A Randomized Phase II Trial of Paclitaxel and Carboplatin vs. Bleomycin, Etoposide, and Cisplatin for Newly Diagnosed Advanced Stage and Recurrent Chemonaive Sex Cord-Stromal Tumors of the Ovary
Phase: PHASE2
Conditions: Ovarian Granulosa Cell Tumor, Ovarian Gynandroblastoma, Ovarian Sertoli-Leydig Cell Tumor, Ovarian Sex Cord Tumor With Annular Tubules, Ovarian Sex Cord-Stromal Tumor, Ovarian Sex Cord-Stromal Tumor, Not Otherwise Specified, Ovarian Steroid Cell Tumor
Sponsor: GOG Foundation

Philip J. DiSaia, M.D. 
President 
 
Administrative Office 
Four Penn Center 
1600 John F. Kennedy Boulevard, Suite 1020 
Philadelphia, Pennsylvania 19103 
Phone: 215-854-0770 Fax: 215-854-0716 
 
Laura L. Reese 
Executive Director of Operations 
 
Larry J. Copeland, M.D. 
Vice President  
 
Finance/Development Office 
2127 Espey Court 
Suite 100 
Crofton, Maryland 21114 
Phone: 410-721-7126 Fax: 301-261-3972 
 
Mary C. Sharp 
Chief Financial Officer 
 
TO: 
 
ALL PRINCIPAL INVESTIGATORS/NURSES/DATA MANAGERS 
 
FROM: 
NICOLE COPELAND 
PROTOCOL SECTION 
 
DATE: 
JUNE 13, 2016 
 
RE: 
 
GOG-0264 – REVISION 4 
 
Protocol Title:  A RANDOMIZED PHASE II TRIAL OF PACLITAXEL AND CARBOPLATIN VS. 
BLEOMYCIN, ETOPOSIDE, AND CISPLATIN FOR NEWLY DIAGNOSED ADVANCED STAGE 
AND RECURRENT CHEMONAIVE SEX CORD-STROMAL TUMORS OF THE OVARY 
 
 
NCI Version Date 12/19/2014 
 
Study Chair: Jubilee Brown, MD; (713) 792-1380 ; E-mail: jbbrown@mdanderson.org  
 
IRB Recommendations 
 
(X) No review required 
(  ) Expedited review; however, site IRB requirements take precedence 
(  ) Full board review recommended because there have been changes to the 
eligibility and/or informed consent 
 
Please direct questions about the recommended level of IRB review and/or re-consenting patients to 
your local IRB. The local IRB will make this determination. If your local IRB does not agree with the 
GOG’s recommended level of review, please document the IRB’s decision and the rationale for the 
decision in your study files. 

Philip J. DiSaia, M.D. 
President 
 
Administrative Office 
Four Penn Center 
1600 John F. Kennedy Boulevard, Suite 1020 
Philadelphia, Pennsylvania 19103 
Phone: 215-854-0770 Fax: 215-854-0716 
 
Laura L. Reese 
Executive Director of Operations 
 
Larry J. Copeland, M.D. 
Vice President  
 
Finance/Development Office 
2127 Espey Court 
Suite 100 
Crofton, Maryland 21114 
Phone: 410-721-7126 Fax: 301-261-3972 
 
Mary C. Sharp 
Chief Financial Officer 
 
 
SUMMARY OF CHANGES 
 
For Protocol Revision #4 to: 
 
NCI Protocol #: GOG-0264 
Local Protocol #: GOG-0264 
 
NCI Version Date: December 19, 2014 
Protocol Date: December 19, 2014 
 
# 
Section 
Page(s) 
Change 
1. 
Title Page 
1-2 
NCI version date has been updated. 
 
Includes Revisions #1-4. 
 
Lead Organization has been added. 
 
Revised footer has been added. 
 
ICD 
 
NCI version date has been update on the Informed Consent 
 

 
GOG-0264 
PROTOCOL GOG-0264 
A RANDOMIZED PHASE II TRIAL OF PACLITAXEL AND CARBOPLATIN VS. BLEOMYCIN, 
ETOPOSIDE, AND CISPLATIN FOR NEWLY DIAGNOSED ADVANCED STAGE AND 
RECURRENT CHEMONAIVE SEX CORD-STROMAL TUMORS OF THE OVARY 
  NCI Version:  December 19, 2014 
Includes Revision 1-4 
 
POINTS: 
PER CAPITA -10 
MEMBERSHIP-3 
TRANSLATIONAL RESEARCH POINTS-1 
Lead Organization: NRG/NRG Oncology  
 
 
STUDY CHAIR  
 
 
 
 
 
STUDY CO-CHAIR 
 
 
 
 
JUBILEE BROWN, M.D.  
 
 
 
 
WILLIAM TEW, M.D. 
M.D. ANDERSON CANCER CENTER  
 
 
 
MEMORIAL SLOAN KETTERING CANCER CTR  
DEPT OF GYN ONCOLOGY 
 
 
 
 
GYN MEDICAL ONCOLOGY 
1155 HERMAN PRESSLER DRIVE, CPB6.3241 
 
 
1275 YORK AVENUE 
HOUSTON, TX  77030 
 
 
 
 
 
NEW YORK, NY  10065  
 
 
 
PHONE: (713) 792-1380  
 
 
 
 
PHONE: (212) 639-6555  
 
 
 
FAX: (713) 792-7586 
 
 
 
 
 
FAX: (212) 717-3272 
 
 
 
 
EMAIL: jbbrown@mdanderson.org 
 
 
 
EMAIL:  teww@mskcc.org 
 
STUDY CO-CHAIR 
 
 
 
 
 
STUDY CO-CHAIR 
JOHN O. SCHORGE, M.D. 
 
 
 
 
ANIL K. SOOD, M.D. 
See GOG Website Directory 
 
 
 
 
See GOG Website Directory 
 
 
 
 
 
NURSE CONTACT (10/24/2011)  
 
 
 
 
PATHOLOGIST 
TAREN JOHNSTON, RN  
 
 
 
 
WILLIAM H. RODGERS, M.D., Ph.D. 
 
M.D. ANDERSON CANCER CENTER 
 
 
 
See GOG Website Directory 
 
DEPT OF GYN ONCOLOGY- UNIT 1360  
 
 
 
 
 
P.O. BOX 301439 
 
 
 
 
 
STATISTICIAN   
 
 
 
 
HOUSTON, TX  77030 
 
 
 
 
 
WILLIAM E. BRADY, M.S. 
 
 
 
FAX: (713) 792-6828 
 
 
 
  
 
See GOG Website Directory 
FAX: (713) 563-5593 
EMAIL: tjohnsto@mdanderson.org 
 
TRANSLATIONAL RESEARCH SCIENTIST 
HEATHER LANKES, Ph.D. 
See GOG Website Directory 
 
OPEN TO PATIENT ENTRY FEBRUARY 8, 2010 
REVISED NOVEMBER 22, 2010 
REVISED OCTOBER 24, 2011 
REVISED JUNE 13, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 

 
GOG-0264 
SCHEMA 
 
Patients diagnosed with histologically confirmed ovarian stromal tumor 
Newly diagnosed, Stage IIA – IVB disease and must be entered within eight weeks from surgery 
OR biopsy-proven recurrent disease with no prior chemotherapy 
↓ 
Randomization (1:1) 
 
    
Arm I 
Treatment: 
• 
Paclitaxel 175 mg/m2 IV over 3 hours 
• 
Carboplatin AUC = 6 IV over 1 hour 
• 
 Every 3 weeks x 6 cycles (=18weeks) 
 
Arm II 
Treatment: 
• 
Bleomycin 20 units/m2 IV Push day 1 
(MAX 30 units/cycle;  Total lifetime 
cumulative dose  should not exceed 120 
units)  
• 
Etoposide** 75 mg/m2 IV Day 1,2,3,4,5 
• 
Cisplatin 20 mg/m2 IV Day 1,2,3,4,5 
• 
 Every 3 weeks x 4 cycles (=12 weeks) 
CT/MRI Scan: prior to the fourth cycle, and after the 
end of treatment: approximately 2 weeks after the 
sixth cycle of therapy 
 
CT/MRI Scan: prior to the fourth cycles, and after 
the end of treatment: approximately 7 weeks after 
fourth cycle of therapy. 
 
*   Pulmonary Function Test (Carbon monoxide diffusion capacity)  prior to  Bleomycin and at day 
1 of 3rd & 4th cycle 
** Patients who have received prior radiation therapy will receive etoposide 60 mg/m2 on Days 1-4 
only (omit Day 5 etoposide dose, give cisplatin alone). 
 
 
 
 
 
 
 
 
 

 
GOG-0264 
                                                  TABLE OF CONTENTS                                                                PAGE  
 
 
1.0 
OBJECTIVES 
1 
2.0 
BACKGROUND AND RATIONALE 
1 
3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS 
5 
4.0 
STUDY MODALITIES 
7 
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 
14 
6.0 
TREATMENT MODIFICATIONS 
18 
7.0 
STUDY PARAMETERS 
25 
8.0 
EVALUATION CRITERIA 
27 
9.0 
DURATION OF STUDY 
34 
10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
35 
11.0 
STATISTICAL CONSIDERATIONS 
40 
12.0 
BIBLIOGRAPHY 
45 
 
 
SUGGESTED PATIENT INFORMED CONSENT 
 
APPENDIX I 
-  Clinical Staging (FIGO) 
 
APPENDIX II       -  Procedures for GOG-0264 Clinical Specimens 
 
APPENDIX III     -  Carboplatin Dose Calculation Instructions (11/22/2010)(10/24/2011) 
 
APPENDIX IV    -   General Chemotherapy Guidelines (10/24/2011)  
     

 
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GOG-0264 
 
1.0 
OBJECTIVES  
 
1.1 
Primary Objective:   
 
 
1.11 
To assess the activity of paclitaxel and carboplatin with respect to progression 
free survival (using bleomycin, etoposide, and cisplatin (BEP) as a reference) 
for newly diagnosed advanced or recurrent chemonaive ovarian sex cord-
stromal tumors. 
 
1.2 
Secondary Objectives:  
 
1.21 
To estimate the toxicity of paclitaxel and carboplatin, and bleomycin, etoposide, 
and cisplatin in this patient population. 
 
1.22 
To estimate overall survival for paclitaxel and carboplatin relative to that of 
BEP. 
 
1.23 
To evaluate response rate in the subset of patients with measurable disease. 
 
1.3 
Translational Research Objective: 
 
1.31 
To collect fixed and/or frozen tumor tissue for future translational research 
 
studies. 
 
1.4 
Exploratory Objectives 
 
1.41 
To explore the utility of inhibin A and inhibin B as prognostic and predictive 
biomarkers for ovarian sex cord-stromal tumors and to examine changes in these 
markers with treatment. 
 
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1 
Background 
 
Sex cord-stromal tumors (SCSTs) of the ovary are rare neoplasms, which account for 
less than 5% of all ovarian malignancies.1 This group of ovarian stromal tumors include 
the granulosa cell tumor, granulosa cell–theca cell tumor, Sertoli-Leydig cell tumor 
(androblastoma), steroid (lipid) cell tumor, gynandroblastoma, unclassified sex cord-
stromal tumor, and sex cord tumor with annular tubules.  SCSTs tend to have an 
indolent course, compared to epithelial ovarian cancer, and can secrete hormones (i.e. 
granulosa cell tumors - estrogen; combined Sertoli-Leydig cell tumor - androgens). 
 
Since SCSTs are uncommon, clinical trials exploring optimal chemotherapy treatments 
are limited.  Most published studies have combined histologic subtypes of SCSTs, so 
the recommendations for treating specific tumors have been based on limited data. Most 
data have been gathered from patients with adult granulosa cell tumors, but treatment 
has often been generalized to other tumor types. Additionally, many of these tumors are 
clinically indolent, so long-term follow-up is required to accurately interpret outcomes 
data. 

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GOG-0264 
 
 
Surgery remains the cornerstone of initial treatment for SCSTs.  Post-operative 
cytotoxic chemotherapy has often been given in attempt to improve cure rate. Over the 
past three decades, the recommended chemotherapy regimen has changed from VAC 
(vincristine, Adriamycin, and cyclophosphamide) to BEP (bleomycin, etoposide, and 
cisplatin). Since the 1980s, platinum-based chemotherapy has been the most widely 
used postoperative treatment.2-5  
 
Studies in 1986 and 1990 investigated combinations of cisplatin, vinblastine, and 
bleomycin for treating advanced and metastatic granulosa cell tumors of the ovary.6,7 In 
1996, Gershenson et al. reported a high response rate to bleomycin, etoposide, and 
cisplatin (BEP) in patients with poor-prognosis SCSTs of the ovary.8 Etoposide was 
substituted for vinblastine based on an earlier study in which patients with testicular 
germ cell tumors demonstrated reduced toxicity and equivalent efficacy.9 The 
Gynecologic Oncology Group (GOG 115) subsequently evaluated BEP in the treatment 
of incompletely resected stage II-IV or recurrent SCSTs of the ovary.10 The 
investigators found that 14 of the 38 patients who underwent second-look laparotomy 
had no evidence of disease, and that the six complete responders had a 24.4-month 
median duration of response. Based on the results of this trial, surgery followed by BEP 
has become a commonly utilized treatment option for patients with advanced SCSTs of 
the ovary. 
 
Unfortunately, BEP is associated with high toxicity and significant risk of disease 
recurrence. GOG 115 showed that only one of seven patients with advanced disease 
experienced a durable remission and that nearly half of the patients with recurrent 
disease experienced progression. Likewise, despite this study’s high response rate, 
Gershenson et al. noted similar limitations in durable remission.8 Both trials also 
revealed significant bleomycin-related toxicity, including two cases of pulmonary 
toxicity and two additional deaths from bleomycin-related pulmonary fibrosis.8,10 In 
addition to the cytopenias, renal dysfunction and neuropathy associated with BEP, 
etoposide can result in the subsequent development of secondary malignancies. 
 
In view of the limited activity and significant toxicity associated with BEP, the 
identification of other regimens with equivalent or improved activity and tolerability 
would be beneficial. Attempts to eliminate bleomycin from the BEP treatment regimen 
and administer etoposide and cisplatin (EP) have previously been unsuccessful in 
patients with nonseminomatous testicular germ cell tumors, resulting in decreased 
toxicity but loss of therapeutic activity.11,12 For this reason, EP alone has been thought 
to constitute inadequate therapy in this group of malignancies, and EP has not been 
pursued as a potential treatment regimen for sex cord-stromal tumors of the ovary.  
 
As first described in two case reports, taxanes have shown activity in patients with 
granulosa cell tumors.13,14 This observation led many to treat patients with newly 
diagnosed or recurrent SCSTs with taxanes, alone or in combination with platinum and 
other agents. In a retrospective analysis of patients with newly diagnosed or recurrent 
SCSTs of the ovary, activity was seen with taxanes, especially when combined with a 
platinum agent.15 Eleven patients received paclitaxel and a platinum agent, as adjuvant 
treatment.  For the nine patients treated in the first-line adjuvant setting, median 
progression-free survival was not reached at 51 months. Of two patients treated for 
measurable disease in the first-line setting, one had a complete response. The clinical 

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GOG-0264 
 
response rate for 30 patients treated with a taxane +/- platinum for recurrent, measurable 
disease was 42%. The presence of platinum correlated with response in this setting. 
Although the effectiveness of single-agent taxanes versus platinum-containing regimens 
could not be compared, these promising results provide the basis for further 
investigation of paclitaxel and carboplatin in patients with ovarian sex cord-stromal 
tumors. 
 
To date, no randomized controlled trial has compared BEP with paclitaxel and 
carboplatin in this patient population. The above studies suggest the utility of paclitaxel 
and carboplatin in this patient group, but it is still considered experimental without 
stronger evidence. This protocol is designed to determine the utility of paclitaxel and 
carboplatin using BEP as a reference for patients with newly diagnosed advanced and 
chemonaive recurrent ovarian sex cord-stromal tumors. 
 
Table 1 below summarizes the available data for BEP in this patient population.  Due to 
the limited historical data that is available and the lack of consistency of results across 
studies, it is not feasible to do a single-arm trial of paclitaxel and carboplatin combination 
chemotherapy and compare the results with historical control data. 
 
Table 1: Results from Past Studies in this Patient Population 
Study 
N 
Population 
Treatment 
PFS (mo) 
Median 
(95% CI) 
Survival (mo) 
Median 
(95% CI) 
GOG 011510 
16 
Stage II, III, IV 
B: 20 units/m2 on d 1 
E: 75 mg/m2 IV on d 1-5 
P: 20 mg/m2 on d 1-15 
q 3 weeks x 4 courses 
66 (13, NE) 
NE (47, NE) 
Gershenson 
(1996)8 
9 
Ia, IIc, IIIc, or 
recurrent 
B: 10-15 mg on d 1-3 
E: 100 mg/m2 IV on d 1-3 
P: 100 mg/m2 on d 1 
q 4 weeks 
14 (NA) 
28 (NA) 
Brown 
(2005)16 
11 
Newly diagnosed 
(Retrospective 
review of cases) 
BEP 
46 (NA) 
97 (NA) 
Pautier 
(2008)17 
20 
advanced ovarian 
granulosa cell 
tumors: initial 
metastatic (n=5) 
or recurrent 
(n=15) 
B: 30 mg on d1, 8, 15 
E: 100 mg/m2 IV on d 1-5 
P: 20 mg/m2 on d 1-5 
q 3 weeks, for 4 courses 
25 (NA) 
46 (NA) 
NE: not estimable 
NA: not available 
 
 
Of note, inhibin A and inhibin B may be helpful immunohistochemical stains to aid in 
the pathologic diagnosis and clinical response of sex cord-stromal ovarian tumors.18-21 In 
a panel of 29 stromal ovarian tumors, all were found to be positive for inhibin A, and 
59% were found to be positive for inhibin B.22 Inhibin B may be particularly helpful in 
identifying recurrent disease.23 Therefore, serum levels of inhibin A and B will be 
collected during this study to explore their use as prognostic and predictive  

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GOG-0264 
 
biomarkers for ovarian sex cord-stromal tumors and to examine changes in these markers 
in response to treatment. 
 
2.2 
Proposed Study 
 
The proposed study will randomize newly diagnosed patients with advanced stage 
SCSTs and chemonaive patients with recurrent SCSTs to either carboplatin/paclitaxel 
OR BEP.  The proposed hypothesis states that carboplatin/paclitaxel will be equally 
effective and less toxic than BEP.   
 
A non-inferiority hypothesis is used for the primary objective.  If a hazard ratio of 1.1 
can be excluded (based on an upper 85% confidence limit), carboplatin/ paclitaxel will 
be considered not inferior to BEP. 
 
2.3 
Translational Research 
 
The translational research component of this study will establish a bank of fixed and/or 
frozen tissue. As study accrual will take place over several years, the specific 
translational research endpoints will be deferred until after the specimen collection is 
complete. Future innovations in technology and biomarker development will guide the 
translational research studies to be done on this valuable tissue collection. 
 
2.4 
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 cancer population treated by participating 
institutions. 
 

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GOG-0264 
 
 3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS  
 
3.1 
Eligible Patients 
 
3.11     Patients diagnosed with histologically confirmed ovarian stromal tumor  
[granulosa cell tumor, granulosa cell–theca cell tumor, Sertoli-Leydig cell tumor 
(androblastoma), steroid (lipid) cell tumor, gynandroblastoma, unclassified sex 
cord-stromal tumor, sex cord tumor with annular tubules]. 
 
3.12 
Patients must have newly diagnosed, Stage IIA – IV disease and must be entered 
within eight weeks from surgery; they may have either measurable residual 
disease by RECIST criteria, or they may have no measurable residual disease; 
OR, they must have biopsy-proven recurrent disease of any stage and have never 
received cytotoxic chemotherapy. 
 
3.13 
Patients must have a GOG performance Grade of 0, 1, or 2. 
 
3.14  
Patients of childbearing potential must have a negative serum pregnancy test and 
must agree to practice an effective means of birth control. 
 
3.15 
Patients in the measureable disease cohort must have at least one “target lesion” 
to be used to assess response on this protocol as defined by RECIST 1.1 
(Section 8.0). Tumors within a previously irradiated field will be designated as 
“non-target” lesions unless progression is documented or a biopsy is obtained to 
confirm persistence at least 90 days following completion of radiation therapy. 
 
3.16 
Patients who have met the pre-entry requirements specified in Section 7.0.
 
Patients must have adequate: 
 
 
 
 
3.161  Bone marrow function: Absolute neutrophil count (ANC) greater  
 
 
 
 
than or equal to 1,500/mcl, equivalent to CTCAE grade 1.    
 
 
 
 
Platelets greater than or equal to 100,000/mcl. 
 
 
 
 
3.162  Renal function:  Creatinine no greater than the institutional upper limits 
 
 
 
 
of normal. (11/22/2010) 
 
3.163  Hepatic function: Bilirubin less than or equal to 1.5 x ULN   
 
(CTCAE grade 1), SGOT (AST) less than or equal to 3.0 x ULN 
            (CTCAE grade 1) and alkaline phosphatase less than or equal to 2.5 x  
            ULN (CTCAE grade 1). 
 
 
 
 
3.164  Neurologic function: Neuropathy (sensory and motor) less than or  
 
 
 
            equal to CTCAE Grade 1. 
 
 
 
 
3.165  Hearing function:  No signs of clinically significant hearing loss. 
 
3.17 
Patients must have signed an approved informed consent and  
authorization permitting release of personal health information. 
 

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GOG-0264 
 
3.18  Patients must have pulmonary function sufficient to receive bleomycin, with 
normal lung expansion, absence of crackles on auscultation, and normal carbon 
monoxide diffusion (DLCO), defined as greater than 80% predicted. 
 
3.19  Patients with a history of hypersensitivity reactions to prior chemotherapy 
administered for previous cancer diagnoses are eligible to participate in the study, 
unless the hypersensitivity reaction consisted of anaphylaxis not amenable to 
desensitization. 
 
 
 
3.110 Recovery from effects of recent surgery, radiotherapy, or chemotherapy.   
 
3.1101     Patients must be entered within 8 weeks after surgery performed for     
                either 1) initial diagnosis, staging, and/or cytoreduction, or 2) (if done)  
    management of recurrent disease in a chemonaive patient. 
 
3.1102     Any hormonal therapy directed at the malignant tumor must be  
                            discontinued at least one week prior to registration.  Continuation    
                            of hormone replacement therapy is permitted. 
 
3.111 Patients must be ≥ 18 years of age.  
 
3.2  
Ineligible Patients 
 
3.21     Patients who have received any prior cytotoxic chemotherapy or biologics for 
sex cord-stromal tumors (SCSTs).  
 
3.22 
Patients with apparent Stage I disease who have not undergone a staging  
 
procedure. 
 
3.23 
Patients with a history of other invasive malignancies, with the exception    
            of non-melanoma skin cancer, are excluded if there is any evidence of   
            other malignancy being present within the last five years.   
 
3.24 
Woman who are pregnant or breastfeeding. 
 
3.25 
Patients with medical history or conditions not otherwise previously specified 
which in the opinion of the investigator should exclude participation in this 
study. The investigator can consult the Study Chair or Study Co-Chairs for 
uncertainty in this regard. 
 
 

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GOG-0264 
 
4.0 
STUDY MODALITIES  
 
4.1 
Paclitaxel (NSC #673089) 
 
 
4.11  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. 
 
4.12   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-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.  
 
4.13   Storage: The intact vials can be stored in a temperature range between 2-25 C 
(36-77°F).  
 
4.14   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. 
 
4.15  Supplier: Commercially available 
 
4.16 
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 5.221) 
 

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GOG-0264 
 
4.17 
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 
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. 
 
4.2   
Carboplatin (Paraplatin®, NSC # 241240)  
 
4.21   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.  
 
  
4.22   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.  
 

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GOG-0264 
 
  
4.23   Storage: Unopened vials of carboplatin are stable for the life indicated on the 
package when stored at controlled room temperature and protected from light. 
  
  
4.24   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.  
 
  
4.25   Supplier: Commercially available  
 
4.26  Administration: See Appendix III for current Carboplatin dose calculation 
instructions (11/22/2010) 
 
4.27   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 
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.  
 
4.3 
Bleomycin (Blenoxane7 - NSC #125066) 
 
4.31 
Formulation:  Bleomycin is available as a dry powder supplied in 15 unit vials. 
 
4.32 
Preparation:  Dissolve the contents of a Blenoxane vial in 1 to 5 ml of sterile 
water for injection, USP, sodium chloride for injection, USP, 5% dextrose 
injection, USP, or bacteriostatic water for injection, USP.  (Note: 1 unit = 1 mg) 
 
4.33 
Storage: The sterile powder is stable under refrigeration (2N-8NC) and should 
not be used after the expiration date is reached.  Blenoxane is stable for 24 hours 
at room temperature in sodium chloride or 5% dextrose solution.  Blenoxane is 

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GOG-0264 
 
stable for 24 hours in 5% dextrose containing heparin 100 units per ml or 1000 
units per ml. 
 
4.34 
Adverse effects: Fever, chills, pulmonary fibrosis, stomatitis, weight loss, 
anorexia, renal and hepatic toxicity, erythema, rash, vesiculation, striae, 
hyperpigmentation, skin tenderness, hyperkeratosis, nail changes and pruritus.  
Rare: Myocardial infarction, CVA, thrombotic microangiopathy (HUS) or 
cerebral arteritis. 
 
4.35 
Supplier:  Commercially available 
 
4.36 
Administration:  See section 5.231 
 
*See FDA-approved package insert for a comprehensive list of adverse events 
associated with carboplatin.  
 
4.4 
VP-16 (Etoposide, VePesid7 - NSC #141540) 
 
4.41 
Formulation: VP-16 injection is available in 100 mg (5 ml) sterile, multiple-dose 
vials.  The pH of the clear, yellow solution is 3 to 4.  Each ml contains 20 mg 
etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg polysorbate 80/tween 
80, 650 mg polyethylene glycol 300 and 30.5% (v/v) alcohol. 
 
4.42 
Preparation: The computed dose should be diluted in 500 mL NS or D5W and 
administered over 1-2 hours IV.  
 
4.43 
Storage: Unopened vials of VP-16 are stable for 24 months at room temperature.  
Vials diluted as recommended to a concentration of 0.2 or 0.4 mg/ml are stable 
for 96 and 48 hours, respectively, at room temperature under normal room 
fluorescent light in both glass and plastic containers. 
 
4.44 
Adverse effects: Leukopenia, thrombocytopenia, alopecia, nausea, vomiting, 
headache, fever, hypotension, anorexia, and allergic reactions. 
 
4.45 
Supplier: Commercially available. 
 
4.46 
Administration:  See Section 5.232 
 
*See FDA-approved package insert for a comprehensive list of adverse events 
associated with carboplatin.  
 
4.5 
Cisplatin (Platinol - NSC #119875) 
 
4.51 
Formulation:  Cisplatin is available as a dry powder supplied in 10 mg and 50 
mg vials and in aqueous solution in 50 mg and 100 mg vials with 100 mg 
mannitol and 90 mg sodium chloride. 
 
4.52 
Preparation:  The 10 mg and 50 mg vials should be reconstituted with 10 ml or 
50 ml with sterile water for injection, USP respectively.  Each ml of the 

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GOG-0264 
 
resulting solution will contain 1 mg of Platinol.  Reconstitution as recommended 
results in a clear colorless solution. 
 
NOTE:   Aluminum reacts with Platinol causing precipitation 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 Platinol. 
 
4.53 
Storage: Unopened vials of dry powder are stable for the lot life indicated on the 
package when stored at room temperature.  The aqueous solution should be 
stored at room temperature and protected from light.  The reconstituted solution 
is stable for 20 hours at room temperature. 
 
NOTE: Once reconstituted, the solution should be kept at room temperature.  If 
the reconstituted solution is refrigerated, a precipitate will form. 
 
4.54 
Administration:  See Section 5.233 
 
4.55 
Adverse effects:  Leukopenia, thrombocytopenia, anemia nausea, vomiting, 
nephrotoxicity, ototoxicity, peripheral neuropathy, electrolyte imbalance, 
hypocalcemia, hypomagnesemia, aminoglycoside, ototoxicity, ocular toxicity 
and allergic reactions.  Infrequent: Cardiac abnormalities, anorexia, elevated 
SGOT, rash and alopecia. 
 
NOTE: Aminoglycoside antibiotics given before, with, or after cisplatin may 
potentiate renal toxicity and should be avoided whenever possible. 
 
Severe renal toxicity can be largely avoided by induction of a diuretic before, 
during and after treatment. 
 
Mild renal dysfunction is a common complication (10%) of chronic therapy and 
may require discontinuation of therapy if BUN > 30 mg/dl or creatinine > 2.0 
mg/dl develop. 
 
Mild or severe electrolyte abnormalities may occur (5%) as acute or chronic 
complications, especially hypokalemia or hypomagnesemia.  Monitoring of 
electrolytes and electrolyte replacement will usually correct these abnormalities.  
Rarely, severe hypomagnesemia and hypocalcemia may require replacement 
therapy and discontinuation of treatment with cisplatin. 
 
Allergic reactions are rare.  If accompanied by respiratory symptoms, allergic 
reactions require discontinuation of treatment.  Patch or skin tests are 
recommended for patients with suspected allergy to cisplatin.  An emergency set 
for the treatment of allergic reactions should be available in the treatment area. 
 
Local necrosis and thrombophlebitis can be avoided by careful administration. 
 
Neurotoxicity may be related to cumulative dose and severe toxicity can be 
largely avoided by careful monitoring for evidence of paresthesias and timely 
discontinuation of treatment.  Ataxia has been described. 

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GOG-0264 
 
 
Ototoxicity may occur. 
 
NOTE:   Eighth (VIII) nerve toxicity resulting in hearing loss and (less 
commonly) vestibular symptoms is a well documented complication of cisplatin 
treatment and is usually related to total cumulative dose.   
 
4.56 
Supplier:  Commercially available 
. 
It is advised that patients placed on cisplatin, whether as a single agent therapy 
or combination, be questioned concerning hearing loss.  Patients with a history 
of hearing loss should be considered for pre-treatment audiometry with 
follow-up audiometry as clinically indicated.  It is recommended that patients be 
queried concerning hearing loss before each cycle of cisplatin. 
 
*See FDA-approved package insert for a comprehensive list of adverse events 
associated with carboplatin.  
 
4.6 
Pathology 
 
4.61 
Malignant tumors of the ovarian stroma are: granulosa cell tumor, 
granulosa-theca cell tumor, Sertoli-Leydig cell tumor (androblastoma), steroid 
(lipid) cell tumor, unclassified sex cord stromal tumor, sex cord tumor with 
annular tubules, and gynandroblastoma. 
 
 
4.62 
The following definitions are those of the World Health Organization: 
(from Tavassoli FA, Devilee P (eds), World Health Organization Classification 
of Tumours, Pathology and Genetics of Tumours of the Breast and Female 
Genital Organs, IARC Press, Lyon, 2003): 
 
Ovarian stromal tumors (sex cord stromal tumors) contain granulosa cells, theca 
cells, collagen producing stromal cells, Sertoli cells, Leydig cells, and cells 
resembling their embryonic precursors, singly or in various combinations.  
Specific nomenclature reflects the cellular constituents of the tumors i.e.: 
 
Granulosa cell tumors (granulosa-theca cell tumors) are tumors containing 
granulosa cells, theca cells, and stromal cells resembling fibroblasts singly or in 
various combinations.  The tumor contains more than a small component of 
granulosa cells.   
 
Sertoli-Leydig cell tumors (androblastomas) are tumors containing Sertoli and 
Leydig cells of varying degrees of maturity; indifferent gonadal cells of 
embryonal appearance are present in certain cases. 
 
Gynandroblastoma is a very rare tumor in which collections of granulosa cells 
with typical Call-Exner bodies coexist with hollow tubules lined by Sertoli cells. 
 

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GOG-0264 
 
Unclassified sex cord stromal tumors are those in which sex cord and/or stromal 
elements are present although they cannot be specifically identified as either 
ovarian or testicular in type. 
 
Sex cord tumor with annular tubules is a rare tumor in the unclassified category 
which is commonly multifocal and of microscopic size.  It is seen 
disproportionately often in patients with the Peutz-Jeghers syndrome, and is 
characterized by simple and complex ring-shaped solid tubules containing cells 
of Sertoli or granulosa type, by the presence of hyaline bodies, and by a 
tendency to calcify in a manner similar to that of the gonadoblastoma. 
 
4.63 
All metastatic implants submitted by the surgeon will be submitted for 
histologic examination if disease is found histologically (if a staging biopsy was 
not performed, or if the biopsies did not show tumor, slides do not have to be 
submitted from the staging procedure). If implants are identified, a 
representative slide confirming the disease as malignant shall be submitted for 
review. 
 
4.64 
Primary tumors should be sampled at a minimum rate of one section per two 
centimeters of greatest diameter of tumor.  All slides containing tumor on these 
cases should be submitted to the GOG.  Form F (Pathology Form) and three 
copies of the dictated pathology report must be submitted with the required 
slides. 
 
4.65 
If the uterus is removed, representative sections of endometrium must be 
submitted.  If the uterus is not removed, endometrial sampling is required and 
sections must be submitted for pathology review.* 
 
4.66 
Peritoneal fluid from the primary surgery must be sent for cytology as an 
aspirate or washing.  Three copies of the dictated cytology report and a 
representative slide (or representative photomicrograph) of positive specimens 
must be submitted. If no tumor is found in the cytology specimen only the 
cytology report should be submitted. 
 
 
 
 
* Section 4.65 is not required if the uterus was previously removed for reasons 
not related to the current illness. 
 
 
 
 
Please see sections 7.2 and 10.2 for additional instructions and requirements. 

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GOG-0264 
 
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 
 
Sites must submit, all IRB approvals (initial and continuing) on NCI sponsored adult 
Cooperative Group phase I, II & III prevention and treatment studies to the CTSU Regulatory 
Office, at the Coalition of Cancer Cooperative Groups in Philadelphia. A CTSU 
IRB/Regulatory Approval Transmittal Sheet should be submitted along with the CTSU IRB 
Certification Form or its equivalent. (CTSU forms can be downloaded at 
https://www.ctsu.org/public/rss2_page.aspx).  IRB submissions can be faxed or e mailed 
(preferred methods) or mailed to:  (11/22/2010) 
 
Email, Mail or Fax to: 
Cancer Trials Support Unit (CTSU) 
ATTN: Coalition of Cancer Cooperative Groups (CCCG) 
Suite1100 
1818 Market Street 
Philadelphia, PA 19103 
FAX: 1-215-569-0206 
CTSURegulatory@ctsu.coccg.org 
 
 
5.1 
Patient Registration 
 
When a suitable candidate has been obtained for protocol entry, the following steps 
should be taken:  
 
5.11 
Patient must have signed an approved informed consent and authorization 
permitting release of personal health information.  Current FDA, NCI and 
institutional regulations concerning informed consent will be followed.  
 
5.12 
All eligibility requirements indicated in section 3.0 must be satisfied.  
 
5.13 
The Fast Fact Sheet data for this protocol must be gathered and the pretreatment 
testing as required in Section 7.0. 
 
5.14 
The institution must register the patient using the web-based registration 
application or when necessary by phone. 
 
5.141 Instructions for web-based registration and randomization can be found 
by going to the GOG Web Menu page, selecting "Start/finish a patient 
registration," and then selecting "Directions" found on the left side of the 
page. Assistance is available from the Statistical and Data center by 
phone if necessary (1-800-523-2917). 
 
5.142 Alternatively, when necessary, patient registration can take place by 
phoning the GOG Statistical and Data Center at:  1-800-523-2917, 
Monday through Friday, 9 a.m. to 5 p.m. EST/EDT.  
Entry/Randomization will take place on the  telephone after 
consideration of Fast Fact Sheet data.  
 

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GOG-0264 
 
5.15 
The institution must enter the patient’s name, and GOG patient study ID,  
 
 
in the appropriate place in their Log Book to verify the patient’s entry. 
 
5.2 
Treatment Plan 
 
 
 
5.21 
Patients will be randomized in a 1:1 ratio to one of the two treatment arms  
 
 
below.  The randomization will be stratified by the presence or absence of  
 
 
measurable disease. 
 
 
 
5.22 
Arm I: Paclitaxel and Carboplatin 
 
If randomized to this arm, patients will receive the following: 
 
5.221 Paclitaxel (175 mg/m2) IV by 3-hour infusion on day 1 every  
 
21 days for 6 cycles (=18 weeks), unless progression or adverse 
 
effects prohibit further therapy. 
 
5.222 Carboplatin (AUC of 6) IV by one hour infusion on day 1 every 21 
 
days for 6 cycles (=18weeks), unless progression or adverse effects  
 
prohibit further therapy. 
 
 
 
5.23 
Arm II: Bleomycin, Etoposide, and Cisplatin (BEP) 
 
If randomized to this arm, patients will receive the following: 
 
5.231 Bleomycin (20 units/m2; max dose is 30 units) is to be given on 
 
day 1 as IV push every three weeks for four cycles (=12 weeks).   
 
The total cumulative bleomycin dose shall not exceed 120 units.   
 
 
Bleomycin will be discontinued permanently if the carbon  
 
monoxide diffusion capacity has decreased more than 20% from  
 
baseline, or at any time if the patient develops rales or lack of 
 
expansion on physical examination of chest (see section 6.56). 
 
5.232 Etoposide (VP-16) (75 mg/m2) IV over 60 minutes daily times five days, 
every three weeks for four cycles (= 12 weeks).   
*Patients who have received prior pelvic radiation therapy will receive 
etoposide on days 1-4 only. 
 
5.233 Cisplatin (20 mg/m2) IV over 30 minutes IV daily times five days,  
every three weeks for four cycles (=12 weeks). 
 
 
5.24 
Methods of Protocol Administration 
 
5.241 Biometric Considerations for Dose Calculation  
 
5.2411     Maximum body surface area used for dose calculations of   
                paclitaxel, etoposide, and cisplatin will be 2.0 m2 as per the   
                GOG Chemotherapy Procedures Manual.  

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GOG-0264 
 
 
5.2412   Maximum body surface area used for dose calculations of 
bleomycin will be 1.5 m2 because the maximum dose 
allowable is 30 units.  
 
5.2413   Weight Change:  If a patient’s weight changes by ≥ 10% 
during the course of the study, the doses of paclitaxel, 
carboplatin, bleomycin, etoposide, and cisplatin will be 
recalculated. 
 
 
 
 
 
5.2414     Rounding Dose:  Doses of paclitaxel and carboplatin,  
 
 
 
 
                may be rounded to the nearest 5 mg.  Doses of bleomycin, 
 
 
 
 
 
    etoposide and cisplatin may be rounded to nearest 1mg. 
 
5.242 Dosing of Carboplatin  
 
See Appendix III for current Carboplatin dose calculation instructions.  
(11/22/2010) 
 
Note: Carboplatin dose will be recalculated if patient has weight 
change ≥ 10% from baseline. (10/24/2011) 
 
5.243 Sequence and timing of drug administration 
 
5.2431 Arm I:  Paclitaxel will be infused over 3 hours.  Due to the risk of 
immediate hypersensitivity reaction, paclitaxel should be infused 
prior to carboplatin.  Carboplatin will be administered as a 60 
minute infusion following paclitaxel. 
 
5.2432 Arm II:  First, bleomycin given as an IV push (day 1 only).  
Second, etoposide given over 60 minutes (day1-5).  Third, 
cisplatin given over 30 minutes (day1-5).   
 
 
Refer to Appendix IV for General Chemotherapy Guidelines. 
(10/24/2011) 
 
5.244 Premedications 
 
 
 
 
 
5.2441    Paclitaxel: 
 
 
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 to these drugs. 
 
 
This regimen should include a standard dose of dexamethasone 
(either IV or PO), an anti-histamine H1 (diphenhydramine 25-              
50mg IVP or orally, or an equivalent dose of an alternate H1 
blocker such as loratadine or fexofenadine), and a standard 

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GOG-0264 
 
dose of antihistamine H2 IVP (such as cimetidine, ranitidine, or 
famotidine). 
 
5.245    Concomitant anti-neoplastic therapy 
 
Prior to documented disease progression, the following therapeutic 
modalities will be considered protocol violations: 
• 
Reassessment or cytoreductive surgery 
• 
Anti-neoplastic therapy not otherwise specified in the current 
protocol, including cytotoxic, biologic, hormonal, or radiation 
therapy, regardless of indication (treatment of measurable disease 
or consolidation therapy). 
• 
Hormone replacement therapy is NOT a protocol violation. 
 
5.246  Antiemetic Regimens 
 
It is anticipated that nausea and vomiting may be a significant side effect 
of each regimen (BEP and carboplatin/paclitaxel). The following 
representative antiemetic regimens are suggested: 
 
• Ondansetron 8-32 mg IV 30 minutes prior to administration of 
chemotherapy and dexamethasone 10-20 mg PO/IV 30 minutes prior to 
drug administration or,  
 
• Granisetron 10 mcg/kg IV (or 2 mg PO) 30 minutes prior to 
 
 
 
 
chemotherapy, with or without lorazepam 0.5-2 mg IV 30   
 
 
 
 
minutes prior to chemotherapy. 
 
•  Aprepitant (Emend) – To treat delayed nausea/vomit for patients on 
either treatment arms, consider the addition of Aprepitant 120mg PO day 
1 and Aprepitant 80mg PO day 2 and 3, along with dexamethasone 12mg 
PO day 2 and day 3.    
 

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GOG-0264 
 
6.0 
TREATMENT MODIFICATIONS    
 
In order to maximize dose intensity on this study, there will be no dose reductions unless 
treatment is delayed for more than two weeks, or if patients experience febrile neutropenia, 
sepsis, or thrombocytopenia as described below.  Any patient who is delayed must be evaluated 
on a weekly basis until adequate hematologic and non-hematologic parameters have been met. 
Treatment delays are to be kept to a minimum and every effort should be made to maintain the 
intended schedule. No treatment delays are permitted for other than documented toxicity. No 
dose escalation is planned for this study. 
6.1  
General Guidelines for Hematologic Toxicity: 
 
6.11 
Treatment modifications will be based on the absolute neutrophil count (ANC) 
rather than the total white count (WBC).  
 
6.12 
Treatment modifications will be employed in a sequential manner using cycle             
delay, dose reduction, and addition of myeloid growth factors, as directed.   
 
 
6.13 
Subsequent cycles of therapy will not begin until the ANC is > 1,500cells/mm3 
and the platelet count is > 100,000 cells/mm3. Therapy will be delayed on a 
week-by-week basis until these values are achieved.  Patients who fail to recover 
adequate counts within a three-week delay will be removed from study only 
after one of the Study Chairs has been contacted. Follow-up on the patient will 
continue as described in Section 7.0. 
 
 
 
Exceptions: 
 
• 
Patients who received G-CSF prior to the current cycle may begin with     
            ANC ≥ 1000 cells/mm3, if clinically appropriate, to allow for transient              
            reductions in ANC after discontinuation of G-CSF. 
 
• 
Patients who are delayed more than 7 days may begin with ANC ≥ 1000      
                                    cells/mm3, if clinically appropriate; as they will receive G-CSF with 
subsequent therapy  
 
 
6.14 
Use of Hematopoietic Cytokines and Protective Agents 
 
 
 
The use of hematopoietic cytokines and protective reagents are restricted as  
 
 
noted: 
 
 
6.141 In general, patients will NOT receive prophylactic filgrastim (G-CSF),  
 
PEG-filgrastim (Neulasta), or sargramostim (GM-CSF) unless they 
experience treatment delays or recurrent neutropenic complications after 
treatment modifications as specified. In particular, hematopoietic growth 
factors should not be used to avoid initial chemotherapy dose 
modifications as stipulated in the protocol. However, patients may also 
receive growth factors for management of neutropenic complications in 
accordance with clinical treatment guidelines. If required, it  is 
recommended that growth factors be initiated the day after the last dose 

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GOG-0264 
 
of chemotherapy and typically continuing for a minimum of 10 days or 
until the ANC is sustained above >1000/mm3. Growth factors should be 
discontinued if the ANC exceeds 10,000/ mm3 and should not be used 
within 72 hours of a subsequent dose of chemotherapy. 
 
6.142 Patients will NOT receive prophylactic thrombopoietic agents unless 
they experience recurrent Grade 4 thrombocytopenia after treatment 
modifications as specified below. 
 
6.143 Patients may receive erythropoietin (EPO), iron supplements, and/or 
transfusions as clinically indicated for management of anemia. Treating 
physicians should be aware of the recent changes in prescribing 
information for the erythropoiesis stimulating agents (including Aranesp, 
Epogen and Procrit) which note that there is a potential risk of shortening 
the time to tumor progression or disease-free survival, and that these 
agents are administered only to avoid red blood cell transfusions. They 
do not alleviate fatigue or increase energy. They should not be used in 
patients with uncontrolled hypertension. They can cause an increased 
incidence of thrombotic events in cancer patients on chemotherapy. The 
updated package inserts should be consulted. 
http://www.fda.gov/Medwatch/safety/2007/safety07.htm 
 
6.144 Patients may NOT receive amifostine or other protective reagents, unless 
indicated in the study design. 
 
6.15 
There will be no dose modifications for paclitaxel, cisplatin or bleomycin based 
on hematologic toxicity. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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GOG-0264 
 
 
6.2  
Modifications for Hematologic Toxicity (Nadirs) 
 
 
 
 
* For patients with prior pelvic radiation, who start on a day1-4 schedule: dose modification would be to 
discontinue day #4 etoposide (first occurrence) and day #3 etoposide (second occurrence). 
 
 
 
 6.21 Initial occurrence of dose-limiting neutropenia (defined in 6.22) or dose 
 
limiting thrombocytopenia (defined in 6.23) will be handled according to   
Table A. 
 
6.22  Dose-Limiting Neutropenia (DLT-ANC) is defined by the occurrence of febrile 
neutropenia or prolonged Grade 4 neutropenia persisting ≥ 7 days.  There will be 
no modifications for uncomplicated Grade 4 neutropenia lasting less than 7 
days. Febrile neutropenia is defined within the CTCAE as fever with or without 
clinically or microbiologically documented  infection with ANC less than 1,000 
/mm3 and fever greater than or equal  to 38.5°C.  
 
6.23  Dose-limiting thrombocytopenia (DLT-PLT) is defined by any occurrence 
 
of Grade 4 thrombocytopenia (<25,000/mm3) or bleeding associated with 
Table A: Modification Instructions for Dose-Limiting Hematologic Toxicity 
(Arm1: Carboplatin/paclitaxel;  Arm 2: BEP) 
DLT 
ANC 
DLT 
PLT 
First occurrence 
Second occurrence 
Third occurrence 
YES 
NO 
Arm 1: Reduce carboplatin 
one AUC unit 
Arm 2: Discontinue day #5 
etoposide.* 
Arm 1:Add G-CSF and maintain all 
current drug doses 
Arm 2: Add G-CSF and maintain all 
current drug doses. 
Discontinue 
chemotherapy 
 
YES 
YES 
Arm 1: Reduce carboplatin 
one AUC unit 
Arm 2: Discontinue day #5 
etoposide.* 
Arm 1: Add G-CSF and decrease 
carboplatin one AUC unit. 
 
Arm 2: Add G-CSF and discontinue 
day #4 etoposide.* 
Discontinue 
chemotherapy 
 
NO 
YES 
Arm 1: Reduce carboplatin 
one AUC unit 
Arm 2: Discontinue day #5 
etoposide.* 
Arm 1: Decrease carboplatin one 
AUC unit. 
 
Arm 2: Discontinue day #4 
etoposide.* 
Discontinue 
chemotherapy 

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GOG-0264 
 
 
Grade 3 thrombocytopenia (25,000 to <50,000/mm3). There will be no 
 
modifications for uncomplicated Grade 3 thrombocytopenia. 
 
 
6.3 
Modifications for Delayed Hematologic Recovery 
 
 
 
 
 
 
 
 
 
 
* For patients with prior pelvic radiation, who start on a day1-4 schedule: dose 
modification would be to discontinue day #4 etoposide. 
 
6.31 
Delay on the basis of neutropenia (Delay-ANC) is defined if the ANC is less 
than 1,500 cells/mm3 (CTCAE Grade 3 or worse) within 24 hours  prior to 
scheduled therapy, or less than 1,000 cells/mm3, if the patient received G-CSF 
during the previous cycle. 
 
6.32  Delay on the basis of thrombocytopenia (Delay-PLT) is defined if the 
 
platelet count is less than 100,000/mm3 within 24 hours prior to scheduled 
 
therapy. 
 
 
6.33  Modifications noted above (TABLE B) are only required for management of 
delays in the absence of dose reductions stipulated by nadir DLT-ANC and/or 
DLT-PLT (as noted above).  
 
 
 
 
Table B: Modifications for Delayed Hematologic Recovery (NOT DLT) 
Category 
Delay 
(days) 
Modification 
Delay-ANC 
1-7: 
No change 
8-21 
Arm1: Add G-CSF with next cycle 
Arm2: Discontinue day #5 etoposide* and add G-CSF 
with next cycle 
>21 
Arm1: Discontinue chemotherapy 
Arm2: Discontinue chemotherapy 
Delay-PLT 
1-7: 
No change 
8-21: 
Arm1: Decrease carboplatin one AUC unit 
Arm2: Discontinue day #5 etoposide.* 
>21: 
Arm1: Discontinue chemotherapy 
Arm2: Discontinue chemotherapy 

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GOG-0264 
 
6.4 
Non-hematologic Toxicity: 
 
Table C: Modifications for Non-hematologic Toxicity 
Drug 
Regimen 
-2 Level 
Regimen  
-1 Level 
Regimen 
Starting Dose 
Paclitaxel 
110 mg/m2 
135 mg/m2 
175 mg/m2 
Carboplatin 4 
5 
6 
Bleomycin 
discontinue 
discontinue 
20 units/m2 
Etoposide 
75mg/m2 day 1-3 
75mg/m2 day1-4 
75mg/m2 day1-5 
Cisplatin 
20mg/m2 day1-3 
20mg/m2 day1-4 
20mg/m2 day1-5 
* For patients with prior pelvic radiation, who start on a day1-4 schedule:  
dose modification would be to discontinue day #4 etoposide or cisplatin (-1Level) 
and discontinue day #3 etoposide or cisplatin (-2Level). 
 
 
6.41  Neurologic Toxicity: Patients who experience > grade 2 neurotoxicity requires 
one dose reduction (Arm 1: paclitaxel only, Arm 2: cisplatin only).  Treatment 
will be delayed up to three weeks until toxicity resolves to < grade 1. If toxicity 
dose not resolve within 3 week delay, patient will discontinue the treatment 
(Arm 1: paclitaxel, Arm 2:cisplatin) and Study Chair will be notified.  Docetaxel 
could be substituted for paclitaxel after 3 week delay, only after discussion with 
Study Chair. 
 
6.42  GI Toxicity: There will be no dose modifications for nausea, vomiting, diarrhea 
or constipation.  It is recommended that routine medical measures be employed 
to manage these symptoms. Any other Grade 4 gastrointestinal toxicity requires 
a one dose level reduction. 
 
6.43  Hepatic Toxicity: Hepatic toxicity is not expected as a direct complication of 
chemotherapy in this untreated patient population using the prescribed dose and 
schedule for each regimen. However, the development of Grade 3 (or greater) 
elevations in SGOT (AST), SGPT (ALT), alkaline phosphatase or bilirubin 
requires reduction of one dose level in paclitaxel (arm 1) and delay in 
subsequent therapy for a maximum of three weeks until recovered to Grade 1. 
 
6.44  Renal Toxicity: For Arm 1, renal toxicity (associated with reduction in GFR) is 
not expected as a direct complication of chemotherapy in this untreated patient 
population using the prescribed dose and schedule of each regimen. As such, 
there are no specific dose modifications for renal toxicity.  
 
However, for Arm 1, the target AUC dose of carboplatin must be recalculated 
each cycle in any patient who develops renal insufficiency, defined by serum 
creatinine greater than 1.5 x institutional upper limit normal (ULN), CTCAE 
Grade ≥ 2.   
 
See Appendix III for current carboplatin dosing instructions. (11/22/2010) 
 
For Arm 2, patients who experience any serum creatinine rise above 2.0 mg/dl 
will require discontinuation of bleomycin (excreted by kidneys) and one dose 
reduction in cisplatin and etoposide.  Treatment will be delayed up to three 
weeks until toxicity resolves to < grade 1. If toxicity dose not resolve within 3 

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GOG-0264 
 
week delay, patient will discontinue the treatment and Study Chair will be 
notified.   
 
To avoid renal toxicity, standard hydration with cisplatin should be 
administered. 
 
6.45  Cardiac Toxicity: Asymptomatic bradycardia is not an indication for 
discontinuation of therapy or for routine monitoring. If any other arrhythmia is 
documented, monitoring may be required. A paclitaxel infusion may be 
discontinued for a cardiac arrhythmia that shows evidence of AV nodal block 
(e.g. Mobitz type l or 2 or total heart block). Any arrhythmia that is felt to 
necessitate discontinuation of paclitaxel should be discussed with the Study 
Chair. (11/22/2010) 
 
6.46  Pulmonary Toxicity:  Decline in pulmonary function as evidenced by  
decreased lung expansion, crackles on ausculation, decrease in oxygen 
saturation (O2 sat <90% on room air) or decrease in pulmonary diffusion 
capacity of carbon monoxide (DLCO) to 20% of its baseline value requires 
discontinuation of the bleomycin from the BEP regimen (Arm 1).  Etoposide 
and cisplatin can be continued for the duration of the planned treatment course. 
 
6.47  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 except where noted below in Section 6.471. 
 
6.471   Special Modifications Study Treatment 
 
6.4711 For any CTCAE Grade 3 non-hematologic adverse event 
(except controllable nausea/emesis) considered to be at least 
possibly related to study treatment, protocol directed treatment 
should be held until symptoms resolve to <= CTCAE Grade 1. 
If a CTCAE Grade 3 adverse event persists for > three weeks or 
recurs after resumption of therapy, the patient may be taken off 
protocol directed treatment after consulting with the Study 
Chair. 
 
6.4712  For any CTCAE Grade 4 non-hematologic adverse event 
(except controllable nausea/emesis), the patient may be taken 
off protocol directed treatment therapy after consulting with the 
Study Chair. 
 
6.48 
Management of Hypersensitivity Reactions and Supportive Care 
 
6.481 Hypersensitivity Reactions:  When hypersensitivity reactions occur to 
paclitaxel or its vehicle (Cremophor), they present almost universally 
during the first few minutes of infusion.  Continued treatment may be 
considered if the reaction if not life-threatening; however, patients must 
be cautioned of potential recurrences of the reaction.  Should the patient 
decide to continue with treatment it is preferable that this be done on the 
same day of the occurrence.  Additional doses of dexamethasone and 
cimetidine may be administered.  

-24- 
GOG-0264 
 
 
A suggested procedure would be to administer the drug first with 1 mL 
of the original IV solution diluted in 100 ml over one hour, then 10 mL 
in 100 ml over one hour, and finally, the original solution at the original 
speed.  No additional dose adjustments should be made for other 
hypersensitive reactions. Subsequent courses of treatment may be 
preceded by 24 hours of premedications (dexamethasone 20 mg orally 
every 6 hours and cimetidine 300 mg orally every 8 hours) prior to 
administering intravenous premedications and incremental 
administration of the offending chemotherapeutic drug, as suggested 
above.  
 
If oral premedication and desensitization results in a hypersensitivity 
reaction, intravenous premedications for 24 hours prior to the 
administration of chemotherapy may be given followed by incremental 
administration of the offending chemotherapeutic drug, as suggested 
above.  
 
 
 
 
 
Docetaxel could be substituted for paclitaxel for significant  
 
 
 
 
hypersensitivity reactions, only after discussion with Study Chair. 
 
If the patients fails intravenous desensitization or substitution to 
docetaxel, then the patient should come off study. 
 
6.482   Supportive care:  In addition to other aspects of supportive care, 
particular attention should be paid for adequate control of nausea and 
vomiting, including use of HT3 receptor antagonists as required.  The 
patient should be transfused as needed without interruption of therapy.  
Platelet transfusions may also be required in rare instances.  See Section 
5.244 and 5.246 for additional information. 
 
 
 

-25- 
GOG-0264 
 
7.0 
STUDY PARAMETERS  (11/22/2010) 
 
 
7.1 
The following observations and tests are to be performed and recorded on the 
appropriate form(s): 
Observations and Tests 
Pre-
treatment 
During Treatment 
Post-Treatment 
Prior to 
initial study 
treatment 
Weekly 
During 
Treatment 
Prior to 
Each Cycle 
Following Cycle 6 
Arm 1 or Cycle 4 
Arm II; Then Every 
3 months x 2 years; 
Then every 6 
months x 3 years, 
then annually 
thereafter 
History & Physical Exam, Pelvic 
Examination, Performance Status 
1 
 
2 
X 
EKG (11/22/2010) 
1 
 
 
 
Biopsy for recurrent disease (10/24/2011) 
3,11 
 
 
 
Serum pregnancy test 
4 
 
X 
 
Toxicity Assessment 
5 
 
X 
X 
Radiographic Tumor measurement 
1 
 
7 
7 
CBC with Differential, Platelet Count 
5 
X 
6 
 
Creatinine, Serum Magnesium, Bilirubin, 
SGOT, Alk. Phosphatase, β-hCG 
5 
 
X,6 
 
Urinalysis 
5 
 
 
 
Inhibin A, Inhibin B 
10 
 
8 
8 
Chest imaging (X-ray or CT scan of 
chest) 
1 
 
 
 
Pulmonary diffusion capacity for carbon 
monoxide (DLCO) 
1 
 
9 
 
1. Must be obtained within 28 days prior to initiating protocol therapy. 
2. Directed history and physical examination and evaluation of performance status should be done prior to each cycle 
of treatment. Pelvic examination may be deferred prior to each cycle, and instead be performed according to the 
schedule for Radiographic Tumor measurement, as noted in Footnote 7 below. 
3. Required only in the setting of recurrent disease; not required for patients with newly diagnosed disease. 
4. Should be done if the patient is of child-bearing potential. A serum sample must be obtained within 72 hours prior 
to initiating protocol therapy.  For subsequent cycles, serum or urine tests are acceptable. 
5. Must be obtained with 14 days prior to initiating protocol therapy. 
6. Must be obtained within 4 days of re-treatment with protocol therapy. 
7. Follow-Up Radiographic Assessment of Disease. In the absence of disease progression by criteria in Section 8.3, 
imaging using the same modality and encompassing the same field as in the initial pre-treatment evaluation should 
be repeated with the following schedule: 
a) 
After cycle 3 (before cycle 4). 
b) 
2 weeks after cycle 6 in the carboplatin/paclitaxel arm or 7 weeks after completion of cycle 4 in the BEP 
arm, then every 3 months for 2 years and then every 6 months thereafter. 
8. Obtain on all patients initially and prior to each cycle of therapy. Obtain every 3 months for two years if elevated 
at time of treatment discontinuation. 
9. Should be obtained just prior to day one of cycle #3 and cycle #4 of bleomycin for patients on the bleomycin-
containing arm only (Arm II).  
10. Should be obtained after surgery but not longer than 28 days before the initiation of treatment. 
11. Should be obtained within 8 weeks prior to study entry. 
 
 

-26- 
GOG-0264 
 
7.2   
Stained  Pathology Slide Requirements For Central Review To Confirm Eligibility 
 
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 pathology reports and Form F to the GOG Statistical 
and Data Center.  Please see sections 4.6 and 10.2 for additional instructions and 
requirements. 
 
7.3 
Research Specimen Requirements  
 
 
 
Twenty-five serial sections on charged slides or a block will be obtained from the 
primary tumor tissue or from biopsy of recurrent disease, when available. If there is 
insufficient tissue to meet these requirements, this does NOT exclude the patient from 
participating. Any tissue that can be submitted, up to the amount listed below, should be 
submitted. 
 
 
Specimen Requirement 
(Specimen Code) 
Collection Time 
Point 
Ship Specimen To 
The GOG Tissue 
Bank 
Twenty-five (25) serial sections on 
charged slides suitable for immuno-
histochemistry OR a block from the 
primary tumor tissue (FP01) or biopsy 
of recurrence 
Archived  
Within six (6) weeks 
following enrollment.  
Ship in a suitable 
container at  room 
temperature (see 
Appendix II) 
 

-27- 
GOG-0264 
 
8.0 
EVALUATION CRITERIA 
 
8.1  
Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest 
diameter (unidimensional measurement) of the tumor lesions and the shortest diameter 
in the case of malignant lymph nodes are used in the RECIST criteria. 
 
 
 
8.11 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time 
of their first treatment on study. 
 
Evaluable for objective response.  Only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for response.  These 
patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the 
end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of the 
lesions.  
 
 
8.12 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) 
as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers 
by clinical exam.  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area will not be 
considered measurable unless progression is documented or a biopsy is obtained 
to confirm persistence at least 90 days following completion of radiation 
therapy. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 
mm short axis), are considered non-measurable disease.  Bone lesions, 

-28- 
GOG-0264 
 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified 
as target lesions and recorded and measured at baseline.  Target lesions should 
be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
 
 
8.13 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler 
or calipers.  All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-
up. Imaging-based evaluation is preferred to evaluation by clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm 
diameter as assessed using calipers (e.g., skin nodules).  In the case of skin 

-29- 
GOG-0264 
 
lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, CT is 
preferable.  
 
Conventional CT and MRI: This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  If 
CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in 
certain situations (e.g. for body scans), but NOT lung.   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement.  Furthermore, the availability of MRI is variable globally.  As 
with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of 
disease.  Furthermore, as with CT, the modality used at follow-up should be the 
same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, 
and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  PET-CT scans are not always done with oral and IV 
contrast.  In addition, the PET portion of the CT introduces additional data 
which may bias an investigator if it is not routinely or serially performed.  For 
these reasons, the GOG will not allow PET-CT use for RECIST 1.1 response 
criteria. 
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement.  Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next.  If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI 
is advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 

-30- 
GOG-0264 
 
 
 
Cytology, Histology: These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases (e.g., residual 
lesions in tumor types, such as germ cell tumors, where known residual benign 
tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met criteria 
for response or stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and progressive 
disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible 
'new' disease).  New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is 
a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.  If the positive FDG-PET at follow-up is 
not confirmed as a new site of disease on CT, additional follow-up CT  
scans are needed to determine if there is truly progression occurring at 
that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of 
the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner 
similar to a biopsy in cases where a residual radiographic abnormality is 
thought to represent fibrosis or scarring.  The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to 
false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation 
corrected image. 
 
Inhibin A and inhibin B: Although these levels are being measured in this 
protocol, inhibin results will not be used to assess response or progression, or to 
make treatment decisions.  
 
 
 
 
 
 

-31- 
GOG-0264 
 
 
 
8.14 
Response Criteria 
 
 
 
 
8.141  
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
 
 
 
 
 
 
 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the baseline sum 
diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest on study).  
In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also considered 
progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, taking as reference the 
smallest sum diameters while on study. 
 
 
 
 
8.142  
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions 
and normalization of tumor marker level.  All lymph nodes must be 
non-pathological in size (<10 mm short axis). 
 
Note:  If CA125 is initially above the upper normal limit, it must 
normalize for a patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 
and/or maintenance of CA125 level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions.  
Unequivocal progression should not normally trump target lesion 
status.  It must be representative of overall disease status change, not 
a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should prevail in 
such circumstances, and the progression status should be confirmed 
at a later time by the review panel (or Principal Investigator). 
  
 
 

-32- 
GOG-0264 
 
 
 
 
8.143  
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start 
of the treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements recorded 
since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
 

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GOG-0264 
 
 
 
8.15 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started, including the 
baseline measurements.  
 
 
8.16 
Progression-Free Survival 
 
Progression-Free Survival (PFS) is defined as the duration of time from start of 
treatment to time of progression or death, whichever occurs first. 
 
 
8.17 
Survival 
 
Survival is defined as the duration of time from start of treatment to time of 
death or the date of last contact. 
 

-34- 
GOG-0264 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

-35- 
GOG-0264 
 
9.0 
DURATION OF STUDY    
 
9.11 
As specified in sections 5.0 and 6.0, depending on the arm to which they are 
randomized, patients will receive 6 cycles of paclitaxel and carboplatin, or 4 cycles of 
bleomycin, etoposide, and cisplatin, unless disease progression or adverse effects 
prohibit further treatment. The patient can refuse the study treatment at any time. 
 
9.12 
Patients will be followed (with completion of all required case report forms) until 
disease progression or study withdrawal. 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 consent is withdrawn. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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GOG-0264 
 
 
10.0 
STUDY MONITORING AND REPORTING PROCEDURES   
 
10.1 
ADVERSE EVENT REPORTING FOR A COMMERCIAL AGENT 
   
10.11 Definition of Adverse Events (AE) (11/22/2010) 
 
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.  
 
The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized 
for AE reporting.  All appropriate treatment areas should have access to a copy 
of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov).  
 
The CTCAE Manual version 4.0 is also available on the GOG member web site 
(http://www.gog.org under MANUALS).  
 
10.12 Reporting Expedited Adverse Events 
 
Depending on the phase of the study, use of investigational or commercial 
agents, and role of the pharmaceutical sponsor, an 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 (AdEERS).  All AdEERS submissions are reviewed by 
GOG before final submission to CTEP.  Submitting a report through AdEERS 
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. 
 
10.13 Phase 2 and 3 Trials Utilizing a Commercial Agent:  AdEERS Expedited 
Reporting Requirements for Adverse Events That Occur Within 30 Days of the 
Last Dose of Any Commercial Study Agent  
 

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GOG-0264 
 
Reporting Requirements for Adverse Events that occur within 30 Days¹ of the Last Dose of the 
Commercial Agent on Phase 2 and 3 Trials 
 
 
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: 
AdEERS 24-hour notification followed by complete report within 3 calendar days for: 
• Grade 4 and Grade 5 unexpected events  
      AdEERS 7 calendar day report: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• Grade 5 expected events 
 
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report 
is required as outlined in the table. 
 
 Please see exceptions below under the section entitled, “Additional Instructions or Exceptions to AdEERS 
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 AdEERS 
within 24 hours of learning of the event followed by a complete AdEERS report within 3 
calendar days of the initial 24-hour report. 
“7 calendar days” – A complete AdEERS 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 AdEERS 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. 
 

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GOG-0264 
 
 
Additional Instructions or Exceptions to AdEERS Expedited Reporting Requirements for Phase 2 
and 3 Trials Utilizing a Commercial Agent: 
 
• There are no additional instructions or exceptions to AdEERS expedited reporting requirements 
for this protocol. 
 
10.14 Procedures for Expedited Adverse Event Reporting: (11/22/2010) 
 
10.141 AdEERS Expedited Reports:  Expedited reports are to be submitted 
using AdEERS 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.  
 
AML/MDS events must be reported via AdEERS (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) 
Myelodysplatic syndrome, or 3) Treatment related secondary 
malignancy. (10/24/2011) 
 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made to NCI by telephone at: 301-897-7497.  An 
electronic report MUST be submitted immediately upon re-establishment 
of internet connection. Please note that all paper AdEERS forms have 
been removed from the CTEP website and will NO LONGER be 
accepted.  
 
 
 
 
10.15 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 AdEERS will also be included with the quarterly CDUS 
data submissions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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GOG-0264 
 
  
 
10.2 
DATA MANAGEMENT FORMS (11/22/2010) 
 
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: the Pathology Report must be 
submitted via the SDC Electronic Data Entry System (SEDES) which is available through the 
GOG website (www.gogstats.org).The GOG Uploader Application in SEDES is an alternate 
method for submitting the pathology report to the GOG SDC. 
 
 
Form 
Due within 
Copies* 
Comments 
Weeks 
Event 
Specimen Consent Application 
1 
Registration 
N/A 
Mandatory submission via 
SEDES  
Form R (Registration Form) 
 
2 
Registration 
1 
Mandatory submission via 
SEDES  
Form OHR (Recurrent 
Gynecologic Cancer – On Study 
History Form) 
2 
Registration 
1 
Mandatory submission via 
SEDES 
Form DR (Pre-Treatment 
Summary Form) 
 
2 
Registration 
1 
Mandatory submission via 
SEDES 
Form D2M (Solid Tumor 
Evaluation Form 
2 
Registration 
1 
Mandatory submission via 
SEDES 
 
Primary disease: 
Form F (Pathology Form) 
Pathology Report 
Stained Slides  
 
Recurrent or Persistent Disease: 
Form F (Pathology Form) 
 
Pathology Report 
Stained Slides  
 
6 
6 
6 
 
 
6 
6 
6 
 
Registration 
Registration 
Registration 
 
 
Registration 
Registration 
Registration 
 
2** 
2** 
** 
 
 
2** 
2** 
** 
 
Submit together to SDC 
via postal mail or  
pathology report via report 
uploader 
 
 
 
Submit together to SDC 
via postal mail or  
pathology report via report 
uploader 
 
 
 
 
Form D2R (Cycle Dose Drug 
Form) 
 
2 
Completion of each 
cycle of therapy 
1 
Mandatory submission via 
SEDES 
Form D2M (Solid Tumor 
Evaluation Form) 
2 
Clinical response 
assessment 
1 
Mandatory submission via 
SEDES 
Form T (Common Toxicity 
Reporting Form) 
2 
Beginning of each 
subsequent cycle 
1 
 
 
Mandatory submission via 
SEDES 
Form Q0 (Treatment Completion 
Form) 
 
2 
Completion of study Rx 
and change in Rx 
1 
Mandatory submission via 
SEDES 

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GOG-0264 
 
Form Q (Follow-up Form) 
 
 
2 
Disease progression; 
death; normal follow-up 
1 
Mandatory submission via 
SEDESquarterly for 2 
years, semi-annually for 3 
more years,then annually 
thereafter 
Form SP-FP01-0264 
6 
Registration 
Online 
SEDES 
Form SP-RP01-0264  
6 
Registration 
Online 
SEDES 
* 
The number of required copies including the original form, which must be sent to the Statistical and Data Center. 
** 
 Please see Sections 4.6 and 7.2 for additional pathology requirements and instructions. 
 
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. 
 
 
 
 

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GOG-0264 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Study design overview and registration 
This is a randomized, two-arm, Phase II clinical trial.  Patients will be randomized in a 
1:1 ratio to paclitaxel and carboplatin or bleomycin, etoposide, and cisplatin (BEP).  A 
BEP control arm is being used because historical data for progression free survival and 
other endpoints are limited and not consistent across studies in this patient population 
(see section 2.1). 
 
The randomization will be stratified by whether the patient has measurable disease. 
 
All patients on this study will be registered and randomized centrally at the GOG 
Statistical and Data Center.  Prior to registration, eligibility will be reviewed via Fast 
Fact Sheet verification.  The treatment assignment will be concealed from institutions 
and patients until registration with verification of eligibility.  Randomization with equal 
probabilities to the two treatment regimens will be carried out following study 
registration.  All reports will include a complete accounting of all patients registered to 
this protocol. 
 
11.2 
Data collection 
 
The principal parameters to be collected, analyzed and reported to examine the 
 
therapeutic effect and tolerability of the treatment regimen are: 
 
11.21 Outcome variables 
11.211 Primary:  progression-free survival  
 
11.212 Secondary:  tumor response rate and overall survival 
 
11.22 Tumor characteristics:  tumor size as measured by the maximum dimension of 
 
the tumor, histologic cell type, and tumor grade 
 
11.23 Host characteristics:  age at entry, performance status, race, and ethnicity 
 
11.24 Adverse effects:  frequency and severity of adverse events as assessed by the 
CTCAE version 4.0. (11/22/2010) 
 
11.3 
Accrual 
 
A survey of GOG institutions was done in September 2006 in order to examine whether 
 
there were sufficient resources and interest in a study of first-line treatment for patients 
 
with newly diagnosed SCSTs of the ovary.  Based on the results from this survey, we 
 
anticipate accrual to be approximately 15 patients per year. 
 
11.4 
Primary Objective and Hypothesis, Sample Size and Design, and Duration 
Primary Objective and Hypothesis: 
The primary objective of the study is to compare PFS for paclitaxel and carboplatin 
versus BEP in women with newly diagnosed SCSTs of the ovary. PFS is being used as 
the primary endpoint in the study for the following reasons.  First, it avoids the 

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GOG-0264 
 
confounding effects of post-progression therapy, which impact analyses of overall 
survival.  Second, it provides an assessment of clinical benefit by measuring tumor 
burden. 
 
For the primary analyses, patients will be included in their randomized treatment group; 
analyses by actual treatment received will be considered exploratory. 
 
The primary analysis of PFS will occur after 38 progressions or deaths have been 
observed in the control arm and will include all patients for an intent-to-treat analysis. 
For the purpose of treatment comparisons, PFS will be assessed from the date of 
randomization, and death due to any cause will be considered a failure event.  
 
A noninferiority hypothesis will be used at the final analysis, in which if the 85% upper 
confidence limit (CL) excludes a noninferiority margin of 1.10, the carboplatin + 
paclitaxel arm will be considered noninferior to BEP. 
 
An adaptive design will be used that will allow the study to be stopped early for 
superiority, i.e., if the experimental arm (paclitaxel and carboplatin) is superior to BEP 
or for futility, i.e., if it is deemed unlikely that the study could declare noninferiority at 
the end of the study.  
 
Sample Size and Design: 
The study will utilize an adaptive, two-stage design.  At the end of the first stage, four 
results are possible based on the analysis of PFS: 
(1) superiority may be declared, 
(2) the study may be deemed futile, 
(3) a second stage may be required and permitted due to the first stage results being 
insufficient to declare superiority, or 
(4) the study may be deemed inconclusive and a second stage of accrual foregone 
due to other priorities. 
 
We allow a relatively large overall α (type I error) of 0.15 because this is a phase II, 
screening design in a rare tumor population.  We target a power of approximately 85% 
for a hazard ratio of 0.67.  Twenty events are required in either arm (i.e., control or 
experimental, not total) for the interim analysis, and 38 events are required in the 
control arm for the final analysis. (11/22/2010) 
 
Table 2 below shows the power and expected analysis times for the interim and final 
analyses. Due to the uncertainty in the expected median PFS value, these are presented 
for two scenarios of median PFS: 60 and 30 months, 
 
For example given a median PFS of 60 months and a hazard ratio of 0.667, we would 
expect the interim analysis to occur after 7.2 years, and at the interim analysis, there 
would be a 3% probability of declaring the study futile, a 10% probability of declaring 
paclitaxel and carboplatin to be superior to BEP, and a 87% chance of the results being 
considered inconclusive, at which point, we could decide to continue to the second 
stage of the study, or forego the second stage and deem the study inconclusive.  If a 
second stage was utilized, we would expect total accrual to take 8.5 years, and the final 

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GOG-0264 
 
analysis to occur after 11.1 years, and overall, the study would have 87% power to 
declare paclitaxel and carboplatin to be superior to BEP. 
 
If the median PFS were 30 months and the hazard ratio were 0.667, we would expect 
the interim analysis to occur after 5.4 years.  If a second stage were utilized, we would 
expect the final analysis to occur after 8.3 years (i.e., at the end of accrual, with no 
additional follow-up period required), and overall, the study would have 89% power to 
declare paclitaxel and carboplatin to be superior to BEP. 
 
GCIG participation is also anticipated, which would increase the accrual and decrease 
the duration of the trial. 
 
Table 2: Operating Characteristics of the Study for Various Median PFS Values and HRs 
(11/22/2010) 
Hazard 
Ratio 
Interim† 
Final‡ 
Expected 
Analysis 
Time 
(yr) 
Pr 
(futility) 
Pr 
(indeterminate) 
 Continue to 
2nd stage? 
Pr 
(superiority) 
[Power] 
Expected 
Analysis 
Time (yr) 
Pr 
(Noninferiority) 
Overall  
Pr 
(superiority) 
Pr (Superiority 
or 
Noninferiority) 
Overall 
[Power] 
Median PFS = 60 months 
0.667 
7.1 
6% 
85% 
10% 
11.1 
10% 
76% 
86% 
0.80 
7.0 
16% 
81% 
3% 
11.1 
15% 
48% 
63% 
1.00 
6.8 
38% 
61% 
1% 
11.1 
11% 
16% 
27% 
1.10 
6.7 
50% 
50% 
0% 
11.1 
7% 
8% 
α = 15% 
Median PFS = 30 months 
0.667 
5.4 
4% 
87% 
9% 
8.2 
10% 
78% 
88% 
0.80 
5.3 
13% 
85% 
2% 
8.2 
15% 
50% 
65% 
1.00 
5.2 
36% 
63% 
0% 
8.2 
12% 
15% 
27% 
1.10 
5.1 
50% 
50% 
0% 
8.3 
8% 
7% 
α = 15% 
† PFS Events required at interim analysis: 20 in either arm (i.e., control or experimental, not total). Decision rules at interim analysis 
are based on the following: superiority will be declared if p ≤ 0.01 for test against null HR=1.00, and futility will be declared if the 
observed HR >1.10. 
‡ PFS Events required at final analysis: 38 in control arms. Decision rule at final analysis is based on a 85% CI for HR excluding HR 
values of 1.10 and 1.00 for noninferiority and superiority, respectively. 
 
Notes: Accrual = 1.25 /month = 15/year. 
 
N projected overall = 128 (8.5 years of accrual [if necessary]). 
 
Based on 10,000 simulations for each scenario. 
 
Based on Cox proportional hazards model. 
 
11.5 
Secondary and Exploratory Analyses 
Secondary Analyses 
The relationship of treatment to overall survival will be assessed using the proportional 
hazards model described above for PFS.  The relationship of treatment to tumor 
response rate will be assessed using logistic regression models adjusted for age and 
stratification factor (measurable disease status). 
 
All patients who receive any therapy will be evaluated for both treatment efficacy and 
toxicity, except for the evaluation of response, in which the minimum length of trial to 

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GOG-0264 
 
evaluate response is defined as receiving 2 cycles of therapy and living at least 3 weeks 
after the second cycle for repeat assessment to be performed.  However, if a patient has 
global deterioration of health status requiring discontinuation of treatment without  
objective evidence of disease progression at that time should be considered evaluable 
and should be classified as having “symptomatic deterioration.” 
 
Translational Research 
The translational component of this study will be developed based on technology 
existing nearing the completion of patient accrual. 
 
Exploratory Analyses 
Pre-treatment levels of inhibin A and inhibin B will be examined in relation to overall 
and progression-free survival in Cox proportional hazards models.  Changes from 
baseline in inhibin levels will be compared between treatment groups using mixed 
effects models accounting for the longitudinal nature of the data.  The repeated 
measures of inhibin also will be explored versus overall survival and PFS using time-
dependent covariates in Cox proportional hazards models. 
 
11.6 
Interim Analysis  
An interim analysis will be done that will allow for stopping early due to superiority, 
futility, or inconclusiveness.  The interim analysis will occur after 20 PFS events have 
been observed in either arm (i.e., control or experimental, not total).  The decision rules 
are based on p-values or the estimated hazard ratio from the analysis of PFS and are as 
follows (11/22/2010): 
• p ≤ 0.01  superiority declared for paclitaxel and carboplatin vs. BEP 
• HR >1.10  futility 
• otherwise  go to second stage or stop or deem study inconclusive.  
 
More details regarding the interim analysis and its expected timing are given in section 
11.4 and Table 2 above. 
 
These rules control the overall α for the PFS endpoint to be 0.15. 
 
11.7 
Anticipated Gender and Minority Inclusion:  This study restricts entry to women by 
nature of the site of disease. 
 
11.8 
The table below lists the anticipated percentages of patients by racial and ethnic 
subgroups (based on previous studies in this patient population). 
 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
 
5 
+ 
0 
= 
 
5 
Not Hispanic or Latino 
 123 
+ 
0 
= 
 123 
Ethnic Category: Total of all subjects 
 128 
+ 
0 
= 
 128 
Racial Category 
 
American Indian or Alaskan Native 
 
0 
+ 
0 
= 
 
0 

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GOG-0264 
 
Asian 
 
8 
+ 
0 
= 
 
8 
Black or African American 
 24 
+ 
0 
= 
 24 
Native Hawaiian or other Pacific 
Islander 
 
0 
+ 
0 
= 
 
0 
White 
 96 
+ 
0 
= 
 96 
Racial Category: Total of all subjects 
 128 
+ 
0 
= 
 128 
 
 
 
 
 
 
 
Accrual Rate: 
1.25 
pts/mont
h 
Total Expected 
Accrual: 
105 Min 
128 Max 
 
 
 
 
 
 
 
 

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GOG-0264 
 
12.0 
BIBLIOGRAPHY 
 
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Brada M, Horwich A, Peckham MJ. Treatment of favorable-prognosis 
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