
Recurrence (following CR) is defined as ANY of the following: 
• Appearance of any new clinical, radiological or histological evidence 
of disease since study entry  
• Global deterioration in health status attributable to the disease 
requiring a change in therapy without objective evidence of recurrence 
• Death due to disease without prior objective documentation of 
recurrence 
• 
Increase in serum CA-125 levels as follows:  
° 
Patients with CA-125 in the normal range must show evidence 
of CA-125 greater than or equal to two times the upper normal 
limit on two occasions at least one week apart. When disease 
progression is defined by CA-125 criteria alone, imaging using 
the same modality and encompassing the same field as in the 
initial pretreatment evaluation should be obtained within 2 
weeks that such progression is documented (see Section 7.1).  
If the disease progression is noted on imaging, then the date of 
progression will be the date of the imaging studies.  Otherwise, 
the date of progression will be the date of the first CA-125 
level that indicates progression. (08/23/10) 
 
8.16 
Survival is the observed length of life from entry into the study to death or 
the date of last contact. 
 
8.17  Progression-Free Survival (measurable disease studies) is the period from 
study entry until disease progression, death or date of last contact. 
 
8.18  Recurrence-Free Survival (non-measurable disease studies) is the period 
from study entry until disease recurrence, death or date of last contact. 
 
8.19  Subjective Parameters including performance status, specific symptoms, 
and side effects are graded according to the CTCAE v4.0. 

 
 
GOG-0213 
 
74 
 
9.0  
DURATION OF STUDY 
 
9.1 
Patients will remain on the designated study regimen until disease progression or 
toxicity precludes further treatment or the patient refuses study treatment.   
 
9.2 
All patients will be followed (with completion of all required case report forms) 
until disease progression, or the patient withdraws consent. In addition, following 
disease progression, patients will be monitored for delayed toxicity and survival 
for a period of 10 years with Q forms submitted to the GOG Statistical and Data 
Center, unless patient’s consent is withdrawn. 
10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
 
10.1 
ADVERSE EVENT REPORTING FOR A TRIAL EVALUATING A 
SURGICAL PROCEDURE (09/29/14) 
 
10.11 Definition of Adverse Events (AE) 
 
An adverse event (AE) is any unfavorable and unintended sign, symptom, 
or disease that occurs in a patient administered a pharmaceutical product 
or protocol procedure, whether the event is considered related or unrelated 
to the study treatment. 
 
 
10.12 Reporting Expedited Adverse Events 
 
All CTCAE v5.0 expedited AEs must be reported to the GOG.  All 
expedited AE reports should be submitted by using the CTEP Adverse 
Event Reporting System (CTEP-AERS).  Submitting a report through 
CTEP-AERS serves as notification to GOG, and satisfies the GOG 
requirements for expedited AE reporting.   
 
10.13 Expedited Reporting of Adverse Events occurring within 30 Days of the 
Study Procedure 
 
The following table summarizes the GOG requirements for expedited 
reporting of AEs that occur within 30 days of the surgical procedure. 
 
Reporting Requirements for Adverse Events that occur within 30 Days¹ of 
the Study Procedure: 
 
From the period of protocol activation through September 30, 2011, 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 
(CTCAE v3.0) are utilized for defining and grading specific adverse 
events reported through the CTEP-AERS system. (09/26/11) 
 
Beginning October 1, 2011, the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) v 4.0 will be utilized for AE reporting through 

 
 
GOG-0213 
 
75 
 
the CTEP-AERS system. CTCAE v 4.0 is located on the CTEP website at 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.h
tm.  All appropriate treatment areas should have access to a copy of this 
Version of CTCAE.  CTCAE v 4.0 definition is also available on the GOG 
member web site (https://gogmember.gog.org under MANUALS). 
(09/26/11) 
 
The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for AE reporting beginning April 1, 2018.  All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0.  
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.ht
m. 
 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
• Expedited AE reporting timelines defined: 
“7 calendar days” – A complete CTEP-AERS report on the AE must be submitted 
within 7 calendar days of the investigator learning of the event. 
 
• Any medical event equivalent to CTCAE grades 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected  
and Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected  Expected 
With  
Hospitali-
zation 
Without 
Hospitali- 
zation 
With  
Hospitali- 
zation 
Without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not Required 
Not 
Required 
7 Days 
Not Required 
7 Days 
Not 
Required 
7 Days 
7 Days 
Possible 
Probable 
Definite 
Not 
Required 
Not Required 
Not 
Required 
7 Days 
Not Required 
7 Days 
Not 
Required 
7 Days 
7 Days 
1 
Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after surgery require 
reporting as follows: 
 
CTEP-AERS 7 calendar day report: 
• At least Grade 3 with hospitalization or prolongation of hospitalization, or 
• Persistent causes, significant disabilities/incapacities 
 
 
2 Grade 5:  All deaths within 30 days of the surgical procedure must be reported within 7 calendar days using expedited 
reporting regardless of causality. 
 
Please see exceptions below under the section entitled, “Additional Instructions or Exceptions to Expedited Reporting 
Requirements for Surgical Trials.” 
March 2005 

 
 
GOG-0213 
 
76 
 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse event 
reporting exclusions. 
 
• Any event that results in persistent or significant disabilities and/or incapacities 
must be reported via CTEP-AERS if the event occurs following a protocol 
procedure. 
 
• Use the NCI protocol number and the protocol-specific patient ID provided 
during trial registration on all reports.  
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Surgical Trials: 
 
• There are no additional instructions or exceptions to CTEP-AERS expedited 
reporting requirements for this protocol. 
 
10.14 Procedures for Expedited Adverse Event Reporting 
 
 
10.141 CTEP-AERS Expedited Reports: Expedited reports are to be submitted 
using CTEP-AERS available at http://ctep.cancer.gov. The CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements for expedited adverse 
event reporting requirements are also available at this site. 
 
Up until September 30, 2011, AML/MDS events must be reported via 
CTEP-AERS (in addition to your routine AE reporting mechanisms).  In 
CTCAE v3.0, the event can be reported as:  “Secondary malignancy-Other 
(specify)”. (09/26/11) 
 
Starting October 1, 2011 when use of CTCAE v4.0 begins: AML/MDS 
events must be reported via CTEP-AERS (in addition to your routine AE 
reporting mechanisms). In CTCAE v4.0, the event(s) may be reported as 
either: 1) Leukemia secondary to oncology chemotherapy, 2) 
Myelodysplastic syndrome, or 3) Treatment related secondary 
malignancy. (09/26/11) 
 
Starting April 1, 2018 when use of CTCAE v5.0 begins: AML/MDS 
events must be reported via CTEP-AERS (in addition to your routine AE 
reporting mechanisms). In CTCAE v5.0, the event(s) may be reported as 
either: 1) Leukemia secondary to oncology chemotherapy, 2) 
Myelodysplastic syndrome, or 3) Treatment related secondary 
malignancy. 
 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made to GOG by telephone at: 215-854-0770. An 
electronic report MUST be submitted immediately upon re-establishment 

 
 
GOG-0213 
 
77 
 
of internet connection. Please note that all paper CTEP-AERS forms have 
been removed from the CTEP website and will NO LONGER be accepted. 
 
 
10.2 
ADVERSE EVENT REPORTING FOR AN INVESTIGATIONAL AGENT (TO 
USE FOR PATIENTS WHO SELECT BEVACIZUMAB AFTER AUGUST 28, 
2011) (12/19/11) 
 
10.21 Definition of Adverse Events (AE) 
 
An adverse event (AE) is any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease that occurs in a 
patient administered a medical treatment, whether the event is considered 
related or unrelated to the medical treatment.  
 
10.22  Reporting Expedited Adverse Events 
 
Depending on the phase of the study, use of investigational agents, and 
role of the pharmaceutical sponsor, an expedited AE report may need to 
reach multiple destinations.  For patients participating on a GOG trial, all 
expedited AE reports should be submitted by using the CTEP automated 
system for expedited reporting (CTEP-AERS).  All CTEP-AERS 
submissions are reviewed by GOG before final submission to CTEP.  
Submitting a report through CTEP-AERS serves as notification to GOG, 
and satisfies the GOG requirements for expedited AE reporting.  All 
adverse reactions will be immediately directed to the Study Chair for 
further action. 
 
The requirement for timely reporting of AEs to the study sponsor is 
specified in the Statement of Investigator, Form FDA-1572.  In signing the 
FDA-1572, the investigator assumes the responsibility for reporting AEs 
to the NCI.  In compliance with FDA regulations, as contained in 21 CFR 
312.64, AEs should be reported by the investigator. 
 
10.23  Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND:  CTEP-AERS  
Expedited Reporting Requirements for Adverse Events That Occur Within 
30 Days of the Last Dose of the Investigational Agent 
 
Reporting Requirements for Adverse Events that occur within 30 Days¹ of 
the Last Dose of the Investigational Agent on Phase 2 and 3 Trials 
 
From the period of protocol activation through September 30, 2011, 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 
(CTCAE v3.0) are utilized for defining and grading specific adverse 
events reported through the CTEP-AERS system. (09/26/11) 
 

 
 
GOG-0213 
 
78 
 
Beginning October 1, 2011, the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) v 4.0 will be utilized for AE reporting through 
the CTEP-AERS system. CTCAE v 4.0 is located on the CTEP website at 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.h
tm.  All appropriate treatment areas should have access to a copy of this 
Version of CTCAE.  CTCAE v 4.0 definition is also available on the GOG 
member web site (https://gogmember.gog.org under MANUALS). 
(09/26/11) 
 
The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for AE reporting beginning April 1, 2018.  All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0.  
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.ht
m. 
 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected  
and Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected Expected 
With  
Hospitali-
zation 
Without 
Hospitali- 
zation 
With  
Hospitali- 
zation 
Without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
7 Calendar 
Days 
Not 
Required 
7 Calendar 
Days 
Not 
Required 
7 Calendar 
Days 
7 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
7 Calendar 
Days 
Not 
Required 
7 Calendar 
Days 
7 Calendar 
Days 
7 Calendar 
Days 
Not 
Required 
24-Hrs; 
3 Calendar 
Days 
7 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of 
treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 3 calendar days for: 
• Grade 4 and Grade 5 unexpected events  
 CTEP-AERS 7 calendar day report: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• Grade 5 expected events 
 
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full 
report is required as outlined in the table. 
 
Please see exceptions below under section entitled “Additional Instructions or Exceptions to CTEP-AERS 
Expedited Reporting Requirements for Phase 2 and 3 Trials Utilizing an Agent under a CTEP  IND.” 
 
March 2005 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.   Attribution to treatment or other cause must be provided. 

 
 
GOG-0213 
 
79 
 
 
• 
Expedited AE reporting timelines defined: 
 “24 hours; 3 calendar days” – The investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete CTEP-AERS 
report within 3 calendar days of the initial 24-hour report. 
 “7 calendar days” - A complete CTEP-AERS report on the AE must be submitted 
within  
7 calendar days of the investigator learning of the event.  
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) with the exception as listed below (grade 2-4 
myelosuppression) must be reported regardless of attribution and designation as expected 
or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs 
following treatment with an agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP-IND: 
 
• Reference the SPEER (Specific Protocol Exceptions to Expedited Report) for 
the subset of AEs that are protocol specific exceptions to expedited reporting 
via CTEP-AERS.  Report AEs on the SPEER ONLY IF they exceed the 
grade noted in parentheses next to the AE in the SPEER.  If the CAEPR for a 
protocol agent is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required.  For questions or comments 
regarding the SPEER or CAEPR, please contact the CTEP-AERS MD Help 
Desk at CTEP-AERSmd@tech-res.com(12/19/11) 
 
•  “All Grades 2, 3 and 4 myelosuppression (including neutropenia, anemia, 
and thrombocytopenia) regardless of the need for hospitalization is exempt 
from expedited reporting.” 
 
10.24  Procedures for Expedited Adverse Event Reporting:(12/19/11) 
 
10.241CTEP-AERS Expedited Reports: Expedited reports are to be 
submitted using CTEP-AERS available at http://ctep.cancer.gov. 
The NCI guidelines for expedited adverse event reporting 
requirements are also available at this site. 
 

 
 
GOG-0213 
 
80 
 
Up until September 30, 2011, AML/MDS events must be reported 
via CTEP-AERS (in addition to your routine AE reporting 
mechanisms).  In CTCAE v3.0, the event can be reported as:  
“Secondary malignancy-Other (specify)”. (09/26/11) 
 
Starting October 1, 2011 when use of CTCAE v4.0 begins: 
AML/MDS events must be reported via CTEP-AERS (in addition 
to your routine AE reporting mechanisms). In CTCAE v4.0, the 
event(s) may be reported as either: 1) Leukemia secondary to 
oncology chemotherapy, 2) Myelodysplastic syndrome, or 3) 
Treatment related secondary malignancy.(09/26/11) 
 
The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 will be utilized for AE reporting beginning April 1, 
2018.  All appropriate treatment areas should have access to a copy 
of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can 
be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_application
s/ctc.htm. 
 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made to NCI by telephone at: 301-897-7497. 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. Please note that all paper 
CTEP-AERS forms have been removed from the CTEP website 
and will NO LONGER be accepted. 
 
10.25  Automated CDUS reporting  
 
For studies using investigational agents, the GOG Statistical and Data 
Center (SDC) routinely reports adverse events electronically to the CTEP 
Clinical Data Update System (CDUS Version 3.0).  The SDC submits this 
data quarterly.  The AEs reported through CTEP-AERS will also be 
included with the quarterly CDUS data submissions. 
 
10.3 
ADVERSE EVENT REPORTING FOR A COMMERICIAL AGENT (TO BE 
USED FOR PATIENTS NOT TAKING BEVACIZUMAB AFTER AUGUST 28, 
2011) (08/29/11) (12/19/11) 
 
10.31 Phase 2 and 3 Trials Utilizing a Commercial Agent:  CTEP-AERS 
Expedited Reporting Requirements for Adverse Events That Occur Within 
30 Days of the Last Dose of Any Commercial Study Agent  
 
 
Reporting Requirements for Adverse Events that occur within 30 Days¹ of 
the Last Dose of the Commercial Agent on Phase 2 and 3 Trials 

 
 
GOG-0213 
 
81 
 
 
From the period of protocol activation through September 30, 2011, 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 
(CTCAE v3.0) are utilized for defining and grading specific adverse 
events reported through the CTEP-AERS system. (09/26/11) 
 
Beginning October 1, 2011, the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) v 4.0 will be utilized for AE reporting through 
the CTEP-AERS system. CTCAE v 4.0 is located on the CTEP website at 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.h
tm.  All appropriate treatment areas should have access to a copy of this 
Version of CTCAE.  CTCAE v 4.0 definition is also available on the GOG 
member web site (https://gogmember.gog.org under MANUALS). 
(09/26/11) 
 
The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for AE reporting beginning April 1, 2018.  All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0.  
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.ht
m. 
 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected  
and Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected Expected 
With  
Hospitali-
zation 
Without 
Hospitali- 
zation 
With  
Hospitali- 
zation 
Without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
7 Calendar 
Days 
Not 
Required 
7 Calendar 
Days 
Not 
Required 
7 Calendar 
Days 
7 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
7 Calendar 
Days 
Not 
Required 
7 Calendar 
Days 
7 Calendar 
Days 
7 Calendar 
Days 
Not 
Required 
24-Hrs; 
3 Calendar 
Days 
7 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of 
treatment with a commercial agent require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 3 calendar days for: 
• Grade 4 and Grade 5 unexpected events  
CTEP-AERS 7 calendar day report: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• Grade 5 expected events 
 
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full 
report is required as outlined in the table. 
 

 
 
GOG-0213 
 
82 
 
Please see exceptions below under the section entitled, “Additional Instructions or Exceptions to CTEP-AERS 
Expedited Reporting Requirements for Phase 2 and 3 Trials Utilizing a Commercial Agent.”          March 2005 
 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
• 
Expedited AE reporting timelines defined: 
 “24 hours; 3 calendar days” – The investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete CTEP-AERS 
report within 3 calendar days of the initial 24-hour report. 
“7 calendar days” – A complete CTEP-AERS report on the AE must be submitted within 
7 calendar days of the investigator learning of the event. 
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of 
attribution and designation as expected or unexpected with the exception of any 
events identified as protocol-specific expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported to GOG via CTEP-AERS if the event occurs 
following treatment with a commercial agent. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing a Commercial Agent: 
 
The following events should be excluded from CTEP-AERS reporting, although they 
should still be reported to the routine AE CRFs: 
•       Grade 3 or 4 myelosuppression, with or without hospitalization (12/19/11) 
 
• There are no additional instructions or exceptions to CTEP-AERS expedited 
reporting requirements for this protocol. 
 
10.32 Procedures for Expedited Adverse Event Reporting: 
 
10.321CTEP-AERS Expedited Reports: Expedited reports are to be 
submitted using CTEP-AERS available at http://ctep.cancer.gov. 
The CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements for expedited adverse event reporting requirements 
are also available at this site. 
 
Starting April 1, 2018 when use of CTCAE v5.0 begins: AML/MDS 
events must be reported via CTEP-AERS (in addition to your routine AE 
reporting mechanisms). In CTCAE v5.0, the event(s) may be reported as 

 
 
GOG-0213 
 
83 
 
either: 1) Leukemia secondary to oncology chemotherapy, 2) 
Myelodysplastic syndrome, or 3) Treatment related secondary 
malignancy. 
 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made to GOG by telephone at: 215-854-0770. 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. Please note that all paper 
CTEP-AERS forms have been removed from the CTEP website 
and will NO LONGER be accepted. 
  
10.33 Automated CDUS reporting 
 
For studies using commercial agents, the GOG Statistical and Data Center 
(SDC) routinely reports adverse events electronically to the CTEP Clinical 
Data Update System (CDUS Version 3.0).  The SDC submits this data 
quarterly.  The AEs reported through CTEP-AERS will also be included 
with the quarterly CDUS data submissions. 
 
10.4 
GOG DATA MANAGEMENT FORMS (08/04/08) (06/22/09) 
(03/15/10)(03/09/15) 
 
The following forms must be completed and submitted to the GOG Statistical and 
Data Center (SDC) in accordance with the schedule below.   All forms except: F-
form, Pathology report, OP report and QOL forms should be submitted via the 
SDC Electronic Data Entry System (SEDES) which is available through the GOG  
website (www.gogstats.org).  Quality of Life questionnaires are to be completed 
on Scantron forms and submitted by mail.  Pathology material (F-form, path 
report and slides) should be submitted together via mail. 
 
Form± 
Due within 
Copies
* 
Comments 
Weeks 
Event 
Form R (Registration Form) 
 
2 
Registration 
 
1 
Mandatory Submission via 
SEDES 
Form OSR (Recurrent 
Gynecologic Cancer  - On Study 
Form) 
2 
Registration 
1 
Mandatory Submission via 
SEDES 
Specimen Consent Application 
1 
Registration o 
N/A 
Complete Online 
Form DR (Pretreatment Summary 
Form 
 
 
 
2 
Registration 
 
Mandatory Submission via 
SEDES  
Form D2M (Solid Tumor 
Evaluation Form) # 
2 
Registration 
1 
Mandatory Submission via 
SEDES 

 
 
GOG-0213 
 
84 
 
Primary Disease 
      Form F (Pathology Form) 
      Pathology Report 
Pathology Slides 
Secondary Cytoreductive Surgery 
      Form F (Pathology Form 
Pathology Report 
 
6 
6 
6 
 
6 
6 
 
Registration 
Registration 
Registration 
 
Surgery*** 
Surgery*** 
 
3 
3  
** 
 
3 
3 
 
Submit together to the 
SDC via postal mail 
 
 
Submit together to the 
SDC via postal mail 
Cytoreductive Surgery: 
Form C (Surgical Reporting 
Form) 
Operative Report  
Discharge Summary 
 
6 
 
6 
6 
Surgery*** 
 
1 
 
2 
2 
Mandatory Submission via 
SEDES 
 
Submit via postal mail 
Submit via postal mail 
Form SP-FT01-02131 
FFPE primary or metastatic tumor 
tissue 
8 
Registration 
 
Mandatory submission via 
SEDES2 
Form SP-SB01-0213 
pre-op serum (optional) 
1 
Surgery 
 
Mandatory submission via 
SEDES2  
Mandatory submission via 
SEDES2 
Mandatory submission via 
SEDES2 
Mandatory submission via 
SEDES2 
Mandatory submission via 
SEDES2 
Mandatory submission via 
SEDES2 
Form SP-PB01-0213 
pre-op plasma (optional) 
1 
Surgery 
 
Form SP-FR01-02131 
FFPE recurrent tumor tissue 
1 
Surgery 
 
Form SP-RR01-02131 
frozen recurrent tumor tissue 
1 
Surgery 
 
Form SP-FN01-02131 
FFPE normal tissue (optional) 
1 
Surgery 
 
Form SP-RN01-02131 
frozen normal tissue (optional) 
1 
Surgery 
 
Form SP-WB01-0213 
whole blood  
26 
Registration 
 
 
Mandatory submission via 
SEDES2 
Form T (Common Toxicity 
Reporting Form) -post op**** # 
2 
Surgery*** 
1 
Mandatory Submission via 
SEDES 
Form D2R-Cycle Dose Drug 
Form # 
 
2 
2 
Completion of each 
cycle of therapy 
1 
Mandatory Submission via 
SEDES 
Form T (Common Toxicity 
Reporting Form) # 
2 
Beginning of each 
subsequent cycle 
1 
Mandatory Submission via 
SEDES 
Form D2M (Solid Tumor 
Evaluation Form) # 
2 
Clinical response 
assessment 
1 
Mandatory Submission via 
SEDES 
Form BMR (Biomarker Reporting 
Form) ± 
2 
Prior to surgery, prior 
to each cycle of therapy 
and during follow-up 
1 
Mandatory Submission via 
SEDES 
FACT-O**** (Scantron Form) 
2 
Prior to surgery 
1 
If randomized to surgery 
submit the original 
Scantron form to the GOG 
SDC via postal mail 
FACT-O**** (Scantron Form) 
2 
Prior to cycle 1, 3 and 6 
and at 6 and 12 months 
1 
Submit the original 
Scantron form to the GOG 
SDC via postal mail 

 
 
GOG-0213 
 
85 
 
after starting 
chemotherapy. 
Form SRGSTAT (Surgical Status 
Form) 
52 
Registration 
1 
Mandatory Submission via 
SEDES 
Form Q0 (Treatment Completion 
Form 
 
2 
Completion of study 
treatment 
1 
Mandatory Submission via 
SEDES 
Form Q (Follow-up Form) 
 
2 
Disease progression, 
death, and post-
treatment follow-up 
1 
Mandatory submission via 
SEDES quarterly for 2 
years, semi-annually for 3 
more years, yearly 
thereafter 
*  
The number of required copies including the original form which must be sent to the Statistical and Data 
Center if the forms are not submitted via SEDES.  No copies are required for forms submitted through 
SEDES.  Forms submitted through SEDES should not be sent through postal mail or fax. 
**  
Pathology slides are required for central review by the GOG Pathology Committee. See Section 7.4 for 
details. 
****  Submit original Scantron QOL forms and coversheet to the GOG Statistical and Data Center.  The patients 
randomized to cytoreductive surgery undergo an assessment prior to surgery as well as prior to initiating 
chemotherapy. 
± 
Serial CA-125 values should be reported on Form BMR   
#  
In the event that it becomes necessary to modify the dose or stop individual study agents for either protocol 
directed reasons or other reasons, continue to submit D2R, T and D2M forms until all study agents are 
stopped or another anti-cancer therapy is initiated.   
o 
Required only for patients randomized to undergo secondary cytoreduction surgery. 
1 
A copy of the corresponding pathology report must be shipped with all tissue specimens (tumor and normal) 
sent to the GOG Tissue Bank. 
2 
Form SP must be submitted regardless of whether the specimen is submitted for research. 
 
This study will be monitored by the Abbreviated Clinical Data System (CDUS) Version 3.0 
CDUS data will be submitted quarterly to CTEP by electronic means. 
 
This study utilizes the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 
v4.0) for defining and grading adverse events to be reported on GOG case report forms. A GOG 
CTCAE v4.0 Manual is available on the GOG member web site (http://www.gog.org under 
MANUALS) and can be mailed to the institution registering a patient to this study if 
requested.(09/26/11) 
 

 
 
GOG-0213 
 
86 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1  Randomization (10/01/12) 
 
The individuals enrolled into this study will have one of two systemic treatments 
assigned and a subset of the enrolled patients will have surgical intervention 
assigned through randomization.  That is, all patients will be randomized to one of 
the following systemic therapies:  (All patients enrolled after August 28, 2011 
will have their surgical cytoreductive treatment determined through 
randomization.  These patients will select one of the following systemic 
treatments and declare their selection prior to enrollment onto the study) 
(08/29/11) (12/19/11) 
 
11.11 CT: A standard regimen consisting of carboplatin (AUC 5) and paclitaxel 
(175 mg/m2) every 21 days for up to 8 cycles unless toxicity or 
progression necessitates discontinuing treatment early.  
 
11.12 GC: A standard regimen consisting of carboplatin (AUC 4) day 1 and 
gemcitabine (1000 mg/m2) day 1 and 8 for up to 8 cycles unless toxicity or 
progression necessitates discontinuing treatment early. 
 
11.13CTB: The standard regimen combined with bevacizumab for up to 8 cycles 
followed by maintenance bevacizumab until disease progression or 
toxicity precludes further treatment.   
 
11.14 GCB: The standard regimen combined with bevacizumab for up to 8 
cycles followed by maintenance bevacizumab until toxicity or progression 
necessitates discontinuing treatment early. 
 
Also, consenting individuals, who are candidates for secondary 
cytoreduction, will have surgery determined through randomization: 
 
 
11.15   No cytoreductive surgery 
 
 
11.16    Cytoreductive surgery performed prior to initiating systemic therapy. 
 
A procedure that tends to allocate the treatments equally across prognostic 
categories will be used.  The prognostic categories for this study will be 
defined with respect to the time from completing first-line chemotherapy 
to registration onto this study (6-12 months vs greater than 12 months).  
Specifically, for those individuals who are not candidates for surgery or 
refuse surgery, one of the two systemic regimens will be allocated with 
equal probability within blocks of treatments (this sentence applies only to 
patients enrolled prior to Aug 29, 2011, thereafter patients select either 
CT, GC, GCB or CTB as their systemic treatment.).  For those who 
consent to have cytoreductive surgery determined through randomization, 

 
 
GOG-0213 
 
87 
 
the systemic therapy as well as surgery will be allocated with equal 
probability within blocks of treatments.  The treatment assignment will 
remained concealed until after the patient has been successfully registered 
onto the study.  All interim and final reports will include an accounting of 
all patients registered, regardless of compliance to the assigned treatment 
or eligibility to the study. (08/29/11) 
 
11.2 
Measures of Efficacy and safety 
 
The principle observations for evaluating the therapeutic effects of treatment are: 
 
11.21 Primary efficacy endpoint: Overall survival 
 
11.22 Secondary efficacy endpoint: Progression-free survival (PFS) 
 
11.23 Safety endpoints: frequency and severity of adverse events (Common 
Terminology Criteria for Adverse Events (CTCAE) – version 4.0). 
 
 
11.3 
Treatment efficacy 
 
Overall type I error: This study includes two primary objectives.  The first 
objective is to determine whether the addition of bevacizumab increases overall 
survival relative to carboplatin and paclitaxel alone. The second objective is to 
determine whether surgical cytoreduction increases overall survival.  The study 
design will allocate 2.5% (one-tail) type I error to each of these two objectives 
accounting for interim analyses.   
 
Expected median survival on the standard treatment: Previous studies indicate 
that the expected death rate for platinum-sensitive patients treated with a 
platinum-taxane regimen who do not undergo debulking surgery is approximately 
0.378 year-1 (median survival time = 22 months).   
 
 
 
Accrual target for evaluating the efficacy of systemic therapy 
The targeted accrual for this component of the study is 660 patients.  It is 
anticipated that 240 eligible patients per year can be enrolled from GOG treatment 
centers.  Therefore, the expected time to accrue the targeted sample size is 2.75 
years.  An additional 1.5 year post-accrual follow-up period is anticipated. 
 
Statistical power for evaluating the efficacy of biologic therapy:  The first 
objective of this study is to determine whether bevacizumab (CTB) reduces the 
overall death rate when compared to the standard treatment (CT).  The null 
hypotheses: H01: ∆01 = λCTB / λCT > 1will be assessed, where λ.is the death rate for 
the indicated treatment.  The treatment regimens will be compared with a logrank 
procedure which includes all of the patients categorized by their randomly 
assigned treatment.  This comparison will not include those patients who were 
enrolled after August 28, 2011 and hence selected their systemic treatment.  The 

 
 
GOG-0213 
 
88 
 
type I error for this comparison will be limited to 2.5% (one-tail) accounting for 
the planned interim analyses.  The logrank test will be stratified by the secondary 
surgical debulking status (randomized to undergo cytoreduction, vs randomized to 
not undergo secondary cytoreduction vs not a candidate or did not consent to 
secondary surgical cytoreduction) and the duration of treatment free-interval prior 
to enrolling onto this study (6-12 months vs > 12 months).(08/29/11)(12/19/11) 
 
If the bevacizumab-containing regimen reduces the overall death rate 25% 
relative to the control regimen, then this is considered clinically significant.  
Assuming proportional hazards, this effect size is comparable to increasing the 
expected proportion surviving at least 22 months (median) 9.5% (50% vs 59.5%).  
In order to provide an 81% chance of detecting this effect size, the study will be 
considered sufficiently mature to permit a final analysis of the systemic regimens 
when there are at least 214 deaths (214/330=0.65) reported among those patients 
assigned to the standard regimen (CT).  If the alternative hypothesis is true then 
the expected total number of deaths at the time of the final analyses is 394.  The 
power curve for comparing the biologic-containing regimens to the control 
regimen is displayed in figure 1. 
 
 
Figure 1. 
 
 
Statistical Power- evaluating the efficacy of surgical cytoreduction: In order to 
assess the hypothesis that cytoreductive surgery does not improve overall survival 
(H02: ∆02 = λsurgery / λNo surgery >1), only those patients who were considered 
candidates for surgery and consented to have their surgical treatment determined 
by randomization will be included in this analysis.  In order to evaluate the 
efficacy of surgical cytoreduction, patients will be grouped by their randomly 
assigned surgical treatment regardless of compliance or the degree of actual tumor 
debulking.  This hypothesis will be assessed with a logrank test stratified by their 
chemotherapeutic/biologic treatment (CT vs CTB vs. CG vs CGB) and the 
duration of the treatment-free interval prior to enrolling onto this study (6-12 

 
 
GOG-0213 
 
89 
 
months vs > 12 months).  The type I error will be limited to 2.5% for a one-tail 
test including the error spent due to interim analyses. (08/29/11)(10/01/12) 
 
This study will be considered sufficiently mature for an analysis of the surgical 
cytoreduction hypothesis, H02, when there are at least 250 deaths reported among 
those enrolled (and randomized) onto the surgical component of this study.  This 
target size provides 80% power, if surgical cytoreduction truly decreases the death 
rate 30%.  This treatment effect size is comparable to increasing the percent 
surviving 22 months or longer 11.5% (50% to 61.5%).  The power curve for this 
study objective is summarized in Figure 2. The anticipated total accrual for this 
component of the study is 360 patients. (08/29/11) 
 
An addendum to the statistical considerations following the amendment to extend 
recruitment to the surgical component of the study.  (12/19/2011) 
 
As of Nov-1-2011, there were 114 patients enrolled onto the surgical component 
of this study and 17 of these patients had died.  The planned total number of 
patients to be enrolled onto the surgical component of this study is 360 patients.  
There were 35 patient enrolled during 2010, and 34 patients are projected to be 
enrolled during 2011.  Therefore, assuming the future accrual is 35 patients per 
year, this study is expected to complete its targeted accrual in 7 years (Nov-2018).  
Patients enrolled after Aug-28-2011 will have their cytoreductive surgery 
determined by randomization.  All of these patients will receive a standard 
carboplatin-paclitaxel regimen and permitted to choose whether to have 
bevacizumab supplement their treatment. 
 
The data currently available from GOG-0213, indicates that the marginal hazard 
of death is approximately 0.021 month-1.  Assuming a constant hazard, the 
expected number of deaths when the accrual is completed among the 114 patients, 
who are already enrolled onto the surgical component of this study is 97.4.  
Assuming a similar death rate for all future patients, Simpson’s rule (Schoenfeld, 
Biometrics 1983) can be used to estimate the number of patients among those 
who will be enrolled over the next 7 years and will have died when the accrual 
has been completed (130.1 deaths).  Hence the expected total number deaths at 
the time when the target accrual is completed is 97.4+130.1 = 227.5.  Likewise, 
the expected number of deaths reported 9 months after the targeted accrual is 
complete is 100.2+150.0=250.2, which is approximately the number required for 
the final analysis. 
 
Therefore, the targeted date for completing the accrual to the surgical component 
of this study is Fall-2018.  The required number of deaths required for the final 
analysis (250 deaths) is expected to occur nearly 1 year after the targeted accrual 
has been completed.  In the event that the required number of deaths for the final 
analysis is observed before the targeted accrual is completed, then accrual will be 
stopped prior to attaining the targeted accrual.  The planned analyses and the 

 
 
GOG-0213 
 
90 
 
power calculations provided above are unchanged by this revised recruitment 
plan.(12/19/2011) 
 
 
Figure 2. 
 
The number of patients to be enrolled onto the surgical component of this study 
depends on the proportion of patients who are candidates for surgery and willing 
to have their surgical treatment determined through randomization.  In the event 
that the targeted accrual for objective 1 (660 patients) is attained and there are too 
few patients enrolled who are either not candidates for surgery or do not consent 
to surgery (objective 2) then consideration will be given to continuing 
randomization to the surgical cytoreduction factor only.  That is, accrual will be 
continued but randomization to the systemic therapies will be stopped, and only 
randomization to the surgical intervention will continue. Adjuvant chemotherapy 
will be determined at that time.  In the event that the chemotherapy objectives are 
known, the choice of regimen will follow that finding the “winning arm”.  In the 
event that this is unknown, adjuvant therapy will be the control arm, paclitaxel 
and carboplatin with or without bevacizumab.  It is anticipated that at least 360 
patients will need to be enrolled onto the surgical component of this 
study.(08/29/11) 
 
An addendum to the statistical considerations to increase the target accrual to the 
surgical component of the study.  (10/13/15) 
The number of individuals originally planned to be enrolled onto the surgical 
component of this study was 360.  As of Aug 1, 2015 there have been 354 patients 
enrolled.  Accrual rate has increased over the past 18 months and the study is 
currently enrolling 6 patients per month.  Women who are deemed to be surgical 
candidates tend to have a better than expected prognosis and the overall death rate 
among those enrolled onto this component of this study is lower than originally 

 
 
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anticipated.  At this time the surgical component of the study is at 30% 
information time.  The target accrual will be increased (125 individuals) from 360 
individuals to 485.  At the current accrual rate this target accrual is expected to be 
completed in Spring-2017.  If the target accrual was unchanged, then the date of 
study maturity is mid-2021 to early 2022.  Increasing the target accrual by 125 
individuals is expected to reduce the time until full maturity by approximately 2.5 
years.  The number of events required for full maturity and the schedule for the 
planned interim analysis are not being changed by this amendment.   
 
Interim Analyses: Interim analyses are planned when there are at least 110 deaths 
reported among all those patients randomly allocated (prior to August 29, 2011) 
to the CT regimen (approximately 50% of the full information of the systemic 
therapy component of this study), The actual time for the interim analyses will 
coincide with the nearest scheduled Data Monitoring Committee (DMC) meeting 
for which the required number of events has occurred.  The semi-annual DMC 
meetings coincide with the GOG business meetings which are held in January and 
July each year and the precise date of these meetings is set without confidential 
knowledge of the study results.  (10/01/12) 
 
The interim analyses will include an assessment of treatment efficacy.  An alpha-
spending function proposed by Lan and DeMets82, which mimics the O’Brien and 
Fleming83 group sequential boundary, will be used to calculate the critical values 
used for the interim analyses.  The proportion of the total information available at 
the interim analysis will be calculated as the fraction: number of observed deaths 
among those randomly allocated to the CT regimen to the planned total number of 
deaths required for final analysis.  For example, if the interim analysis occurs at 
55% of the information time, H01 will be assessed using the previously described 
stratified logrank test and the critical p-value set to 0.0082 for the interim analysis 
and 0.0475 for final analysis.  (08/29/11) 
 
H02 will also be assessed at this interim analysis with a similar error spending 
function, but the critical values for this assessment will be based on the proportion 
of the total information calculated as the number of reported deaths among those 
enrolled into this component of the study relative to the total number of deaths 
required for the final analyses.  Finally, a second interim analysis of H02 will 
occur when at least 50% of the planned number of deaths has been reported. The 
critical values for this assessment will be based on the error spending function, the 
type I error spent on the previously mentioned interim analysis, and the actual 
proportion of deaths reported at the time of this interim analysis.  
 
The interim analysis that will occur at approximately the 50% of the total 
information time for H01 (or H02) will also include futility analyses.  Since the 
purpose of the study is to identify interventions that increase overall survival 
duration, consideration will be given to stopping randomization to the 
experimental interventions (CTB or cytoreductive surgery) if it exhibits poorer 
survival relative to its control treatment (CT or no surgical intervention, 

 
 
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92 
 
respectively) indicated by an adjusted hazard ratio, ∆01 > 1.0 (or ∆02> 1.0) at the 
time of the interim analyses.  This interim decision rule decreases the statistical 
power for each pair-wise comparison by less than 1%.  The results of the interim 
analyses are reviewed by the GOG Data Monitoring Committee (DMC).  The 
decision to terminate randomization to any particular regimen includes 
consideration of toxicities, treatment compliance, progression-free survival, and 
results from external studies.   
 
Final analysis: The study will be considered sufficiently mature to permit a final 
assessment of H01 when there are at least 214 deaths reported among those 
patients assigned to the standard regimen (CT).  The study will be considered 
sufficiently mature to permit an assessment of H02 when there at least 250 deaths 
reported among those enrolled (and randomized) onto the surgical component of 
this study.  The previously described logrank test will be performed and the 
corresponding treatment hazard ratio will be estimated.  The critical values for 
rejecting the null hypotheses will be adjusted for interim analyses, using the 
O’Brien and Fleming-like type I error spending function proposed by Lan and 
DeMets (1986).   
 
Supplemental final analyses: A proportional hazards model will be fitted to the 
survival data. Apart from the randomized therapy, other factors such as: prior 
exposure to bevacizumab, histologic cell type, initial performance status, and age 
will be included in the model as potential confounders because there exists 
evidence that these factors may have an effect on survival in these patients.  Race 
and ethnicity will also be assessed, but there is no specific hypothesis concerning 
an interaction between these factors and treatment proposed.  
 
Due to the lack of knowledge concerning interactions between treatments and 
these confounders, prior to assessing the main effects of the treatment, the 
homogeneity of the treatment effects will be assessed by testing the null 
hypothesis of no interactions.  The likelihood ratio test will be performed by 
comparing models with and without interaction terms. Rejecting the null 
hypothesis of homogeneity at the 5% significance level will be considered 
sufficient evidence to warrant reporting the relative treatment effects within each 
factor and a cautious interpretation of the pooled estimates.   
 
Safety Analyses: The GOG Data Safety and Monitoring Board (DSMB) reviews 
accumulating summaries of toxicities, serious adverse event (SAE) reports and 
deaths in which study treatment may have been a contributing cause.  This 
committee does not review efficacy results.  The DSMB may recommend study 
amendments pertaining to patient safety. 
 
Grading and classification of adverse events will follow the CTCAE v. 4.0 
toxicity criteria.  The primary analysis will consist of comparing the relative odds 
of grade 3 or worse toxicities occurring during and following study treatment that 
are reported to be at least possibly related to study treatment.  Specific attention 

 
 
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will be given to the frequency of neutropenia, anemia, thrombocytopenia, 
hypertension, proteinuria, rash and gastrointestinal toxicities, which are 
unintended but not infrequent side effects from the study treatments.  The safety 
analysis will focus on those patients who at least initiated study therapy.  A 
logistic model will permit an estimate of the relative odds of grade 3 or worse 
adverse treatment effects for both randomized factors while adjusting for potential 
confounders like age.  Deaths considered to be at least partially attributable to 
treatment will be reported and summarized.  Reasons for stopping study treatment 
(e.g. patient refusal, toxicity, progression or death) will be reported. 
 
11.4 
Quality of Life 
 
 
There are primarily three quality of life issues of interest: 
 
11.41 Patients undergoing secondary cytoreduction may initially experience a 
decrease in QOL after the surgery. 
 
11.42 Patients undergoing secondary cytoreduction may have better QOL 
compared to patients without surgery, after surgical healing. 
 
11.43 Patients receiving carboplatin and paclitaxel only may experience a better 
QOL relative to those who receive these agents combined with 
bevacizumab.  
 
The primary measures used in this study to assess the quality of life (QOL) are the 
self-administered FACT-O TOI for ovarian cancer patients and the Physical 
Functioning (PF) subscale of the Rand-SF 36.  Each patient will be asked to 
complete these questionnaires at the following time points during their 
participation in the study: 
i. Prior to surgery (only those undergoing surgical cytoreduction), 
ii. Prior to cycle 1  
iii. Prior to cycle 3 (6 weeks after staring systemic therapy),  
iv. Prior to cycle 6 (12 weeks after starting systemic therapy),  
v. 6 months after starting systemic therapy, 
vi. 12 months after starting systemic therapy. 
 
The times in parentheses indicate the assessment points for those patients who do 
not complete the entire study regimen. 
 
 
Construct and content 
The Functional Assessment of Cancer Therapy scale developed for ovarian cancer 
(FACT-O TOI) is a tool that provides a general QOL score.  It consists of 3 
subscales: physical well being (7 items), functional well being (7 items) and the 
Ovarian Cancer subscale (12 items) 43.  The Physical Functioning (PF) subscale of 
the Rand-SF 36 is the 10-item subscale of this general quality of life 
questionnaire44. 

 
 
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94 
 
 
Descriptive analyses of baseline QOL scores 
Descriptive statistics from the baseline QOL data will be calculated. These will 
include descriptions of the distribution of QOL scores (mean, standard deviation, 
median, etc.).  For all patients the baseline scores will be calculated using the 
questionnaire completed prior to treatment cycle 1, except for those undergoing 
cytoreductive surgery.  In that case, the baseline score is calculated using the 
questionnaire completed prior to surgery.  Therefore, comparisons involving the 
patients who were allocated to surgery, the effects of time are confounded with 
effects of surgery. 
 
Differences in FACT-TOI scores between patients receiving CT and CTB:  Data 
available from GOG-172 provides some estimates that can be used for planning 
the current study.  In that study women with advanced ovarian cancer received 6 
cycles of a platinum-taxane based treatment.  The mean and variance of the 
baseline FACT-TOI scores were 67.2 and 15.9, respectively.  The correlation 
between the baseline FACT-TOI score and the same score reported 3 to 6 weeks 
after the sixth cycle of treatment was 0.36.  The target sample size for this study is 
based on study objective 1 and is 660 patients (330 patients in each arm).  It is 
anticipated that 90% of the patients will report FACT-TOI scores prior to 
initiating treatment and prior to treatment cycle 6.  If bevacizumab truly changes 
patients’ FACT-TOI scores 4.0 units after 6 cycles of treatment, the targeted 
sample size has about 91% power for an analysis of covariance, when the type I 
error is limited to 5% for a two tail test.  However, a linear mixed model will be 
used for the final analysis of this data since this approach is more efficient, 
accommodates missing data, and accounts for correlations due to repeated 
measurements from the same individual.  The actual power for this analysis, 
however, depends on the unknown pattern of missing values. 
 
 
Difference in Rand SF-36 Physical Functioning (PF) subscale after surgery: 
This analysis will include those patients who were candidates for surgery and 
consented to have their surgical intervention determined through randomization.  
A paired t-test will be used to test the null hypothesis that there is no difference 
between baseline PF scores and the PF scores prior to cycle 1 for those patients 
randomized to cytoreductive surgery.  The paired t-test is generally robust for 
moderate sample sizes when the distribution of PF scores is not normal.  Data 
from GOG-2222 can be used for planning purposes.  In that study, patients with 
newly diagnosed endometrial cancer completed the SF-36 PF subscale prior to 
initiating study treatment.  When the scores are rescaled (0-100), the mean and 
standard deviation were 75.9 and 27.8, respectively.  Assuming that at least 485 
patients will be eligible and consent to participate in this component of the study, 
this sample size has 84% power for detecting a true difference of 7.5 units, when 
type I error is limited to 5% for a two-tail test. (10/13/15) 
 
Differences in FACT-TOI scores between patients undergoing cytoreductive 
surgery and patients not undergoing cytoreductive surgery.  This analysis will 

 
 
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95 
 
include those patients who were candidates for surgery and consented to have 
their surgical intervention determined through randomization.  There will be up to 
5 or 6 time points for patients to report their FACT-TOI scores, depending on 
whether the patient was randomized to the secondary cytoreductive surgery arm 
of the study.  There are no specific hypotheses being posited for how the 
treatment groups will differ in their mean QOL scores over time.  Therefore, a 
linear mixed model will be used to model the difference in mean QOL scores over 
time.  That is, the mean QOL scores will be modeled in order to compare those 
patients randomized to secondary cytoreductive surgery vs no surgery, as well as, 
the differences in mean QOL scores among the three types of systemic therapy.  
The model will assess whether there is evidence of a treatment-time interaction as 
well as whether differences in mean QOL scores between treatment groups varies 
as a linear or possibly a quadratic function of time. 
 
11.5 
Translational Research Statistical Considerations 
 
Overview 
The overall goal for the translational research component of this study is to 
discover molecular and/or biochemical profiles that may be useful for determining 
which patients from this patient population are likely to respond or experience 
longer survival.  There are no specific up-front hypotheses proposed.  The 
primary challenges related to this component of the study are the practicality of 
finding useful biomarker profiles from among potentially tens of thousands of 
biomarkers, as in the case of a gene microarray experiment.  This challenge is 
further exasperated due to the limited number of available biologic specimens.  In 
order to address these challenges, this study will utilize a training dataset to 
develop a prognostic index from the biomarker measurements and a separate and 
distinct validation dataset to assess the predicative value of the index.  The steps 
to be used in this study for developing a molecular/biochemical profile are: 
 
a) Identifying those individuals to be included in the training data set. 
b) Developing an index from the molecular marker data and outcome data 
contained in the training set. 
c) Assess reliability of the putative prognostic index. 
d) Validate the putative prognostic index. 
 
Anticipated sample size for translational objectives 
The targeted accrual for the randomized systemic treatment component of this 
study is 660 patients.  It is anticipated that 30% - 50% (approximately 198-330 
patients) of these individuals will be candidates for and consent to secondary 
surgical cytoreduction.  Only half of these individuals (99-165 patients) will be 
randomized to cytoreductive surgery.  It is expected that viable tissue collected 
during cytoreductive surgery will be available in most of these cases.  Also, a 
serum sample, which is drawn prior to surgery, will be available.  The ratio of the 
size of the training dataset to the size of the validation dataset will range from 1:1 
to 3:1.   

 
 
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96 
 
 
Therefore, assuming that a biologic specimen is available from 130 eligible and 
evaluable patients who were treated with a randomized systemic treatment and 
undergoing surgery, the size of the training set is expected to range from 65-98 
patients and the size of the validation dataset is expected to range from 32-65 
patients. 
 
Training and validation set 
In order to establish a training dataset for the primary translational research 
objectives a sample of sequentially enrolled eligible and evaluable patients will be 
established in which at least 50 deaths have been reported.  This requirement may 
need to be relaxed for follow-up studies since samples will eventually become 
depleted.  A validation cohort will be derived in a similar fashion as the training 
cohort.  That is, the training and validation cohorts will consist of sequentially 
enrolled eligible and evaluable patients.  Individuals will not be permitted to be 
members of both the training and the validation cohorts. 
 
Identifying biologic/molecular profiles 
Investigators will not be restricted to utilizing a particular technique for building 
the classifier.  In fact, several classifiers may be identified.  However, prior to the 
validation phase a single classifier corresponding to the primary study objective 
will be selected and deemed the ‘final’ classifier.  Data from the validation dataset 
will not be used to select the ‘final’ classifier.   
 
Reliability 
The classifier should provide similar results for the same experimental unit.  That 
is, a biologic specimen with a high prognostic index score should exhibit a high 
prognostic index score when it is re-evaluated.  An index score which cannot be 
replicated lacks test-retest reliability.  This occurs when there are other sources of 
between-specimen variation that are uncontrolled in the experiment.   
 
In order to assess reliability some specimens will be selected from the training set 
for repeat assessment.  While randomly selecting specimens from the training set 
for replication is preferable, it may be necessary to randomly select from a subset 
of the training set due to the availability of adequate biologic material.  When 
possible, the samples will be identified in such a way that the laboratory 
investigator will be unable to identify which specimens are replicates.  These 
samples will have their biomarkers (i.e. gene expression, serum marker) assessed 
twice.  Since replication can be expensive, depending of the laboratory procedure, 
the number of samples selected for replication will vary from a dozen to a few 
dozen, depending on practical considerations like cost and feasibility.    The data 
from the replicated samples will be used to assess reliability of the putative index 
before proceeding to the validation phase.  Reproducibility is a prerequisite for a 
clinically useful classifier. 
 
Validation 

 
 
GOG-0213 
 
97 
 
Prior to initiating the validation phase, the ‘final’ classifier will be completely 
documented (i.e. computer program or pseudo-code).  This documentation will be 
reviewed by individuals in the GOG Statistical and Data Center (SDC) who are 
not participating in the analyses.  The purpose of this review will be to determine 
whether the final classifier has been unambiguously defined.   
 
The c-index will be used to measure the classifier’s predictive ability.  This index 
assesses the strength of the rank correlation between the predicted outcome and 
the actual outcome.  If the classifier produces a continuous prognostic score and 
response is dichotomous, then the c-index is comparable to the Wilcoxon two-
sample rank score.  It can be calculated by taking all possible pairs of individuals 
in which one individual responded and the other did not respond.  In this case, the 
c-index is the proportion of these pairs in which the responder has a higher 
predicted probability of responding.  A c-index value of 0.5 indicates a useless 
classifier, and a value of 1.0 indicates perfect prediction.  The c-index is Somer’s 
rank correlation index when it is rescaled to vary linearly from 0 to 1.  The c-
index can be used when the outcome is partially censored survival time.  In this 
case it measures the proportion of all pairs of individuals in the data set in which 
the individual with the expected lower risk of failure is known to survive longer. 
 
Other descriptive summaries of predictive ability will also be considered 
including: Kaplan-Meier curves when the outcome is a time-to-failure or a ROC 
curve when the outcome is dichotomous. 
 
The publication which describes the results for the primary objective of this study 
will include a description of the accuracy of the final classifier.  While other 
classifiers may also be described, the final classifier will be clearly distinguished 
from the other classifiers.  The documentation describing the final classifier will 
be available to other investigators from the SDC upon request.   
 
After the study objectives have been completed, the GOG may elect to make 
some or all of the validation data set available to other investigators, since the 
specimens in the training set may become exhausted. Any classifiers developed 
subsequently will not be permitted to claim that they were independently 
validated without additional supporting external evidence.   
 
11.6 
The anticipated distribution of patients’ race and ethnicity for the systemic 
therapy portion of this trial is (all are female): 
White (not Hispanic)   
 
 
  584 
Black (not Hispanic)  
 
 
    39 
Hispanic  
 
 
 
 
    14 
Asian   
 
 
 
 
    17 
American Indian or Alaskan Native   
      3 
Native Hawaiian or other Pacific Islander        3 

 
 
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APPENDIX I 
 
FIGO STAGE GROUPING FOR PRIMARY CARCINOMA OF THE OVARY 
 
(1985) 
 
These categories are based on findings at clinical examination and/or surgical exploration.  The histologic 
characteristics are to be considered in the staging, as are results of cytologic testing as far as effusions are 
concerned.  It is desirable that a biopsy be performed on suspicious areas outside the pelvis. 
 
Stage I  
Growth limited to the ovaries. 
 
Stage IA 
Growth limited to one ovary; no ascites.   
 
 
No tumor on the external surface; capsule intact. 
 
Stage IB 
Growth limited to both ovaries; no ascites. 
 
 
No tumor on the external surfaces; capsules intact. 
 
Stage IC* 
Tumor either Stage IA or IB but with tumor on the surface of one or both ovaries; or with 
capsule ruptured; or with ascites present containing malignant cells or with positive peritoneal 
washings. 
 
Stage II  
Growth involving one or both ovaries with pelvic extension. 
 
Stage IIA 
Extension and/or metastases to the uterus and/or tubes. 
 
Stage IIB 
Extension to other pelvic tissues. 
 
Stage IIC* 
Tumor either Stage IIA or IIB but with tumor on the surface of one or both ovaries; or with 
capsule(s) ruptured; or with ascites present containing malignant cells or with positive 
peritoneal washings. 
 
 
Stage III 
Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or 
positive retroperitoneal or inguinal nodes.  Superficial liver metastasis equals Stage III.  
Tumor is limited to the true pelvis but with histologically verified malignant extensions to 
small bowel or omentum. 
 
Stage IIIA 
Tumor grossly limited to the true pelvis with negative nodes but with histologically 
confirmed microscopic seeding of abdominal peritoneal surfaces. 
 
Stage IIIB 
Tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal 
surfaces, none exceeding 2 cm in diameter.  Nodes negative. 
 
Stage IIIC 
Abdominal implants >2 cm in diameter and/or positive retroperitoneal or inguinal nodes. 
 
Stage IV 
Growth involving one or both ovaries with distant metastasis.  If pleural effusion is present 
there must be positive cytologic test results to allot a case to Stage IV.  Parenchymal liver 
metastasis equals Stage IV. 
 
* 
In order to evaluate the impact on prognosis of the different criteria for allotting cases to Stage IC or 
IIC, it would be of value to know if rupture of the capsule was (1) spontaneous or (2) caused by the surgeon 
and if the source of malignant cells detected was (1) peritoneal washings or (2) ascites.

 
 
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APPENDIX II 
 
SECONDARY CYTOREDUCTIVE SURGICAL PROCEDURE 
 
Purpose : 
Maximum resection of recurrent ovarian cancer. 
 
Timing:  Surgical exploration should be undertaken within 4 weeks of study entry. 
 
Content of Procedure: 
1.0 The abdominal incision must be adequate to explore the entire abdominal cavity and 
allow safe cytoreductive surgery. A vertical incision is recommended but not 
required. 
2.0 All peritoneal surfaces including the undersurface of both diaphragms and the serosa 
and mesentery of the entire gastrointestinal tract will be visualized and palpated for 
evidence of metastatic disease. 
3.0 Visible metastatic abdominal and pelvic disease should be resected or ablated 
completely, if possible. 
4.0 Diaphragmatic recurrent disease should be resected.  Ablation of disease with 
electrocautery (e.g. Argon Beam Coagulator) is acceptable. 
5.0 Surgical evaluation of the pelvic and paraortic node bearing areas requires resection if 
not performed on initial staging/debulking procedure.  If incomplete nodal resection 
was previously documented, unresected areas should be excised. 
6.0 Solid organ metastases (spleen and liver) should be considered for resection.  
Treatment by Radio Frequency Ablation (RFA) is acceptable.   
 
Goal:  Surgical goal of cytoreduction is to reduce volume of residual disease to smallest 
quantity possible (no visible residual). 
 
Reporting: The size (two dimensions) and location of residual disease will be recorded. 

 
 
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APPENDIX III (03/09/15) 
– TRANSLATIONAL RESEARCH SPECIMEN PROCEDURES 
 
I. Summary of the Specimen Requirements 
If the patient gives permission for her specimens to be collected and used for this optional 
translational research component, then participating institutions within the United States are 
required to submit the patient’s specimens as outlined below (unless otherwise specified). 
 
Specimen (Specimen Code) 
Collection Time Point 
Sites Ship Specimens to 
ALL PATIENTS 
Whole Blood (WB01) 
7-10mL drawn into purple top (EDTA) tube(s) 
Prior to or after starting study 
treatment 
GOG Tissue Bank within 
26 weeks of registration2 
SURGICAL ARM PATIENTS ONLY 
FFPE Primary or Metastatic Tumor (FT01)* 
1st Choice: Block 
2nd Choice: 16 unstained slides (charged, 5µm) 
Prior to all treatment 
GOG Tissue Bank within 8 
weeks of registration2 
Pre-Op Serum (SB01) 
Prepared from 7-10mL of blood drawn into plain 
red top tube(s) 
Optional - Prior to secondary 
cytoreductive surgery 
GOG Tissue Bank within 1 
week of surgery2 
Pre-Op Plasma (PB01) 
Prepared from 7-10mL of blood drawn into 
purple top (EDTA) tube(s) 
FFPE Recurrent Tumor (FR01)* 
1st Choice: Block 
2nd Choice: 16 unstained slides (charged, 5µm) 
At time of secondary 
cytoreductive surgery 
Snap Frozen Recurrent Tumor (RR01)* 
At least 0.2g in foil 
FFPE Normal Tissue (FN01)* 
1st Choice: Block 
2nd Choice: 16 unstained slides (charged, 5µm) 
Optional - At time of 
secondary cytoreductive 
surgery 
Snap Frozen Normal Tissue (RN01)* 
At least 0.2g in foil 
1 A copy of the corresponding pathology report must be shipped with all tissue specimens (tumor and normal) sent to the 
GOG Tissue Bank. 
2 GOG Tissue Bank / Protocol GOG-0213 Nationwide Children’s Hospital, 700 Children’s Drive, WA1340, Columbus, OH 
43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: GOGBank@nationwidechildrens.org 
 
II. Obtaining a GOG Bank ID for Translational Research Specimens 
Only one GOG Bank ID (# # # # - # # - G # # #) is assigned per patient. All translational research 
specimens and accompanying paperwork must be labeled with this coded patient number. A 
GOG Bank ID can be obtained online via the Tissue Bank Portal on the GOG website (under 
Tools on the Web Menu page). 
 
Obtain the patient’s study ID (GOG #) for all protocols with translational research specimen 
requirements before requesting a Bank ID from the Tissue Bank Portal. Be sure to indicate if 
the patient has a previous GOG # when registering. This will ensure the patient is only 
assigned one Bank ID. The GOG ID - Bank ID Lookup on the Tissue Bank Portal can be used to 
search for an existing Bank ID. 
 
Contact Support if you need assistance or have assigned more than one Bank ID to a patient 
(Email: support@gogstats.org; Phone: 716-845-7767). 

 
 
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III. Requesting Translational Research Specimen Kits 
One single chamber specimen kit will be provided per patient for the collection and shipment of 
frozen serum, plasma, and tissue. 
 
Translational research specimen kits can be ordered online via the Kit Management link on the 
GOG website (under Data Entry on the Web Menu page). Each site may order two kits per 
protocol per day (daily max = 6 kits). 
 
Please contact the GOG Tissue Bank if you need assistance (Email: 
GOGBank@nationwidechildrens.org; Phone: 866-GOG-BANC/866-464-2262). 
 
Be sure to plan ahead and allow time for kits to be shipped by ground transportation. 
 
Note: Unused materials and kits should be returned to the GOG Tissue Bank. 
 
IV. Labeling Translational Research Specimens 
A waterproof permanent marker or printed label should be used to label each translational 
research specimen with: 
 
GOG Bank ID (# # # # - # # - G # # #) 
GOG protocol number (GOG- # # # #) 
specimen code (see section I) 
collection date (mm/dd/yyyy) 
surgical pathology accession number (tissue specimens only) 
block number (tissue specimens only) 
 
Note: If labeling slides, only label on the top, front portion of the slide. Do not place a label on 
the back of the slide or over the tissue. The label must fit on the slide and should not be wrapped 
around the slide or hang over the edge. 
 
V. Submitting Formalin-Fixed, Paraffin-Embedded Tissue   
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the 
specimen type (primary, metastatic, recurrent, normal). Primary and metastatic tumor should be 
collected prior to all treatment. Recurrent tumor and normal tissue should be collected prior to the 
study treatment. Only one block may be submitted per tissue type. 
 
Every attempt should be made to provide a FFPE block; however, if a block cannot be provided 
on a permanent basis, then 16 unstained slides (charged, 5µm) should be submitted.  All tissue 
sections should be cut sequentially from the same block. 
 
Note: Stained slides to confirm patient eligibility by central pathology review are required 
for this protocol, but are NOT sent to the GOG Tissue Bank (see protocol for details). If 
these slides will be cut from the same block that will be submitted for translational research, your 
pathology department should cut these slides prior to submitting the block for translational 
research. 

 
 
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The type of specimen (block or slides) should be specified on Form SP. 
 
If submitting recurrent tumor, include a comment on Form SP noting whether the tumor is from 
the primary site or the metastatic site. 
 
 
All FFPE tissue should be submitted with the corresponding pathology report. 
 
VI. Submitting Frozen Tissue   
1.  Label the zip-lock bag as described above. If using an adhesive label, place it inside the bag. 
2. Snap freeze tissue within 15 minutes after surgery for optimal preservation. Place tissue on a 
piece of foil and fold foil around tissue as shown in diagram below. Snap freeze tissue on dry 
ice or in the vapor phase liquid nitrogen (do not submerge the tissue in liquid nitrogen). If 
neither dry ice nor liquid nitrogen is available, slow freeze tissue in a -70°C to -80°C freezer. 
 
3. Once the tissue is frozen, place in pre-labeled zip-lock bag. 
4.  Immediately store snap frozen tissue in a liquid nitrogen freezer (at vapor phase), a -70°C to -
80°C freezer, or by direct exposure with dry ice until ready to ship. 
 
VII. Submitting Plasma 
1.  Label cryovials and a 15mL conical tube as described above. Use 2mL cryovials if plasma 
will be shipped to the GOG Tissue Bank. 
2.  Draw 7-10mL of blood into lavender/purple top (EDTA) tube(s).  
3.  Immediately after collection, gently invert the blood collection tube 5-10 times to mix the 
blood and EDTA. 
4.  Centrifuge the blood at 1000g for 15 minutes at 4ºC (preferred) or room temperature to 
separate the plasma (top, straw-colored layer) from the red blood cells (bottom, red layer).  
5.  Transfer the plasma into a pre-labeled 15mL conical tube and gently mix. 
6. Quickly, evenly dispense (aliquot) the plasma into the pre-labeled cryovials and cap the tubes 
securely. Place a minimum of 0.25mL into each cryovial. 
7.  Immediately freeze the plasma in an upright position in a -70oC to -80oC freezer or by 
direct exposure with dry ice until ready to ship. If a -70oC to -80oC freezer is not available for 
storage, store, and ship, on dry ice within 24 hours of collection. 

 
 
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VIII. Submitting Serum 
1.  Label cryovials and a 15mL conical tube as described above. Use 2mL cryovials if serum 
will be shipped to the GOG Tissue Bank. 
 2.  Draw 7-10mL of blood into red top tube(s).  
3.  Allow the blood to clot at 4°C (or in a bucket with ice) for at least 30 minutes but no longer 
than 3 hours. 
4.  Centrifuge the blood at 1000g for 15 minutes at 4ºC (preferred) or room temperature to 
separate the serum (top, straw-colored layer) from the red blood cells (bottom, red layer). 
5.  Transfer the serum into a 15mL conical tube and gently mix. 
6. Quickly, evenly dispense (aliquot) the serum into the pre-labeled cryovials and cap the tubes 
securely. Place a minimum of 0.25mL into each cryovial. 
7.  Immediately freeze the serum in an upright position in a -70oC to -80oC freezer or by 
direct exposure with dry ice until ready to ship. If a -70oC to -80oC freezer is not available for 
storage, store and ship on dry ice within 24 hours of collection. 
 
IX. Submitting Whole Blood    
1.  Label the lavender/purple top (EDTA) collection tube(s) as described above. Multiple tubes 
may be used to collect the required amount. 
2. Draw 7-10mL of blood into the labeled lavender/purple top tube(s). A minimum of 3mL is 
needed for processing. 
3.  Immediately after collection, gently invert the tube 5-10 times to mix the blood and EDTA. 
4. Whole blood specimens should be refrigerated (4°C) until the specimens can be shipped. 
Ship whole blood to the GOG Tissue Bank the day the specimen is collected. If the whole 
blood absolutely cannot be shipped the day it is collected, the tube(s) should be refrigerated 
(4°C) until the specimen can be shipped. 
 
 
 
X. Submitting Form SP 
Form SP must be submitted via SEDES for each required specimen regardless of whether the 
specimen is submitted for research. 
 
A copy of the SEDES-completed Form SP must accompany each specimen shipped to the GOG 
Tissue Bank (or alternate laboratory). Handwritten forms will not be accepted. 
 
Note: A copy does not need to be sent if the specimen is not collected. 
 
Retain a printout of the completed form for your records. 
 
Please contact Support if you need assistance (Email: support@gogstats.org; Phone: 716-845-
7767). 
   
XI. Shipping Translational Research Specimens 
A SEDES-completed copy of Form SP must be included for each translational research 
specimen. 
 
A. FFPE Tissue 

 
 
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FFPE tissue and a copy of the corresponding pathology report should be shipped using your own 
container at your own expense to: 
 
GOG Tissue Bank / Protocol GOG-0213 
Nationwide Children’s Hospital 
700 Children’s Dr., WA1340 
Columbus, OH 43205 
Phone: (614) 722-2865 
FAX: (614) 722-2897 
Email: GOGBank@nationwidechildrens.org 
 
Do not ship FFPE tissue for Saturday delivery. 
 
B. Frozen Specimen 
Frozen serum, plasma, and tissue, including a copy of the corresponding pathology report for 
frozen tissue, should be shipped using the specimen kit provided to the GOG Tissue Bank 
(address above). 
 
Frozen specimens should be shipped Monday through Thursday for Tuesday through Friday 
delivery. Do not ship frozen specimens on Friday or the day before a holiday. Note: Saturday 
delivery is not available for frozen specimens.  
 
Frozen specimens should be stored in an ultra-cold freezing/storage space (i.e., ultra-cold ≤-70oC 
freezer, liquid nitrogen, or direct exposure with dry ice) until the specimens can be shipped. 
 
Shipping Frozen Translational Research Specimens in a Single Chamber Kit  
1. Pre-fill the kit chamber about 1/3 full with dry ice. 
2. Place the frozen specimens from each time point in a separate zip-lock bag. 
3. Place the zip-lock bags in the biohazard envelope containing absorbent material. Do not put 
more than 20 vials in the biohazard envelope. Put the secondary envelope into a Tyvek 
envelope. Expel as much air as possible before sealing both envelopes. 
4. Place the Tyvek envelope containing the frozen specimens into the kit and fill the chamber to 
the top with dry ice. 
5. Insert a copy of Form SP for each specimen.  
6. Place the cover on top of the kit. Tape the outer box of the kit closed with filament or other 
durable sealing tape. Please do not tape the inner chamber.  
7. Print a pre-paid FedEx air bill using the Kit Management application (found under Data 
Entry on the Web Menu page). Attach the air bill. 
8. Attach the dry ice label (UN1845) and the Exempt Human Specimen sticker. 
9. Arrange for FedEx pick-up through your usual institutional procedure or by calling 800-238-
5355. 
 
C. Whole Blood 
Whole blood specimens should be shipped to the GOG Tissue Bank (address above). 
 

 
 
GOG-0213 
 
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Whole blood specimens can be shipped to the GOG Tissue Bank Monday through Friday for 
Tuesday through Saturday delivery. Do not ship whole blood the day before a holiday. Use 
your own shipping container to ship specimens via FedEx priority overnight. 
 
When shipping whole blood specimens, your institution must comply with IATA standards 
(www.iata.org). If you have questions regarding your shipment, contact the GOG Tissue Bank at 
GOGBank@nationwidechildrens.org or by phoning 866-GOG-BANC (866-464-2262).  
 
To ship whole blood specimens you will need (1) a sturdy shipping container (e.g., a cardboard 
or styrofoam box), (2) a leak proof biohazard envelope with absorbent material*, (3) a puncture 
and pressure resistant envelope (e.g. Tyvek envelope), (4) an Exempt Human Specimen sticker, 
and (5) a pre-paid FedEx air bill. 
 
*If you will be shipping whole blood specimens from more than one patient, please put each 
specimen in a separate plastic zip-lock bag before placing the specimens in the shipping bag. 
You may include up to four different blood specimens in one biohazard envelope. 
 
If you do not have these materials available at your institution, you may order them from any 
supplier (e.g., Saf-T-Pak; Phone: 800-814-7484; Website: www.saftpak.com). 
 
Shipping Whole Blood Using Your Own Shipping Container 
1. Place the whole blood specimen in a biohazard envelope containing absorbent material. 
Expel as much air as possible before sealing the bag. 
2. Wrap the biohazard envelope in bubble wrap or another padded material. 
3. Place the padded tube(s) into a Tyvek envelope. Expel as much air as possible before sealing 
the envelope. 
4. Place the Tyvek envelope in a sturdy shipping container (e.g., cardboard FedEx box). 
5. Insert a copy of Form SP for each specimen. 
6. Attach an Exempt Human Specimen sticker to the outside of the shipping container. 
7. Print a pre-paid FedEx air bill using the Kit Management application (found under Data Entry 
on the Web Menu page). Attach the air bill. 
8. Make arrangements for FedEx pick-up through your usual institutional procedure or by 
calling 800-238-5355. 
 
XII. Distributing Translational Research Specimens 
Note: Testing of banked samples will not occur until an amendment to this treatment protocol (or 
separate correlative science protocol) is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies. 
 
The GOG Statistical and Data Center and Tissue Bank will coordinate the distribution of 
specimens to approved investigators. 
 
Investigators will not be given access to any personal identifiers. 
 
Investigators will be responsible for the direct supervision and oversight of translational research 
and for keeping accurate records. 

 
 
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Investigators will ensure the results are linked to the appropriate specimen-specific identifiers 
and are responsible for transferring relevant laboratory data to the Statistical and Data Center. 
 
At the discretion of the Chair of the Committee on Experimental Medicine and the Director of 
the GOG Tissue Bank, investigators may be required to ship any specimens (or by-products) 
remaining after the completion of the translational research to the GOG Tissue Bank. 
 
A. FFPE Tissue 
Unstained sections of conventional blocks and/or TMAs will be batched shipped upon trial 
completion to: 
 
Dr. Michael Birrer 
Massachusetts General Hospital Cancer Center 
Phone: (617) 726-8624 
Fax: (617) 724-6898 
Email: mbirrer@partners.org 
 
B. Frozen Tissue 
Unstained sections of frozen tissue will be batched shipped upon trial completion to Dr. Michael 
Birrer (address above). 
 
 
C. Serum and Plasma 
Aliquots of frozen serum and plasma will be batched shipped upon trial completion to Dr. 
Michael Birrer (address above). 
 
D. Whole Blood 
The GOG Tissue Bank will isolate DNA from whole blood. Aliquots of DNA will be batch 
shipped upon trial completion to Dr. Michael Birrer (address above). 
 
XIII. Banking Translational Research Specimens for Future Research 
Specimens will remain in the GOG Tissue Bank and made available for approved research 
projects if the patient has provided permission for the use of her specimens for future health 
research. The patient’s choices will be recorded on the signed informed consent document and 
electronically via the online Specimen Consent Application. At the time of specimen selection 
for project distribution, the most recent consent information will be used. 
 
GOG institutions can amend a patient’s choices regarding the future use of her specimens 
at any time if the patient changes her mind. 
 
If the patient revokes permission to use her specimens, the GOG Tissue Bank will destroy or 
return any remaining specimens. The patient’s specimens will not be used for any further 
research; however, any specimens distributed for research prior to revoking consent cannot be 
returned or destroyed. In addition, the patient cannot be removed from any research that has been 
done with her specimens distributed prior to revoking consent. 
 

 
 
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Note: If return of specimens is requested shipping will be at the institution’s expense. 
 
 
 

 
 
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APPENDIX IV 
 
NCI Standard Protocol Language (as of March 26, 1998) Standard Language to Be 
Incorporated into All Protocols Involving Agent(s) Covered by a Clinical Trials Agreement 
(CTA) or a Cooperative Research and Development Agreement (CRADA): 
 
The agents (hereinafter referred to as “Agent”), Bevacizumab and Erlotinib, used in this 
protocol are provided to the NCI under a Clinical Trials Agreement (CTA) or a Cooperative 
Research and Development Agreement (CRADA) between Genentech, Inc. (hereinafter referred 
to as “Collaborator”) and the NCI Division of Cancer Treatment, Diagnosis.  Therefore, the 
following obligations/guidelines apply to the use of the Agent in this study: 
 
1. Agent may not be used outside the scope of this protocol, nor can Agent be transferred or 
licensed to any party not participating in the clinical study.  Collaborator data for Agent are 
confidential and proprietary to Collaborator and should be maintained as such by the 
investigators. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different CTAs or CRADAs, the access to 
and use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as “Multi-Party Data.”):  
 
a.  
NCI must provide all Collaborators with written notice regarding the existence 
and nature of any agreements governing their collaboration with NIH, the design 
of the proposed combination protocol, and the existence of any obligations which 
would tend to restrict NCI’s participation in the proposed combination protocol. 
 
b.  
Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
 
c.  
Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own investigational Agent. 
 
3. The NCI encourages investigators to make data from clinical trials fully available to 
Collaborator for review at the appropriate time (see #5).  Clinical trial data developed under a 
CTA or CRADA will be made available exclusively to Collaborator, the NCI, and the FDA, as 
appropriate. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for cooperative group 
studies, or PI for other studies) of Collaborator’s wish to contact them. 

 
 
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5. Any data provided to the Collaborator must be in accordance with the guidelines and policies 
of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial should be provided to CTEP for 
immediate delivery to Collaborator for advisory review and comment prior to submission for 
publication.  Collaborator will have 30 days from the date of receipt for review.  An additional 
30 days may be requested in order to ensure that confidential and proprietary data, in addition to 
Collaborator’s intellectual property rights, are protected.  Copies of abstracts should be provided 
to Collaborator for courtesy review following submission, but prior to presentation at the 
meeting or publication in the proceedings.  Copies of any manuscript and/or abstract should be 
sent to: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Room 7111 
Bethesda, Maryland 20892 
FAX:  (301) 402-1584 
 
The Regulatory Affairs Branch will then distribute them to the Collaborator.

 
 
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APPENDIX V 
 
CARBOPLATIN DOSE CALCULATION INSTRUCTIONS 
 
1) The Cockcroft-Gault formula will be used in GOG trials (not the Jelliffe formula). 
2) Conversion of IDMS creatinine levels to “non-IDMS” values will not be permitted.  
3) The carboplatin calculation tool on the GOG website has been updated.  A legacy carboplatin 
calculator (using the Jelliffe formula and IDMS to “non-IDMS” conversion) is also available, if needed 
for dose modifications (see below). 
Dosing of Carboplatin: 
 
1) The carboplatin dose will be calculated to reach a target area under the curve (AUC) according to 
the Calvert formula using an estimated glomerular filtration rate (GFR) from the Cockcroft-Gault 
formula. 
2) The initial dose of carboplatin must be calculated using GFR. In the absence of renal toxicity greater 
than or equal to CTCAE Grade 2 (serum creatinine >1.5 x ULN) or toxicity requiring dose 
modification, the dose of carboplatin will not need to be recalculated for subsequent cycles, but will 
be subject to dose modification for toxicity as noted in the protocol. 
3) Carboplatin doses will be based on the subject’s weight at baseline and will remain the same 
throughout the study. However, the doses will be recalculated if the patient has a weight change of 
greater than or equal to 10% from baseline. 
4) In patients with an abnormally low serum creatinine (less than 0.7 mg/dl), the creatinine clearance 
should be estimated using a minimum value of 0.7 mg/dl.  If a patient is currently being dosed using 
a creatinine value less than 0.7 mg/dl, adjust dose with next planned treatment. 
5) For trials where patients enter and are treated within less than or equal to 12 weeks of surgery:  If a 
more appropriate (higher) baseline creatinine value is available from the pre-operative period 
(within 4 weeks of surgery date), that value may also be used for the initial estimation of GFR. 
CALVERT FORMULA: 
 
Carboplatin dose (mg) = target AUC x (GFR + 25) 
 
NOTE:  the GFR used in the Calvert formula should not exceed 125 ml/min. 
 
Maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 ml/min. 
 
The maximum allowed doses of carboplatin are: 
 
AUC 6 = 900 mg 
 

 
 
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AUC 5 = 750 mg 
 
AUC 4 = 600 mg 
 
For the purposes of this protocol, the GFR is considered to be equivalent to the estimated creatinine 
clearance. The estimated creatinine clearance (ml/min) is calculated by the method of Cockcroft-Gault 
using the following formula: 
 
Creatinine Clearance (mL/min) =    [140-Age (years)] x Weight (kg) x 0.85  
                                                             
72 x serum creatinine (mg/dl)  
 
Notes: 
 
1) Weight in kilograms (kg): 
a. Body Mass Index (BMI) should be calculated for each patient.  A BMI calculator is available at 
the following link:  http://www.nhlbisupport.com/bmi/ 
b. Actual weight should be used for estimation of GFR for patients with BMI of less than 25.   
c. Adjusted weight should be used for estimation of GFR for patients with BMI of greater than or 
equal to 25. 
d. Adjusted weight calculation: 
Ideal weight (kg) = (((Height (cm)/2.54) – 60) x 2.3) + 45.5 
 
Adjusted weight (kg) = ((Actual weight – Ideal weight) x 0.40) + Ideal weight 
 
e. If a patient with BMI of greater than or equal to 25 is currently being dosed using actual weight, 
adjust dose with next planned treatment. 
 
2) The Cockcroft-Gault formula above is specifically for women (it includes the 0.85 factor). 
At the time of a dose modification for toxicity:  
 
1) If the creatinine at the time of a dose modification is lower than the creatinine used to calculate the 
previous dose, use the previous (higher) creatinine; if the creatinine at the time of a dose 
modification is higher than the creatinine used to calculate the previous dose, use the current 
(higher) creatinine.  This will ensure that the patient is actually receiving a dose reduction.  
2)  If the dose of carboplatin (mg) at the time of dose modification, is higher than the previous dose 
due to the use of the Cockcroft-Gault formula [when the previous dose was calculated using the 
Jelliffe formula and IDMS to “non-IDMS” conversion (if applicable)], use the same method that was 
used to calculate the previous dose [Jelliffe formula and IDMS to “non-IDMS” conversion (if 
applicable)], to calculate the dose of carboplatin (mg) at the time of dose reduction.  A legacy 
carboplatin calculator is available on the GOG website for this purpose.  This will ensure that the 
patient is actually receiving a dose reduction.