A Randomized Phase III Trial of Paclitaxel Plus Carboplatin Versus Ifosfamide Plus Paclitaxel in Chemotherapy-Naive Patients With Newly Diagnosed Stage I-IV, Persistent or Recurrent Carcinosarcoma (Mixed Mesodermal Tumors) of the Uterus, Fallopian Tube, Peritoneum or Ovary
Phase: PHASE3
Conditions: Mixed Mesodermal (Mullerian) Tumor, Ovarian Carcinosarcoma, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma, Stage I Ovarian Cancer AJCC v6 and v7, Stage IA Fallopian Tube Cancer AJCC v6 and v7, Stage IA Ovarian Cancer AJCC v6 and v7, Stage IA Uterine Sarcoma AJCC v7, Stage IB Fallopian Tube Cancer AJCC v6 and v7, Stage IB Ovarian Cancer AJCC v6 and v7, Stage IB Uterine Sarcoma AJCC v7, Stage IC Fallopian Tube Cancer AJCC v6 and v7, Stage IC Ovarian Cancer AJCC v6 and v7, Stage IC Uterine Sarcoma AJCC v7, Stage II Ovarian Cancer AJCC v6 and v7, Stage IIA Fallopian Tube Cancer AJCC v6 and v7, Stage IIA Ovarian Cancer AJCC V6 and v7, Stage IIA Uterine Sarcoma AJCC v7, Stage IIB Fallopian Tube Cancer AJCC v6 and v7, Stage IIB Ovarian Cancer AJCC v6 and v7, Stage IIB Uterine Sarcoma AJCC v7, Stage IIC Fallopian Tube Cancer AJCC v6 and v7, Stage IIC Ovarian Cancer AJCC v6 and v7, Stage IIIA Fallopian Tube Cancer AJCC v7, Stage IIIA Ovarian Cancer AJCC v6 and v7, Stage IIIA Primary Peritoneal Cancer AJCC v7, Stage IIIA Uterine Sarcoma AJCC v7, Stage IIIB Fallopian Tube Cancer AJCC v7, Stage IIIB Ovarian Cancer AJCC v6 and v7, Stage IIIB Primary Peritoneal Cancer AJCC v7, Stage IIIB Uterine Sarcoma AJCC v7, Stage IIIC Fallopian Tube Cancer AJCC v7, Stage IIIC Ovarian Cancer AJCC v6 and v7, Stage IIIC Primary Peritoneal Cancer AJCC v7, Stage IIIC Uterine Sarcoma AJCC v7, Stage IV Fallopian Tube Cancer AJCC v6 and v7, Stage IV Ovarian Cancer AJCC v6 and v7, Stage IV Primary Peritoneal Cancer AJCC v7, Stage IVA Uterine Sarcoma AJCC v7, Stage IVB Uterine Sarcoma AJCC v7, Uterine Carcinosarcoma
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 
 
 
SUMMARY OF CHANGES 
 
For Protocol Revision #11 to GOG-0261 
 
NCI Protocol #: GOG-0261 
Local Protocol #: GOG-0261 
 
NCI Version Date: December 19, 2014 
Protocol Date: December 19, 2014 
 
# 
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Page(s) 
Change 
1. 
Title Page 
1-2 
NCI version date has been updated. 
 
Includes Revisions #1-11. 
 
Lead Organization has been added. 
 
Revised footer has been added. 
 
ICD 
 
NCI version date has been update on the Informed Consent 
 
 
i 

NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
 
 
PROTOCOL GOG-0261 
A RANDOMIZED PHASE III TRIAL OF PACLITAXEL PLUS CARBOPLATIN VERSUS IFOSFAMIDE 
PLUS PACLITAXEL IN CHEMOTHERAPY-NAIVE PATIENTS WITH NEWLY DIAGNOSED STAGE I-IV, 
PERSISTENT OR RECURRENT CARCINOSARCOMA (MIXED MESODERMAL TUMORS) OF THE 
UTERUS, FALLOPIAN TUBE, PERITONEUM OR OVARY (06/1/10) (11/19/2012) NCT #00954174 
(05/05/2014) 
NCI Version Date: 12/19/2014 
Includes Revision  #1-11 
POINTS: 
PER CAPITA – 20 
MEMBERSHIP -6 
 
TRANSLATIONAL RESEARCH PER CAPITA – Award based on specimen submission with 1.0 point for formalin-fixed, 
paraffin-embedded primary, metastatic, or recurrent tumor and 0.5 point for whole blood (MAX = 1.5).  (04/02/2012) 
Lead Organization: NRG/NRG Oncology  
STUDY CHAIR 
 
 
 
 
STUDY and QOL CHAIR (12/20/2010) 
MATTHEW A. POWELL, MD  
 
 
MARTEE L. HENSLEY, MD 
WASHINGTON UNIV. SCHOOL OF MED 
 
MEMORIAL SLOAN-KETTERING CANCER CTR 
DEPARTMENT OF OB/GYN  
 
 
1275 YORK AVE 
4911 BARNES-JEWISH HOSPITAL PLAZA  
NEW YORK, NY 10021 
ST. LOUIS, MO  63110 
 
 
 
(212) 639-6902  
 
(314) 362-3181  
 
 
 
 
FAX: (212) 717-3272  
 
 
FAX: (314) 362-2893  
 
 
 
EMAIL: hensleym@mskcc.org   
EMAIL: powellm@wudosis.wustl.edu 
 
NURSE CONTACT (12/20/2010) 
 
 
 
PATHOLOGIST 
CHRISANN ACCARIO-WINSLOW, RN, MSN, AOCN 
MEENAKSHI SINGH, MD 
 
WASHINGTON UNIV. SCHOOL OF MED. 
 
 
See GOG Website Directory 
4911 BARNES-JEWISH HOSPITAL PLAZA  
 
 
 
 
 
ST. LOUIS, MO 63110  
 
 
 
 
 
 
 
(314) 362-1794  
 
 
 
 
 
STATISTICIAN 
 
 
FAX: (314) 362-8644  
 
 
 
 
GINNY FILIACI, PhD  
EMAIL:  winslowc@wudosis.wustl.edu  
 
 
See GOG Website Directory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QOL STATISTICIAN 
TRANSLATIONAL RESEARCH COORDINATOR (04/02/2012) 
HELEN HUANG, MS 
BRANDON MARZULLO, MS  
 
 
 
 
See GOG Website Directory 
See GOG Website Directory 
 
 
 
 
 
 
OPEN TO PATIENT ENTRY AUGUST 17, 2009; REVISED SEPTEMBER 7, 2009; REVISED JUNE 1, 2010; 
REVISED DECEMBER 20, 2010; REVISED; MARCH 21, 2011; REVISED SEPTEMBER 6, 2011; REVISED 
APRIL 2, 2012; REVISED NOVEMBER 19, 2012; REVISED OCTOBER 21, 2013; CLOSED TO PATIENT 
ENTRY MARCH 24, 2014; REVISED MAY 5, 2014; REVISED
 
This protocol was designed and developed by the Gynecologic Oncology Group (GOG).  It is intended to be used 
only in conjunction with institution-specific IRB approval for study entry.  No other use or reproduction is 
authorized by GOG nor does GOG assume any responsibility for unauthorized use of this protocol. 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
 
 
PROTOCOL GOG-0261 
A RANDOMIZED PHASE III TRIAL OF PACLITAXEL PLUS CARBOPLATIN VERSUS IFOSFAMIDE 
PLUS PACLITAXEL IN CHEMOTHERAPY- NAIVE PATIENTS WITH NEWLY DIAGNOSED STAGE I-IV, 
PERSISTENT OR RECURRENT CARCINOSARCOMA (MIXED MESODERMAL TUMORS) OF THE 
UTERUS, FALLOPIAN TUBE, PERITONEUM OR OVARY (06/1/10) (11/19/2012) 
NCI Version Date: 12/19/2014 
Includes Revision #1-11 
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION (06/1/10) 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data  directly to the Lead 
Cooperative Group unless otherwise 
specified in the protocol:  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Please refer to the patient 
enrollment section for 
instructions on using the 
OPEN system. 
GOG Statistical and Data Center at Roswell 
Park Cancer Institute 
Elm and Carlton Streets  
Buffalo, NY 14263 
Phone: 716-845-5702 
 
Call GOG User support 716-845-7767 to 
obtain user name and password to submit 
electronic data 
 
Do not submit study data or forms to CTSU 
Data Operations. Do not copy the CTSU on 
data submissions.   
The study protocol and all related forms and documents must be downloaded from the protocol-specific Web 
page of the CTSU Member Web site located at https://www.ctsu.org.  Sites must use the current form version and 
adhere to the instructions and submission schedule outlined in the protocol. 
 
CTSU sites should follow procedures outlined in the protocol for Site registration, Patient Enrollment, Adverse 
Event Reporting, Data Submission (including ancillary studies), and Drug Procurement. 
 
For patient eligibility or treatment-related questions contact the Study PI of the Coordinating Group.  
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help Desk by 
phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence will 
be triaged to the appropriate CTSU representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites, please review the 
CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org 
The CTSU Web site is located at   https://www.ctsu.org 
 
OPEN TO PATIENT ENTRY AUGUST 17, 2009; REVISED SEPTEMBER 7, 2009; REVISED JUNE 1, 2010; 
REVISED DECEMBER 20, 2010; REVISED: MARCH 21, 2011; REVISED SEPTEMBER 6, 2011;  
REVISED APRIL 2, 2012; REVISED NOVEMBER 19, 2012; REVISED OCTOBER 21, 2013; CLOSED TO PATIENT 
ENTRY MARCH 24, 2014; REVISED MAY 5, 2014; REVISED 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
 
SCHEMA (12/20/2010) 
 
A RANDOMIZED PHASE III TRIAL OF PACLITAXEL PLUS CARBOPLATIN VERSUS 
IFOSFAMIDE PLUS PACLITAXEL IN CHEMOTHERAPY-NAÏVE PATIENTS WITH NEWLY 
DIAGNOSED STAGE I-IV, PERSISTENT OR RECURRENT CARCINOSARCOMA (MIXED 
MESODERMAL TUMORS) OF THE UTERUS, FALLOPIAN TUBE, PERITONEUM OR OVARY 
(11/19/2012) 
 
Stage I- IV, Persistent or Recurrent Carcinosarcoma (chemotherapy-naïve) 
 
Patients may have prior pelvic and/or vaginal radiation therapy 
 
Stratification: 
• History of Pelvic Radiation 
• Disease Status/Stage at time of Study registration 
• Measurable Disease 
 
 
 
 
 
TREATMENT RANDOMIZATION 
 
REGIMEN I                                                         
 
REGIMEN II 
 
Paclitaxel 175 mg/m2* IV over 3 hours Day 1 
Ifosfamide 1.6 g/m2** IV days 1, 2, 3 Mesna*** 
Carboplatin (AUC=6*) IV Day 1 
 
 
 
Paclitaxel 135 mg/m2 by 3-hour infusion on Day 1 
 
Repeat q 3 weeks x 6-10 cycles (see Section 5.21) 
Repeat q 3 weeks x 6-10 cycles (see 
Sections 5.22 and 6.3 for dose modifications 
AS EACH CYCLE DOSE MAY CHANGE 
BASED ON NADIR COUNTS.) 
 
 
 
 
 
 
 
 
 
G-CSF Support: Filgrastim or Pegfilgrastim 
 
 
 
 
 
 
 
 
beginning Day 4-6 (See Section 5.22.) 
 
*Initial dose reduced to Paclitaxel 135 mg/m2 and Carboplatin (AUC=5) if prior whole pelvic 
radiotherapy (may be escalated if patient tolerates lower dose—see Section 6.134) 
 
** Initial dose reduced to Ifosfamide 1.2 g/m2/day x 3 days if prior whole pelvic radiotherapy 
(subsequent dosing MAY INCREASE OR DECREASE EACH CYCLE BASED ON NADIR 
COUNTS) (11/19/2012) 
 
*** See Sec. 5.22 for Mesna administration information. 
 
PLEASE NOTE THAT REGIMEN II UTILIZES DOSE ESCALATIONS—See Section 6.3 for details    
(11/19/2012) 
 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
Translational Research requirements include formalin-fixed, paraffin-embedded tumor and pre-
treatment whole blood for banking. See Section 7.3 for details. (04/02/2012) 
 
Quality of Life assessments required at: Baseline; approximately Week 6 (prior to Cycle 3); Week 15 
(prior to Cycle 6); Week 30 post initiation of therapy.  See Section 7.4 for details. 
 
 
 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
PAGE 
 
 
 
1.0 
OBJECTIVES 
- 7 - 
1.1 
Primary Objectives 
- 7 - 
1.2 
Secondary Objectives 
- 7 - 
1.3 
Translational Research Objective 
- 7 - 
2.0 
BACKGROUND AND RATIONALE 
- 7 - 
2.1 
Banking Tumor Tissue and Whole Blood for Future Research (04/02/2012) 
- 12 - 
2.2 
Inclusion of Women and Minorities 
- 12 - 
3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS 
- 13 - 
3.1 
Eligible Patients 
- 13 - 
3.2 
Ineligible Patients 
- 14 - 
4.0 
STUDY MODALITIES 
- 16 - 
4.1 
Paclitaxel (NSC #673089) 
- 16 - 
4.2 
Carboplatin (Paraplatin® - NSC #241240) 
- 17 - 
4.3 
Ifosfamide - (IFEX® - NSC #10724) 
- 18 - 
4.4 
Mesna - (Mesnex - NSC #113891) 
- 18 - 
4.5 
Filgrastim (G-CSF, Neupogen®) 
- 19 - 
4.6 
Pegfilgrastim (G-CSF, Neulasta®) 
- 20 - 
4.7  
Quality of Life assessments 
- 20 - 
4.8 
Pathology Requirements 
- 21 - 
4.81 Pathology Eligibility Criteria 
- 21 - 
4.82 Pathology Ineligibility Criteria 
- 21 - 
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE (06/1/10) 
- 22 - 
5.1 
Patient Entry and Registration (06/1/10) 
- 22 - 
5.2 
Treatment Plan 
- 24 - 
5.3 
Criteria for removal from study treatment 
- 28 - 
6.0 
TREATMENT MODIFICATIONS 
- 29 - 
6.1 
Hematologic Toxicity: REGIMEN I (Paclitaxel and Carboplatin) 
- 29 - 
6.2 
Non-Hematologic Toxicity:  REGIMEN I (Paclitaxel and Carboplatin) 
- 30 - 
6.3 
Hematologic Toxicity:  REGIMEN II (Ifosfamide + Paclitaxel) (11/19/2012) 
- 32 - 
6.4 
Non-Hematologic Toxicity:  REGIMEN II (Ifosfamide + Paclitaxel) 
- 34 - 
7.0 
STUDY PARAMETERS 
- 36 - 
7.1 
Observations and Tests 
- 36 - 
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Version Date: 12/19/2014 
7.2 
Stained Pathology Slide Requirements for Central Review to Confirm Protocol Eligibility- 37 - 
7.3 
Translational Research (04/02/2012) 
- 38 - 
7.4 
Quality of Life 
- 39 - 
8.0 
EVALUATION CRITERIA 
- 41 - 
8.1 
Parameters of Outcome – GOG RECIST Criteria 
- 41 - 
9.0 
DURATION OF STUDY 
- 43 - 
9.1 
A total of 6 cycles of chemotherapy… 
- 43 - 
9.2 
Follow-up is required as outlined in Section 7.0. 
- 43 - 
9.3 
A patient is considered off study therapy. . . 
- 43 - 
10.0 STUDY MONITORING AND REPORTING PROCEDURES 
- 44 - 
10.1 ADVERSE EVENT REPORTING FOR A COMMERCIAL AGENT 
- 44 - 
10.2 GOG DATA MANAGEMENT FORMS 
- 47 - 
11.0 STATISTICAL CONSIDERATIONS 
- 50 - 
11.1 Study design overview and registration: 
- 50 - 
11.2 Data collection: 
- 50 - 
11.3 Accrual rate, sample size, and study duration: 
- 51 - 
11.4 Primary hypotheses, planning parameters, and sample size justification: 
- 52 - 
11.5 Interim Analyses: 
- 56 - 
11.6 Secondary endpoints, hypotheses or analyses: (10/21/2013) 
- 57 - 
11.7 Anticipated Gender and Minority Inclusion: (09/07/2009) (10/21/2013) 
- 60 - 
12.0 BIBLIOGRAPHY  (06/1/10) 
- 61 - 
APPENDIX I (12/20/2010) 
- 64 - 
APPENDIX II 
- 65 - 
APPENDIX III 
- 67 - 
APPENDIX IV 
- 73 - 
APPENDIX V (04/02/2012) 
- 75 - 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
1.0 
OBJECTIVES 
 
 
1.1 
Primary Objectives 
 
1.11 
To determine if treatment with combination paclitaxel and carboplatin (TC) 
chemotherapy does not result in an inferior death rate when compared to 
ifosfamide, mesna, and paclitaxel chemotherapy. 
 
 
1.2 
Secondary Objectives 
 
1.21 
To determine if treatment with combination paclitaxel and carboplatin (TC) 
chemotherapy does not result in an inferior progression-free survival when 
compared to ifosfamide, mesna, and paclitaxel chemotherapy. 
 
1.22 
To determine if acute toxicity, specifically physician-assessed 
neurotoxicity and infection, associated with combination paclitaxel and 
carboplatin chemotherapy is reduced compared to that of ifosfamide, 
mesna, and paclitaxel chemotherapy. 
 
1.23 
To determine if treatment with combination paclitaxel and carboplatin 
chemotherapy is associated with superior patient-reported quality of life 
and neurotoxicity scores compared to that of ifosfamide, mesna, and 
paclitaxel chemotherapy. 
 
 
 
1.3 
Translational Research Objective 
 
To bank formalin-fixed, paraffin-embedded (FFPE) tumor tissue and DNA 
extracted from whole blood for future research. (04/02/2012) 
 
2.0 
BACKGROUND AND RATIONALE 
 
Uterine sarcomas represent 2-6% of all uterine malignancies.  In a review of tumor 
registries in Britain, carcinosarcomas (CS) and leiomyosarcomas (LMS) made up almost 
90% of all uterine sarcomas registered over a 15-year period.  The overall five-year 
survival for patients with these tumors was 31%.1,2  In a prospective staging study by the 
GOG, 53% of patients with clinical Stage I-II carcinosarcoma of the uterus recurred 
within five years of initial therapy.3  Studies have confirmed recurrence rates of 53 –56%, 
the majority of which include an extra-pelvic component.4,5  Post-operative therapy in the 
form of pelvic radiotherapy or chemotherapy is often prescribed but neither has been 
proven beneficial.  Of the multiple GOG trials evaluating response to chemotherapy in 
patients with CS of the uterus, cisplatin, ifosfamide, paclitaxel, and doxorubicin have 
demonstrated the greatest tumor response.  In a Phase II trial using cisplatin alone as first-
line chemotherapy for advanced and recurrent uterine sarcomas, including 63 CS, Thigpen 
et al reported 12/63 (19%) overall responses with 5/63 (8%) achieving a Complete 
Response (CR).6  The median survival was 7 months for all patients and 9.3 months for 
complete responders.  Twenty-eight of 63 (44%) of these patients were treated with prior 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
pelvic RT.  Significant hematologic and gastrointestinal toxicities were noted.  Another 
GOG Phase II trial evaluated ifosfamide-mesna as first-line chemotherapy in patients with 
advanced or recurrent CS.7  The investigators reported 9/28 (32%) overall responses and a 
5/28 (18%) CR.  Eight of 28 (29%) of these patients were treated with prior pelvic RT.  
The median PFI was 3.8 months.  There was a significant incidence of Grade 3-4 
neutropenia and neurotoxicity, as well as one treatment-related death.  GOG-0108 
evaluated the combination of ifosfamide-mesna with or without cisplatin as first-line 
therapy in patients with advanced, persistent, or recurrent CS.8  The combination regimen 
demonstrated a significantly improved overall response rate (54%) when compared to the 
single-agent regimen (36%).  The combination regimen demonstrated only a two-month 
prolongation (statistically significant) in the median progression free interval (six vs. four 
months) with no improvement in overall survival.  Grade 3-4 toxicities were two-ten times 
more toxic in the combination arm.  This data serves to underscore the lack of curative 
adjuvant and salvage therapy in this setting and the current need for less toxic alternatives 
in the treatment of uterine CS.  
 
Findings from GOG-0161 were recently published.9  There was a 31% decrease in the 
adjusted hazard of death (hazard ratio (HR) = 0.69; P = 0.03) and a 29% decrease in the 
adjusted hazard of death or progression (HR = 0.71; P = 0.03) in those patients receiving 
paclitaxel-ifosfamide- mesna-growth factor relative to ifosfamide alone.  Sensory 
neuropathy was significantly worse with the combination regimen (Grades 1–4: 8% vs. 
30%).  
 
Results of GOG-0150 were recently published.  The combination of cisplatin, ifosfamide, 
and mesna (CIM) given for three cycles as treatment for patients with Stage I-IV uterine 
CS (resected to <1cm and disease confined to the abdomen) was favored over whole 
abdominal irradiation (WAI).10 Although not statistically significant, adjusting for stage, 
the recurrence rate was 21% lower for CIM patients relative to WAI patients (hazard ratio: 
0.79, p = 0.245).  Similarly, the estimated death rate for CIM is 29% lower relative to 
WAI (Hazard ratio: 0.71, p = 0.085).  The investigators concluded that, due to a high 
relapse rate and poor OS, the imperative for new adjuvant therapies remains. 
 
There is also evidence for activity of a third combination chemotherapy regimen: 
paclitaxel plus carboplatin.  The rationale for the frequent use of paclitaxel-carboplatin in 
treating carcinosarcoma is based on the following:   
 
 
1. Retrospective studies have shown high response rates, and median progression-
free survival of 18 months, and overall survival of 25 months among patients with 
Stage III or IV, mostly measurable, disease.11,12, 13 
2. Carboplatin-paclitaxel is equivalent to cisplatin-paclitaxel in advanced ovarian 
cancer in terms of efficacy, and is better tolerated (GOG-0158).14   
3. Paclitaxel as a single agent achieved an 18% response rate as second-line therapy 
in advanced carcinosarcoma.15 
4. Tolerability and convenience of paclitaxel-carboplatin is considered to be better 
than that of ifosfamide-cisplatin, especially in light of the toxicities observed with 
ifosfamide-cisplatin in GOG-0108.8 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
5. The GOG Phase II trial (GOG-0232B) formally testing the efficacy of this regimen 
in advanced disease has been completed and accepted for publication in the 
Journal of Clinical Oncology.  The proportions of patients with confirmed 
complete and partial responses were 13% and 41%, respectively, resulting in a 
total overall response rate of 54% (95% CI, 37% to 67%) with a median 
progression-free survival of 7.0 months and median survival was 14.4 months. 
(06/1/10) 
 
Since we now have evidence from two randomized Phase III trials that treatment with 
combination chemotherapy improves survival in women with carcinosarcoma, it is 
reasonable to compare combination chemotherapy regimens with respect to overall 
survival.   
 
Given the survival advantage achieved with paclitaxel-ifosfamide for advanced disease 
compared to ifosfamide alone, the known activity of platinum agents, the activity of 
single-agent paclitaxel as second-line therapy, and the growing evidence for efficacy and 
known excellent tolerability of paclitaxel-carboplatin, we propose a randomized Phase III 
trial with the following treatment arms:  paclitaxel plus ifosfamide versus paclitaxel plus 
carboplatin.  We hypothesize that paclitaxel-carboplatin will be associated with a non-
inferior survival compared to paclitaxel-ifosfamide.  Both activity against the disease and 
lesser toxicity may contribute to this hypothesized non-inferiority. 
 
Paclitaxel-carboplatin is a very commonly used cytotoxic regimen that has evidence for 
efficacy in over nine different solid tumor types.  Looking to the future, one of the goals of 
this trial is to develop an acceptable “cytotoxic backbone” regimen that biologic therapies 
could be added to with acceptable toxicity.  Paclitaxel-carboplatin appears to be just such 
a regimen.  If in fact paclitaxel-carboplatin is found to be non-inferior to ifosfamide-
paclitaxel, then further development of cytotoxic plus biologic regimens should be 
expedited.  Development of these regimens could be much more efficient as the cytotoxic 
backbone would be shared among ovarian, perhaps endometrium (GOG-0209) and uterine 
carcinosarcoma.  Thus, this trial is a vital step forward in the future development of 
therapies for this rare tumor type. 
 
Inclusion of Ovarian, Fallopian Tube and Peritoneal Carcinosarcomas (06/1/10) 
(11/19/2012) 
 
Ovarian carcinosarcomas are even more rare than the uterine counterparts that represent an 
aggressive cancer that are routinely widely metastatic at the time of initial presentation.16  
There is no uniform agreement  about the optimal treatment of these malignancies except 
that achieving optimal debulking at the time of initial surgery is associated with 
significantly improved overall survival.17,18  Most published data are limited to 
retrospective reviews, and because of the rarity of the disease, few institutions are able to 
accrue a sufficient number of patients for prospective studies. A prior Gynecologic 
Oncology Group study presented data involving 136 patients with ovarian 
carcinosarcomas treated with cisplatin 50 mg/m2 every 3 weeks until disease progression 
or unacceptable toxicity occurred.19  Cisplatin was found to be active as initial therapy for 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
these tumors. The median survival in 130 patients was 11.7 months.  Silasi et al. recently 
published (2007) their experience and review of the literature (nine other studies included) 
for a total of 417 patients.20  They compared the patients receiving cisplatin / ifosfamide to 
the group receiving carboplatin / paclitaxel and there was no statistically significant 
difference in survival.  A power analysis was performed utilizing their retrospective 
findings and 58 patients were needed to see a difference in progression-free-survival and 
558 for a difference in overall survival.  These tumors are felt to be too rare to study as 
part of an independent trial.  Ovarian carcinosarcomas are currently excluded from other 
GOG ovarian cancer trials.  Both uterine and ovarian carcinosarcomas share similar 
biologic, pathologic and clinical management questions and thus it is reasonable to 
combine this tumor type into this current ongoing clinical trial (GOG 261).  Fallopian tube 
and peritoneal carcinomas are even more rare than ovarian carcinosarcomas but share a 
similar clinical management dilemma with the ovarian and uterine carcinosarcomas and 
thus will be included in this trial. (11/19/2012) 
 
Quality of Life Assessment:  (06/1/10) 
 
Since the regimens differ in schedule, convenience, and side effect profile, the toxicities 
and the quality of life impact of the two regimens will be compared. 
 
Rationale for assessment of patient-reported quality of life and neurotoxicity: 
   
Physical well-being, functional well-being, and neurotoxicity will be assessed using 
patient-reported outcomes, given the potential differences in short- and longer-term 
toxicities between the two treatment arms.   
 
The regimens being tested in this trial will differ in treatment schedule, patient 
convenience, and expected side effect profile.  Ifosfamide will be given daily for 3 days in 
a row, with mesna for bladder protection, in combination with paclitaxel on Day 1.  This 
regimen will require granulocyte growth factor support, and in some institutions, this 3-
day regimen may be given as inpatient therapy.  In contrast, the paclitaxel-carboplatin 
regimen is given all on Day 1, does not routinely require granulocyte growth factor 
support, and is an outpatient treatment.  While both regimens can cause myelosuppression, 
it is possible that the paclitaxel-ifosfamide arm will be more myelosuppressive.  The 
requirement of granulocyte growth factor with the paclitaxel-ifosfamide treatment means 
that patients in that arm may have more bone pain and physical discomfort.  While the 
paclitaxel that is part of both regimens can be associated with peripheral neurotoxicity 
(which may be reversible), ifosfamide is associated with reversible, central neurotoxicity 
(confusion, hallucinations).  Because of these differences in the schedule and side effect 
profile, and since it is possible that the survival difference between the two arms may not 
be very great, understanding the impact of the two regimens on patient-reported quality of 
life and neurotoxicity is very important. 
 
 
This study will include patients with Stage I, II, III, and IV disease, many of whom will 
have had their disease completely removed by surgery prior to starting study treatment.  
Such patients may have few or no symptoms related to their cancer.  Therefore, a formal 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
evaluation of the patient-reported impact of treatment on quality of life is particularly 
important in this group. 
 
The Functional Assessment of Cancer Therapy, including the endometrial subscale will be 
used as the measure of patient-reported quality of life.  The trial outcome index (TOI) will 
comprise the 7-item physical well-being subscale (PWB) plus the 7-item functional well-
being subscale (FWB) plus the 16-item endometrial cancer subscale.  This is the same TOI 
that was chosen for GOG-0209.   
 
Patient-reported neurotoxicity will be measured using the GOG-NTX (neurotoxicity) 
subscale of the FACT.  The NTX subscale efficiently measures patient perception of 
neurotoxicity such as pain and paresthesias.21  
 
Rationale for delivering 6 cycles of therapy (maximum of 10 allowed): 
 
The duration of chemotherapy has differed across GOG trials for patients with 
carcinosarcoma.  GOG-0150 enrolled patients with Stage I, II, III, or IV carcinosarcoma 
whose disease had been resected to less than 1 cm residual.  The chemotherapy arm 
comprised only three cycles of ifosfamide plus cisplatin.  Even with this relatively short 
course of chemotherapy, a survival benefit was observed, compared with whole abdominal 
radiation.  This benefit occurred in patients in all disease-stage subgroups.  Subsequent to 
the design of this study, it has become commonplace to offer more cycles of 
chemotherapy to patients, particularly those patients with more advanced disease, as we 
have determined that chemotherapy is active in carcinosarcoma, and also as we have 
developed better supportive care measures that help ameliorate toxicities. 
 
In GOG-0161, patients with advanced, measurable disease were treated with a total of 
eight cycles of therapy, and then observed.  This trial design was able to yield a superior 
outcome in terms of progression-free and overall survival among women with advanced 
carcinosarcoma. 
 
In GOG-0209, the advanced endometrial cancer trial, patients may have measurable or 
non-measurable disease since the primary endpoint is overall survival.  In that study all 
patients are offered a total of seven cycles of therapy, and are then observed for 
progression-free and overall survival.  The rationale for offering seven cycles in this trial 
is at least partly to limit the cumulative dose of doxorubicin in order to limit the risk of 
cardiotoxicity. 
 
In GOG-0232B, patients with advanced, measurable carcinosarcoma are treated with an 
unlimited number of cycles of paclitaxel-carboplatin.  This is a Phase II trial in which 
objective response, rather than survival, is the primary endpoint.  In general, GOG Phase 
II trials have permitted patients to remain on active therapy until progression or 
unacceptable toxicity. 
 
For patients with a partial response and persistent disease at the completion of 6 cycles of 
chemotherapy the treating physician may elect to continue therapy for a maximum of 10 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
cycles.  Patients will come off the active treatment portion of study with progression or if 
dictated by toxicity. 
 
Rationale for chemotherapy dosing: 
 
The dosing of the paclitaxel-ifosfamide arm will mirror GOG-0161 with the dose 
reduction for prior radiation therapy.  The dosing of the paclitaxel-carboplatin arm will be 
similar to GOG-0232B (paclitaxel 175 mg/m2 IV plus carboplatin AUC = 6 IV every 21 
days).  GOG-0209 has noted increased myelosuppression in patients who have previously 
received pelvic radiotherapy.  Therefore for these patients the initial dosing will be 
paclitaxel 135 mg/m2 IV plus carboplatin AUC = 5 IV every 21 days.  Scudder et al. 
reported on the SWOG protocol S9720 that used carboplatin (AUC = 6), paclitaxel (175 
mg/m2) and amifostine (740 mg/m2) every 4 weeks for endometrial cancer patients most 
of whom had previously received radiation therapy.13  The toxicity of this regimen was 
tolerable.   
 
2.1 
Banking Tumor Tissue and Whole Blood for Future Research (04/02/2012) 
 
FFPE tumor and whole blood will be collected from women who agree to 
participate in this optional translational research study. Tumor and DNA extracted 
from whole blood will be banked for future research. 
 
2.2 
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 carcinosarcoma population with Stage I-
IV, persistent or recurrent disease treated by participating institutions. 
(11/19/2012) 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS  
 
3.1 
Eligible Patients 
 
3.11 
Patients must have newly diagnosed Stage I-IV, persistent or recurrent 
(including unstaged) uterine carcinosarcoma (malignant mixed mullerian 
tumor-MMMT or with ovarian, fallopian tube or peritoneal carcinosarcoma 
and an enrollment date prior to 10/21/2013; pathology confirmed by 
site/institutional pathologist prior to enrollment) and be chemotherapy 
naïve as directed against their carcinosarcoma. Unstaged patients (patients 
who have not had hysterectomy or ovarian surgery) are eligible and should 
be included as “unstaged” if the only histologic (pathology) documentation 
of the disease is a biopsy or curettage of the uterus.  If these patients have 
documented metastatic disease, it should be assigned the appropriate Stage 
(III/IV). (06/1/10) (11/19/2012) (10/21/2013) 
  
3.12 
Patients may have received prior adjuvant external beam radiation therapy 
and/or vaginal brachytherapy.  Patients should be at least 4 weeks from the 
completion of external beam radiotherapy prior to beginning protocol 
chemotherapy.  Patients do not need to be delayed if receiving vaginal 
brachytherapy only. (12/20/2010) 
 
3.13 
Patients must have a GOG Performance Status of 0, 1, or 2. 
 
3.14 
Patients must have recovered from effects of recent surgery, radiotherapy or 
other therapy. 
 
3.15 
Patients must be free of active infection requiring antibiotics. 
 
3.16 
Any hormonal therapy directed at the malignant tumor must be 
discontinued at least one week prior to beginning protocol chemotherapy.  
Continuation of hormone replacement therapy is permitted. (06/1/10) 
 
3.17 
Patients must have adequate:  
 
Bone marrow function: Platelet count greater than or equal to 100,000/mcl, 
and ANC count greater than or equal to 1,500/mcl, equivalent to CTCAE 
v3.0 Grade 1.  
 
Renal function: creatinine less than or equal to 1.5 x institutional upper 
limit normal (ULN), CTCAE v3.0 Grade 1. 
 
Hepatic function: Bilirubin less than or equal to 1.5 x ULN (CTCAE v3.0 
Grade 1).  SGOT and alkaline phosphatase less than or equal to 2.5 x ULN 
(CTCAE v3.0 Grade 1).  Serum Albumin should be equal to or greater than 
3g/dL. 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
 
Neurologic function:  Neuropathy (sensory and motor) less than or equal to 
CTCAE v3.0 Grade 1.  
 
3.18 
Patients must have signed an approved informed consent and authorization 
permitting release of personal health information. 
 
3.19 
Patients of childbearing potential must have a negative serum pregnancy 
test prior to study entry and be practicing an effective form of 
contraception. 
 
3.110 Patients may have measurable disease or non-measurable disease.  
Measurable disease is defined as at least one lesion that can be accurately 
measured in at least one dimension (longest dimension to be recorded).  
Each lesion must be ≥ 20 mm when measured by conventional techniques, 
including palpation, plain x-ray, CT, and MRI, or ≥ 10 mm when measured 
by spiral CT. Measurable disease patients must have at least one “target 
lesion” to be used to assess progression on this protocol as defined by 
RECIST (Section 8).  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. 
 
3.111 Patients must be 18 years of age or older. (09/07/09) 
 
  
3.2 
Ineligible Patients  
 
3.21 
Patients who have received prior cytotoxic chemotherapy for management 
of uterine or ovarian carcinosarcoma.   (06/1/10) 
 
3.22 
Patients with a history of other invasive malignancies or with a 
concomitant invasive malignancy, with the exception of non-melanoma 
skin cancer, if there is any evidence of other malignancy being present 
within the last five years.  Patients are also ineligible if their previous 
cancer treatment contraindicates this protocol therapy. 
 
3.23 
Patients for whom radiotherapy is planned after or during study 
chemotherapy prior to progression of cancer. 
 
3.24 
Patients with a known hypersensitivity to E. coli-derived drug preparations 
(Pegfilgrastim and Filgrastim). 
 
3.25 
Patients with a known hypersensitivity to mesna or other thiol compounds. 
 
3.26 
For enrollment prior to 10/21/2013, patients who are not biopsy proven to 
have carcinosarcoma of the uterus, fallopian tube, peritoneum or ovary. For 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
enrollment after 10/21/2013, patients who are not biopsy proven to have 
carcinosarcoma of the uterus.  (06/1/10) (11/19/2012) (10/21/2013) 
 
 
 
 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
4.0 
STUDY MODALITIES 
 
4.1 
Paclitaxel (NSC #673089) 
 
4.11 
Formulation:  Paclitaxel is supplied as a 6mg/mL non-aqueous solution in 
multi-dose vials containing 30mg/5mL, 100mg/16.7mL, or 300mg/50mL 
of paclitaxel.  In addition to 6mg of paclitaxel, each mL of sterile non-
pyrogenic solution contains 527mg of purified Cremophor® EL 
(polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP. 
 
4.12 
Storage:  Unopened vials of paclitaxel are stable to the date indicated on 
the package when stored between 20 to 25°C (68 to 77°F).  Protect from 
light. 
 
4.13 
Preparation:  Paclitaxel must be diluted prior to infusion.  Paclitaxel should 
be diluted in 0.9% Sodium Chloride for Injection, USP; 5% Dextrose 
Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; or 
5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 
1.2mg/mL.  The solutions are physically and chemically stable for up to 27 
hours at ambient temperature (approximately 25°C / 77°F) and room 
lighting conditions. 
 
NOTE:  In order to minimize patient exposure to the plasticizer DEHP, 
which may be leached from PVC infusion bags or sets, diluted paclitaxel 
solutions should be stored in bottles (glass, polypropylene) or plastic 
(polypropylene, polyolefin) bags and administered through polyethylene-
lined administration sets. 
 
Paclitaxel should be administered through an inline filter with a 
microporous membrane not greater than 0.22 microns.  Use of filter devices 
such as IVEX-2® or IVEX-HP®, which incorporate short inlet and outlet 
PVC-coated tubing, has not resulted in significant leaching of DEHP. 
 
All patients should be premedicated with corticosteroids, diphenhydramine, 
and H2 antagonists prior to paclitaxel administration in order to prevent 
severe hypersensitivity reactions.  Patients who experience severe 
hypersensitivity reactions to paclitaxel should not be rechallenged with the 
drug. 
 
4.14 
Adverse Effects:  Consult the package insert for the most current and 
complete information. 
 
4.15 
Supplier:  Commercially available both from Bristol-Myers Squibb 
Oncology as well as generic manufacturers.  Consult the American 
Hospital Formulary Service Drug Information guide, Facts and 
Comparisons, or the package insert for additional information. 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
 
4.16 
Administration:  See Section 5.2. 
 
4.2 
Carboplatin (Paraplatin® - NSC #241240) 
 
4.21 
Formulation: Carboplatin is supplied as a sterile, pyrogen-free, 10mg/mL 
aqueous solution in multi-dose vials containing 50mg/5mL, 150mg/15mL, 
450mg/45mL, or 600mg/60mL of carboplatin. (12/20/2010) 
 
4.22 
Storage:  Unopened vials of carboplatin are stable to the date indicated on 
the package when stored at 25°C (77°F).  Excursions from 15 to 30°C (59 
to 86°F) are permitted.  Protect from light.  Carboplatin multidose vials 
maintain microbial, chemical, and physical stability for up to 14 days at 
25°C following multiple needle entries. 
 
4.23 
Preparation:  Carboplatin aqueous solution can be further diluted to 
concentrations as low as 0.5mg/mL with 5% Dextrose in Water or 0.9% 
Sodium Chloride for Injection, USP.  When prepared as directed, 
carboplatin aqueous solutions are stable for 8 hours at room temperature 
(25°C / 77°F).  Since no antibacterial preservative is contained in the 
formulation, it is recommended that carboplatin solutions be discarded 8 
hours after dilution. 
 
See Appendix IV for current dosing instructions. (12/20/2010) 
Note that carboplatin dose will be recalculated if patient has weight change 
of greater than or equal to 10% from baseline. (3/21/2011) 
 
NOTE:  Aluminum reacts with carboplatin causing precipitate formation 
and loss of potency; therefore, needles or intravenous sets containing 
aluminum parts that may come in contact with the drug must NOT be used 
for the preparation or administration of carboplatin. 
 
4.24 
Adverse Effects:  Consult the package insert for the most current and 
complete information. 
 
4.25 
Supplier:  Commercially available both from Bristol-Myers Squibb 
Oncology as well as generic manufacturers.  Consult the American 
Hospital Formulary Service Drug Information guide, Facts and 
Comparisons, or the package insert for additional information. 
 
4.26 
Administration:  See Section 5.2. 
 
 
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NCI Protocol #: GOG-0261 
 
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4.3 
Ifosfamide - (IFEX® - NSC #10724) 
 
 
 
4.31 
Formulation:  Ifosfamide is available as a white crystalline powder in 1 
gram or 3 gram single-dose vials. 
 
 
 
4.32 
Preparation:  Injections are prepared by adding sterile water for injection, 
USP or bacteriostatic water for injection, USP to the vial and shaking to 
dissolve.  Use the quantity of diluent below for reconstitution. 
 
 
 
 
Strength          Quantity of diluent         Final concentration 
 
 
 
 
 
1 gram                  20 ml                      50 mg/ml 
 
 
 
3 grams                 60 ml                      50 mg/ml 
 
 
4.33 
Storage:  The dry powder may be stored at room temperature.  The sterile 
reconstituted solution is stable for 1 week at 30°C or 3 weeks at 5°C. 
 
 
 
4.34 
Adverse effects:  Myelosuppression, genitourinary (hemorrhagic cystitis, 
dysuria, urinary frequency and other symptoms of bladder irritation), 
nausea and vomiting, CNS (somnolence, confusion, depressive psychosis 
and hallucinations), alopecia and liver dysfunction.  Other less frequent 
side effects include phlebitis, pulmonary symptoms, fever of unknown 
origin, allergic reactions, stomatitis, cardiotoxicity, and polyneuropathy. 
 
4.35 
Supplier:  Commercially available from Bristol-Myers Oncology.  Please 
refer to 
the package insert for additional information. 
 
 
 
4.36 
Administration:  See Section 5.2 
 
4.4 
Mesna - (Mesnex - NSC #113891)  
 
 
 
4.41 
Formulation:  Mesna is available in a sterile preservation-free aqueous 
solution (100 mg/mL) and as oral tablets (400 mg).  The colorless solution 
is supplied in clear glass ampules for IV or oral administration. 
 
 
 
4.42 
Preparation:  For IV administration, the drug can be diluted by adding the 
contents of a mesna ampule to any of the following solutions: 5% D/W, 5% 
D/NaCl injection, 0.9% NaCl injection, and lactated ringers injection.  The 
vial should be inspected visually for particulate matter and discoloration 
prior to administration.  For oral administration of the intravenous 
formulation, prepare and dispense mesna undiluted in BD syringe 
 
 
 
4.43 
Storage:  When mesna is exposed to oxygen, mesna is oxidized.  Any 
unused drug remaining in the ampules after dosing should be discarded and 
new ampules used for each administration.  Store ampules and vials at 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
room temperature.  Multidose vials may be stored and used for up to 8 days 
after initial entry.  Syringes prepared for oral administration are stable for 9 
days at room temperature and under refrigeration.  Diluted solution is 
sterile for 24 hours at 25°C (77°F).  It is recommended that solutions of 
mesna be refrigerated and used within six hours. 
 
 
 
4.44 
Adverse effects:  Mesna should not be given to patients known to be 
hypersensitive to mesna or other thiol compounds.  Mesna in high doses 
can cause acetone in the urine, occasional irritation at the infusion site and 
nausea and vomiting. 
 
4.45 
Supplier:  Commercially available from Baxter Healthcare Corp.  Please 
refer to the package insert for additional information. (12/20/2010) 
 
 
 
4.46 
Administration:  See Section 5.2 
 
4.5 
Filgrastim (G-CSF, Neupogen®) 
 
4.51 
Formulation:  Filgrastim (G-CSF) is available at a concentration of 300 
mcg/ml in 1.0 and 1.6 single-use glass vials.  It is formulated as a sterile, 
clear, colorless liquid in a 10 mm sodium acetate buffer at pH 4.0.  The 
quantitative composition (per ml) is: 
 
 
Filgrastim (G-CSF) 
 
 
 
300 mcg 
 
Acetate 
 
 
 
 
0.59 mg 
 
Sorbitol 
 
 
 
 
50.0 mg 
 
Tween 80™ 
 
 
 
 
0.004% 
 
Sodium 
 
 
 
 
0.035 mg 
 
Water for injection USP q.s. ad. 
 
1 ml 
 
4.52 
Preparation:  For this protocol, filgrastim will be given subcutaneously.  It 
can be used directly from the vial. 
 
 
4.53 
Storage:  The intact vials of filgrastim should be stored under refrigeration 
(2-8ºC).  Avoid shaking. 
 
4.54  
Adverse Effects:  The adverse effects associated with Filgrastim (G-CSF) 
are usually mild and include bone pain and, rarely, splenomegaly.  
Laboratory effects include increases in alkaline phosphatase, LDH, WBC 
and uric acid.  Filgrastim should not be used in patients with known 
hypersensitivity to E. Coli-derived drug preparations.  
 
4.55 
Supplier:  Commercially available from Amgen. 
 
4.56 
Administration:  See Section 5.2.  
 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
 
 
*Refer to Package Insert for additional information. 
 
4.6 
Pegfilgrastim (G-CSF, Neulasta®) 
 
 
 
4.61 
Formulation:  Pegfilgrastim (G-CSF) is available commercially at a 
concentration of 6 mg /0.6 ml solution in a premeasured sterile syringe. 
 
 
4.62 
Preparation:  For this protocol, Pegfilgrastim will be administered 
subcutaneously directly from the premeasured syringe. 
 
 
4.63 
Storage:  Syringes of Pegfilgrastim should be stored in a refrigerator at 2-8° 
C and protected from light. 
 
 
4.64 
Adverse Effects:  The adverse effects associated with Pegfilgrastim are 
usually mild and include bone pain, flu-like symptoms, nausea, vomiting, 
adult respiratory distress syndrome, splenomegaly, and sickle cell crisis (in 
patients with sickle cell anemia).  Laboratory effects include increases in 
alkaline phosphatase, LDH, WBC, and uric acid.  Pegfilgrastim should not 
be used in patients with known hypersensitivity to E. Coli-derived drug 
preparations. 
 
 
4.65 
Supplier:  Commercially available from Amgen. 
 
4.66 
Administration:  See Section 5.2. 
 
 
*Refer to Package Insert for additional information 
 
4.7  
Quality of Life assessments:  
 
 The Functional Assessment of Cancer Therapy – General (FACT-G) Trial 
Outcome Index (FACT-TOI) will be used to assess the physical dimension of 
health-related quality of life.  The FACT-G is a validated instrument that assesses 
the multidimensional aspects of QOL including: physical well-being, social/family 
well-being, emotional well-being, and functional well-being.  In this study, three 
subscales that are clinically relevant to the physical and functional well-being of 
cancer patients will be used, two of which are general to cancer, and one that is 
targeted specifically to endometrial cancer.  These three subscales comprise 
approximately three-fourths of the FACT-Endometrial (FACT-En), and are 
referred to as the “Trial Outcome Index,” or TOI.  Therefore, the FACT-En TOI, 
comprised of a 7-item Physical Well-being (PWB) scale, a 7-item Functional 
Well-being (FWB) scale, and a 16-item Endometrial Cancer Subscale (EnCS) will 
be administered at each time point.   
 
The FACT-En has been utilized in two recent Phase III GOG endometrial cancer 
trials.  In GOG-0122, quality of life (QOL) outcomes were prospectively compared 
in patients with advanced endometrial cancer treated with whole abdominal 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
irradiation (WAI) or doxorubicin-cisplatin (AP) chemotherapy.22 Reliability of the 
FACT-G was assessed in the GOG-0122 study population and demonstrated a high 
internal consistency (Cronbach's alpha=0.89 at pretreatment).  Health-related QOL 
is currently being assessed in GOG-0209, which is a randomized Phase III trial of 
doxorubicin/cisplatin/paclitaxel and G-CSF Versus carboplatin/paclitaxel in 
patients with Stage III and IV or recurrent endometrial cancer.  Since GOG-0209 
continues to accrue, patient-reported outcome data are not available.  However, 
psychometric data on the FACT-TOI will provide meaningful information for 
future endometrial cancer trials, and will substantiate support for use of the 
proposed subscales in this study. 
 
Patient-reported neurotoxicity will be measured using the FACT/GOG-Ntx 
subscale (11 items). 
 
 
4.8 
Pathology Requirements: 
 
 
 
See Section 3.1 for eligibility requirements: 
 
4.81 
Pathology Eligibility Criteria: 
 
Patients must have newly diagnosed Stage I-IV, persistent or recurrent 
(including unstaged) uterine carcinosarcoma (malignant mixed mullerian 
tumor-MMMT) or ovarian, fallopian tube or peritoneal carcinosarcoma 
with an enrollment date prior to 10/21/2013 and be chemotherapy-naïve as 
directed against carcinosarcoma. (06/1/10) (12/20/2010) (11/19/2012) 
(10/21/2013) 
 
4.82 
Pathology Ineligibility Criteria: 
 
 
For enrollment prior to 10/21/2013, patients who are not biopsy proven to 
have carcinosarcoma of the uterus, fallopian tube, peritoneum or ovary. For 
enrollment after 10/21/2013, patients who are not biopsy proven to have 
carcinosarcoma of the uterus.   (06/1/10) (11/19/2012) (10/21/2013) 
 
4.83 
Stained pathology slides are required for central review by the GOG 
Pathology Committee to confirm eligibility.  See Section 7.2 and 10.2 
 
4.84 
See Section 7.3 and Appendix III for information and instructions 
regarding the specimen requirements for Translational Research. 
 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE (06/1/10) 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Cooperative Group or a CTSU CICRS site.    Each investigator must have 
an NCI investigator number and must maintain an “active” investigator registration status 
through the annual submission of a complete investigator registration packet (FDA Form 
1572 with original signature, current CV, Supplemental Investigator Data Form with 
signature, and Financial Disclosure Form with original signature) to the Pharmaceutical 
Management Branch, CTEP, DCTD, NCI.  These forms are available on the CTSU Web 
site (enter credentials at https://www.ctsu.org; then click on the Register tab) or by 
calling the PMB at 301-496-5725 Monday through Friday between 8:30 a.m. and 4:30 
p.m. Eastern time.  
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients. Study centers can check the status of 
their registration packets by querying the Regulatory Support System (RSS) site 
registration status page of the CTSU member web site by entering credentials at 
https://www.ctsu.org. 
 
 
Requirements for GOG-0261 site registration:  
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
 
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: 
 
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 (12/20/2010) 
 
5.1 
Patient Entry and Registration (06/1/10) 
 
Patient registration can occur only after pre-treatment evaluation is complete, 
eligibility criteria have been met, and the study site is listed as ‘approved’ in the 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
CTSU RSS.  Patients must have signed and dated all applicable consents and 
authorization forms.  
 
All baseline laboratory tests and pre-study evaluations must be performed, 
including tumor and blood samples, within the time period specified in the 
protocol.  
 
All site staff (Lead Group and CTSU Sites) will use OPEN to enroll patients to 
this study.  OPEN can be accessed at https://open.ctsu.org or from the OPEN tab 
on the CTSU members’ side of the website at https://www.ctsu.org. 
  
Prior to accessing OPEN site staff should verify the following: (06/1/10) 
  
• All eligibility criteria have been met within the protocol stated 
timeframes. Site staff should use the registration forms provided on the group 
or CTSU web site as a tool to verify eligibility. 
• All patients have signed an appropriate consent form and HIPPA 
authorization form (if applicable).  
  
Access requirements for OPEN: (06/1/10) 
  
• Site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account. This is the same account (user ID and password) used 
for the CTSU members' web site.  
• To perform registrations, the site user must have been assigned the 'Registrar' 
role on the relevant Group or CTSU roster.  
• To perform registrations on protocols for which you are a member of the Lead 
Group, you must have an equivalent 'Registrar' role on the Lead Group roster.  
Role assignments are handled through the Groups in which you are a member  
• To perform registrations to trials accessed via the CTSU mechanism (i.e., non-
Lead Group registrations), you must have the role of Registrar on the CTSU 
roster. Site and/or Data Administrators can manage CTSU roster roles via the 
new Site Roles maintenance feature under RSS on the CTSU members' web 
site. This will allow them to assign staff the "Registrar" role.  
  
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.   Please print this confirmation for 
your records.  The confirmation provides the patient identification number, 
treatment arm and if applicable, any necessary instructional information. To 
print a copy of the completed Fast Fact Sheet, go to the confirmation page and 
open the “view summary” box. 
  
Further instructional information is provided on the OPEN tab of the CTSU 
members’ side of the CTSU website at https://www.ctsu.org or at 
https://open.ctsu.org. For any additional questions contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
  
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 must be gathered, which can be downloaded 
from the CTSU GOG-0261 web page in the Patient Enrollment section of 
the registered members’ web site at https://www.ctsu.org  (06/1/10) 
 
 
5.14 
The institution will enter the patient's name, GOG number, and assigned 
regimen in the appropriate place in their Log Book to verify the patient's 
entry. 
 
5.2 
Treatment Plan 
 
Stratification factors for randomization (11/19/2012) 
1.  History of pelvic radiation:  any or none 
2.  Disease status at time of study registration: (06/1/10) (12/20/2010) 
      a) FIGO clinical Stage I-II carcinosarcoma 
b) FIGO surgical Stage I-II (pelvic lymph nodes not surgically and 
pathologically assessed), carcinosarcoma 
c) FIGO surgical Stage I-II (pelvic lymph nodes surgically and 
pathologically assessed), carcinosarcoma 
d) FIGO Stage III-IV carcinosarcoma or  
e) recurrent carcinosarcoma 
3. Measurable disease at time of study registration:  any or none 
 
Baseline Quality of life forms must be filled out prior to starting treatment. 
 
MAXIMUM BODY SURFACE AREA USED FOR DOSE CALCULATION 
WILL BE 2.0 m2 AS PER GOG CHEMOTHERAPY PROCEDURES 
MANUAL.  DOSING FOR THE REGIMENS SHOULD NOT BE CHANGED 
FROM CYCLE TO CYCLE UNLESS MANDATED BY THE PROTOCOL.  All 
modifications are relative to the actual starting doses for the specific regimen. For 
application of individual dose modifications, see specific guidelines below. 
(06/1/10) 
 
All patients should be premedicated with corticosteroids, diphenhydramine, and 
H2 antagonists prior to paclitaxel administration in order to prevent severe 
hypersensitivity reactions.  Patients who experience severe hypersensitivity 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
reactions to paclitaxel should not be re-challenged with the drug. 
 
5.21 
Regimen I: 
 
Paclitaxel 175 mg/m2 IV* with a 3-hour infusion time, Day 1 followed by 
Carboplatin AUC 6 IV* Day 1 with a 30-60 minutes infusion time 
(06/1/10) 
 
Carboplatin Dosing: Refer to Appendix IV for current instructions. 
(12/20/2010) 
 
 
 
Note that carboplatin dose will be recalculated if patient has weight 
change of  
 
 
greater than or equal to 10%.  (3/21/2011) (04/02/2012) 
 
Doses of paclitaxel or carboplatin may be rounded according to 
institutional standard or to the nearest 5 mg. After initial treatment, doses 
of paclitaxel should be re-calculated based only on body weight change of 
≥ 10%. (06/1/10)(12/20/2010) 
 
*Prior Radiotherapy: Patients who have had prior external beam 
radiotherapy involving the whole pelvis or abdomen or over 50% of 
the spine for this or any other cancer must initiate Regimen I 
(Paclitaxel-Carboplatin) at the -1 reduced dose. 
 
5.22   Regimen II: 
 
Ifosfamide 1.6 g/m2* IV Days 1, 2, 3 with a one-hour infusion time 
with Mesna (multiple dosing options available and allowed) (oral [tablets 
or liquid] or IV-see dosing below) pre ifosfamide and at hours 4 and 8 
(oral liquid) or at 2 and 6 hours for tablets). (11/19/2012) 
 
The Ifosfamide infusion is followed by Paclitaxel 135 mg/m2 IV over 3 
hours Day 1 (06/1/10) 
 
Filgrastim (Neupogen®) 5 mcg/kg/day beginning Day 4-6 and given for at 
least 10 days OR pegfilgrastim (Neulasta®) 6 mg day 4** 
NOTE: Japanese institutions will use 2 mcg/kg/day dosing of G-CSF. 
Rounding of Filgrastim (G-CSF) dose to the nearest vial size is 
acceptable. 
 
*Prior Radiotherapy: Patients who have had prior external beam 
radiotherapy involving the whole pelvis or abdomen or over 50% of 
the spine for this or any other cancer must initiate Regimen II 
(Ifosfamide-Paclitaxel) dose of Ifosfamide 1.2 g/m2 IV Days 1, 2, 3. 
 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
Doses of paclitaxel and ifosfamide may be rounded according to 
institutional standard or to the nearest 5 mg. After initial treatment, doses 
of paclitaxel and ifosfamide should be re-calculated based only on body 
weight change of ≥ 10%.  See Section 6.3 for dose modifications FOR 
EACH CYCLE BASED ON NADIR COUNTS. (06/1/10)(12/20/2010) 
 
**Pegfilgrastim can be given between 24-72 hours after chemotherapy 
is administered.  Pegfilgrastim should not be administered within 14 
days of subsequent chemotherapy. 
 
Repeat cycle every 3 weeks for 6 planned cycles. Patients who entered the 
study with measurable disease and have a partial response after 6 cycles 
many continue on therapy to a maximum of 10 cycles until progression or 
unacceptable toxicity develops. 
 
Mesna dosing: Mesna can be given either IV (bolus or infusional) or by 
mouth (liquid or table).  Dosing suggested below is recommended dosing, 
but minor variances in institutional methods of the dosing of Mesna are 
acceptable.  Below is suggested dosing for Mesna. Please read carefully as 
this is complicated by the multiple options available: (06/1/10) 
 
For IV continuous infusional mesna, begin mesna 15 minutes before 
ifosfamide infusion at the rate of 2 g/m2 IV over 12 hours. For use with 
continuous infusion ifosfamide, mesna may be administered as a bolus 
dose equal to 20% of the total ifosfamide dose followed by a continuous 
infusion of mesna equal to 40% of the ifosfamide dose, continuing for 12 
hours after completion of the ifosfamide infusion. (06/1/10) 
 
The recommended dose and schedule (ASCO guidelines 2002) is to 
administer mesna as an IV bolus injection in a dosage equal to 20% of the 
ifosfamide dosage (weight/weight) at the time of ifosfamide 
administration. It is suggested that the 
daily dose of mesna be calculated to equal 60% of the total daily dose of 
ifosfamide, administered as three bolus doses given 15 minutes before, 
and 4 and 8 hours after, administration of each dose of ifosfamide when 
the ifosfamide dose is less than 2.5 g/m2/d administered as a short 
infusion. (06/1/10) 
 
For oral (liquid) mesna: (06/1/10) 
 
For oral (liquid) mesna, the total daily oral dose of mesna is 4 grams 
divided into three doses (1.33 grams each) given one hour before and four 
and eight hours after (for oral liquid) or two and six hours after (for 
tablets) the infusion of ifosfamide on each of the three days of ifosfamide 
therapy.  If outpatient, give mesna in syringe (stable at room temperature 
for five days) to patient with instructions for time of oral administration.  
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
Often the initial dose of mesna is given IV, with the second and third dose 
delivered orally.  From ASCO guidelines:  “Administration of the first 
dose of mesna intravenously (IV) at a dose equal to 20% of the total daily 
ifosfamide dose, followed at 2 and 8 hours by 40% weight/weight of the 
ifosfamide dose administered orally, may be considered an acceptable 
alternative to the three-dose IV mesna regimen when the total ifosfamide 
daily dose is less than 2.0 g/m2.”23 (06/1/10) 
 
Mesna liquid is bitter and can be mixed 1:10 in milk (regular or 
chocolate), orange juice, apple juice, Coke, Pepsi, Dr. Pepper, Sprite, 
Seven-Up, or Ginger Ale.  Once mixed for oral intake, mesna is stable for 
24 hours. (06/1/10) 
 
For mesna tablets: (06/1/10) 
 
Mesna tablets have been approved by the United States Food and Drug 
Administration (FDA) to prevent hemorrhagic cystitis in patients receiving 
ifosfamide chemotherapy and are encouraged to be used.  Mesna tablets 
are given orally in a dosage equal to 40% of the ifosfamide dose at 2 and 6 
hours after each dose of ifosfamide.  The total daily dose of mesna is 
100% of the ifosfamide dose. Patients who vomit within 2 hours of taking 
oral mesna should repeat the dose or receive IV mesna. 
 
The dosing schedule should be repeated on each day that ifosfamide is 
administered.  Mesna tablets are supplied as 400 mg tablets.  Oral Mesna 
dosing of the tablets should be rounded up to the next tablet when 
necessary (excess Mesna is preferred to under dosing). 
 
5.23  Disease Surveillance: 
 
Baseline assessment for all patients:  CT or MRI (for contrast allergy 
patients if non-contrast CT is inadequate to assess) scan of the 
chest/abdomen/pelvis within 4 weeks prior to starting protocol therapy is 
required for all patients.   
 
Requirements for Patients WHO DO NOT HAVE MEASURABLE 
disease (“NON-MEASURABLE”) at study entry: CT or MRI scans and 
CA-125 will be repeated every three cycles for 6 cycles (baseline, then 
after Cycles 3, and 6) to rule out progression.  After the 6th cycle of 
therapy, patients with no evidence of progression will obtain a CA-125 
every 3 months for the next 1 year, then every 6 months for three years, 
then annually, up until disease progression is documented.  Imaging will 
be performed if there is clinical concern based on a clinically significant 
rise (in the investigator’s opinion) in the CA125 or symptoms develop.  
Following completion of therapy, surveillance imaging should be obtained 
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NCI Protocol #: GOG-0261 
 
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every 6 months for 2 years then annually thereafter until disease 
progression is documented. (04/02/2012) (11/19/2012) 
 
Requirements for Patients WITH MEASURABLE DISEASE at study 
entry:   CT or MRI scans and CA-125 will be repeated every other cycle 
while on therapy for a planned 6 cycles (maximum of 10) (baseline, then 
after 2, 4, 6, (continued every other if additional therapy is given to 
maximum of 10 cycles) to rule out progression.  After the last cycle of 
therapy, patients with no evidence of progression will be imaged and 
obtain CA-125 every 3 months for the next 2 years, then every 6 months 
for three years, then annually, up until disease progression is documented.  
Imaging will be performed if there is clinical concern based on a clinically 
significant rise (above institutional normal) in the CA-125 or symptoms 
develop.   
 
Patients with evidence of progression of disease will remain on study in 
terms of determining overall survival but are permitted to receive 
treatment for the progression of disease, and are no longer required to 
have imaging for the purposes of this study.   
 
5.24 
QOL evaluations:  baseline; approximately Week 6 (prior to Cycle 3); 
Week 15 (prior to Cycle 6); Week 30. 
 
5.3 
Criteria for removal from study treatment 
 
5.31 
Inability to tolerate the lowest doses because of toxicity. 
 
5.32 
Patients may withdraw from the study at any time for any reason.  Patients 
with evidence of disease progression or significant side effects will be 
removed from study therapy.  
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
 
6.0 
TREATMENT MODIFICATIONS 
 
6.1 
Hematologic Toxicity: REGIMEN I (Paclitaxel and Carboplatin)  
 
6.11 
Dose reduction levels: 
 
Study Drug            -2 Level reduction   -1 Level reduction* 
 
Initial dose level 
Carboplatin  
AUC = 4  
AUC = 5  
AUC = 6  
Paclitaxel  
105 mg/m
2
 
135 mg/m
2
 
175 mg/m
2 
 
*Initial dose for prior pelvic RT patients        
 
 
 
 
6.12 
Treatment modifications will be based on the absolute neutrophil count 
(ANC) rather than the total white cell count (WBC).  Subsequent cycles of 
therapy will not begin until the ANC is greater than or equal to1,500 
cells/mcl and the platelet count is ≥100,000 cells/mcl.  Therapy will be 
delayed on a week-by-week basis until these values are achieved.  
Treatment modifications will be employed in a sequential manner using 
cycle delay and dose reduction.  If greater than a 3-week delay (6 weeks 
from last chemotherapy administration) occurs, the patient will be 
removed from study therapy. 
 
 
 
 
6.13 
Dose reductions will be as follows: 
 
6.131 Dose-limiting thrombocytopenia, defined as Grade 4 
thrombocytopenia (<25,000/mcl) or bleeding associated with 
Grade 3 thrombocytopenia (25,000/mcl to <50,000/mcl), will have 
a dose reduction of carboplatin only to one level less without a 
change in paclitaxel dosage. (06/1/10) 
 
6.132 There will be no dose modifications based on uncomplicated 
nadirs. 
 
6.133 Dose-limiting neutropenia, defined as febrile neutropenia (ANC < 
1,000/mcl and fever ≥38.5° C, per CTCAE v 3.0) or Grade 4 
neutropenia lasting ≥ 7 days will receive a dose reduction of one 
level using the table above without addition of G-CSF. If dose-
limiting neutropenia occurs after prescribed dose reductions to the 
dose level -2, then G-CSF or Pegfilgrastim may be utilized. 
 
6.134 There will be an initial dose reduction based on prior pelvic 
radiotherapy to the “-1” level.  This includes patients with prior 
radiotherapy involving the whole pelvis or abdomen or over 
50% of the spine for this or any other cancer, dose re-escalation 
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NCI Protocol #: GOG-0261 
 
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is allowed and their subsequent dose may be escalated, providing 
these patients exhibited no hematologic or non-hematologic 
toxicity > Grade 1 except alopecia. 
 
6.135 Patients who have been dose reduced will not be re-escalated under 
any circumstances for Regimen I on this study other than if initial 
reduction was due to history of prior radiotherapy. 
 
6.14 
Grade 4 neutropenia uncomplicated by fever or lasting < 7 days will not 
require a dose reduction. 
 
6.15 
Patients with uncomplicated Grade 4 neutropenia, who are already at the 
lowest reduced dose level, may remain on current protocol therapy if 
counts recover on time and if platelet toxicity ≤ Grade 2. (06/1/10) 
 
6.16 
Protocol therapy will be discontinued in patients who require a delay of > 
21 days.  
 
6.2 
Non-Hematologic Toxicity:  REGIMEN I (Paclitaxel and Carboplatin)  
 
6.21 
Grade 2 (or greater) peripheral neuropathy requires reduction of one dose 
level of both paclitaxel and carboplatin and delay in subsequent therapy 
for a maximum of 2 weeks until recovered to Grade 1.  If Grade 2 or 
greater peripheral neuropathy persists beyond the two-week period of 
delay, the paclitaxel will be discontinued and treatment will be allowed 
with carboplatin at the reduced dose level. 
 
 
6.22 
Grade 2 (or greater) renal toxicity requires reduction of one dose level of 
carboplatin and delay in subsequent therapy for a maximum of 2 weeks 
until recovered to Grade 1.  Should Grade 3 or unusual toxicity occur, the 
study chair must be notified.  If creatinine rises to > 2.0 mg/dL, a 
calculated creatinine clearance (CalCcr) should be obtained.  If CalCcr is 
less than 50 ml/min, hold treatment and check weekly CalCcr.  Resume 
therapy when CalCcr is ≥ 50 ml/min.  If CalCcr is < 50 ml/min or serum 
creatinine is > 2 mg/dL after treatment has been held for 2 weeks, protocol 
therapy will be discontinued and the study chair must be notified.  No 
treatment is to be given to a patient with CalCcr < 50 ml/min. 
 
Selective renal tubular defects are observed with platinum compounds.  
Hypocalcemia, hypomagnesemia, and hypokalemia are common and 
potentially severe.  Replacement of calcium, magnesium, and potassium is 
usually effective.  Severe defects, although uncommon, may require 
chronic replacement therapy and, rarely, discontinuation of current 
protocol drugs. 
 
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6.23 
Grade 3 (or greater) hepatic toxicity with elevations in SGOT (AST), 
SGPT (ALT), alkaline phosphatase or bilirubin requires reduction of one 
dose level of the agent felt to be responsible for the elevation (usually 
paclitaxel) and delay in subsequent therapy for a maximum of 2 weeks 
until recovered to Grade 1.  Patients whose treatment is delayed > 14 days 
because of such toxicity should have protocol therapy discontinued.  
Bilirubin must have recovered to Grade 1 or 0 prior to further therapy. 
(06/1/10) 
 
6.24 
There will be no dose modifications for alopecia, fatigue, or myalgias.  
Myalgias in the several days following paclitaxel treatment may be severe, 
and should receive aggressive symptomatic treatment, including narcotics 
or steroids as required.  They are not, however, an indication for dose 
reduction. 
 
6.25 
It is expected that patients with nausea, emesis, diarrhea, or constipation 
will receive appropriate medical management without dose modification.  
However, patients with persistent (greater than 24 hours) Grade 3 (or 
greater) toxicity in spite of optimal medical management require reduction 
of one dose level of both paclitaxel and carboplatin and delay in 
subsequent therapy for a maximum of 2 weeks until recovered to Grade 1.  
 
6.26 
Paclitaxel hypersensitivity reaction: If hypersensitivity reactions to 
paclitaxel or its vehicle (Cremophor) occur, it will usually be during the 
first few minutes of infusion.  Appropriate symptomatic therapy should be 
given.  Continued treatment may be considered if the reaction is not life 
threatening; however, patients must be cautioned about potential 
recurrences of the reaction.  Should the patient decide to continue with 
treatment, it is preferable that this be done on the same day as the 
occurrence.  A suggested procedure would be to administer the drug first 
with 1 cc of the original IV solution diluted in 100 ml over one hour, then 
5 cc in 100 ml over one hour, then 10 cc in 100 ml over one hour, and 
finally, the original solution at the original speed.  Patients who elect not 
to have continued treatment with paclitaxel after experiencing a 
hypersensitivity reaction may continue on protocol therapy with 
carboplatin only.  
 
6.27 
Supportive Care: In addition to other aspects of supportive care, particular 
attention should be paid to the likely development of non-hemolytic 
anemia after several cycles of treatment.  The patient should be transfused 
as necessary while continuing therapy.  No treatment delays are permitted 
for anemia.  Erythropoietin therapy in addition to iron supplementation is 
permitted to ameliorate anemia, at the investigator’s discretion.  
 
6.28 
Other non-hematologic toxicities with an impact on organ function of 
Grade 2  
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NCI Protocol #: GOG-0261 
 
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(or greater) require reduction of one dose level and delay in subsequent 
therapy for a maximum of 2 weeks until recovered to Grade 1, or pre-
therapy baseline. 
 
6.29 
For patients with prior radiotherapy involving the whole pelvis or 
abdomen or over 50% of the spine for this or any other cancer, dose 
escalation (from the initial “-1” level) is allowed and their subsequent 
doses may be escalated, providing these patients exhibited no hematologic 
or nonhematologic toxicity > Grade 1 except alopecia. (11/19/2012) 
 
6.3 
Hematologic Toxicity:  REGIMEN II (Ifosfamide + Paclitaxel) (11/19/2012) 
 
  
 
 
 
 
 
 
*Starting dose for patients with prior pelvic radiation therapy should be the “-1” 
level. 
 
DOSE MODIFICATIONS ARE BASED UPON BOTH INTERIM NADIRS (see 
Section 6.31) AND PRE-TREATMENT COUNTS (see Section 6.32).  If both 
criteria warrant a dose reduction, the lowest dose indicated should be given.  Dose 
Reductions and Dose Escalations are for BOTH ifosfamide and paclitaxel except 
where specified in Sections 6.41 and 6.44.  (06/1/10) 
 
6.31 
Interim Nadirs (Note: Dose modification may also be required due to 
pretreatment counts—see Section 6.32.) 
 
 
6.311 Grade III or IV bleeding or infection requires a 1-level dose 
reduction regardless of documented ANC or platelet values. 
 
6.312 No dose escalation (increase) above the maximum dose levels (+2) 
indicated in the table below (6.313) is allowed.  Dose escalation is 
mandated by the ANC Nadir grade (0 or 1) and the platelet nadir is 
0, 1, or 2. (06/1/10) 
 
 
 
Dose Level 
Study Drug 
-3 
-2 
-1* 
Start 
+1 
+2 
Ifosfamide g/m2 
0.5 
0.8 
1.2 
1.6 
2 
2 
Paclitaxel mg/m2 
100 
100 
135 
135 
175 
200 
*starting dose for patients with prior pelvic RT 
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NCI Protocol #: GOG-0261 
 
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6.313 No reduction below the lowest dose level specified above is 
allowed.  If a patient is already at the “-3” dose and counts call for 
further reduction, the patient is to be removed from the study 
therapy and the study chair notified. 
 
ANC Nadir Grade 
Action for BOTH 
ifosfamide and paclitaxel 
0 (≥ LLN) 
Escalate dose by 1 Level 
1 (< LLN to 1500/mcl) 
Escalate dose by 1 Level 
2 (<1,500/mcl to 1,000/mcl) 
No Change 
3 (<1,000/mcl to 500/mcl) 
No Change 
4 (<500/mcl) 
Reduce dose by 1 Level 
 
Platelet Nadir Grade 
Action for BOTH 
ifosfamide and paclitaxel 
0 (≥ LLN) 
No Change or escalate 
dose based on ANC nadir 
1 (<LLN to 75,000/mcl) 
No Change or escalate 
dose based on ANC nadir 
2 (<75,000/mcl to 50,000/mcl) 
No Change or escalate 
dose based on ANC nadir 
3 (<50,000/mcl to 25,000/mcl) 
Reduce dose by 1 Level 
4 (<25,000/mcl) 
Reduce dose by 1 Level 
 
 
6.32 
Pre-treatment Counts (Note: dose modification may also be required due 
to interim nadirs laboratory values – see Section 6.31.) 
 
6.321 No subsequent course of therapy should be given until the ANC is 
greater than or equal to 1,500/mcl and the platelet count is greater 
than or equal to 100,000/mcl.  If dose is held due to pre-treatment 
myelosuppression, recheck counts weekly.  If therapy is delayed 3 
weeks or longer from scheduled administration, the Study Chair 
should be notified and the patient should be removed from study 
therapy. 
 
6.322 ANC and/or platelet nadir values dictate treatment doses for each 
cycle, according to the above table for interim counts if no other 
significant (Grade 2 or greater) organ toxicity is noted.  Treatment-
related alopecia, fatigue, or myalgias will typically not be used as 
reasons for NOT escalating doses. 
 
6.323 If treatment is delayed greater than 1 week but less than three from 
scheduled administration due to pre-treatment counts, the dosage 
modification is a one dose level reduction. 
 
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NCI Protocol #: GOG-0261 
 
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6.4 
Non-Hematologic Toxicity:  REGIMEN II (Ifosfamide + Paclitaxel)  
 
6.41 
Patients experiencing significant ifosfamide-related (i.e., not related to 
ureteral stents, tumor infiltration, or infection) microscopic hematuria 
(defined at 1+ or greater on urine dipstick or greater than 25 red blood 
cells per 1 high power field) should have the dose of ifosfamide reduced 1 
level.  If  the microscopic hematuria persists on the urinalysis prior to the 
next cycle, reduce one additional level.  If symptoms persist, remove 
patient from study therapy.  If the patient develops gross hematuria at any 
ifosfamide dose level, remove from study therapy. (11/19/2012) 
 
 
If hematuria develops during the three-day treatment cycle, other sources 
of bleeding should be investigated (infection, tumor-related, etc) and dose 
should be held only if hematuria is thought to be ifosfamide-related and 
Mesna was taken properly.  Daily urinalysis during the 3-day infusion is 
not required by this protocol (only prior to the beginning of a new cycle). 
(11/19/2012) 
 
6.42 
If the serum albumin drops below 3 g/dL, hold therapy until albumin is at 
least 3g/dL.  If  > 6 weeks pass from the last dose of ifosfamide, remove 
patient from study therapy. 
 
6.43 
There will be no dose adjustment based on serum albumin. 
 
6.44 
If Grade 2 ifosfamide-related neurologic symptoms develop (e.g., 
confusion), reduce ifosfamide dose 1 level.  If symptoms recur (Grade 2 or 
worse), remove patient from study therapy.  If Grade 3 or 4 neurologic 
symptoms develop, remove patient from study therapy. 
 
6.45 
Grade 2 (or greater) peripheral neuropathy requires reduction of one dose 
level of both paclitaxel and ifosfamide and delay in subsequent therapy for 
a maximum of 2 weeks until recovered to Grade 1.  If Grade 2 or greater 
peripheral neuropathy persists beyond the two-week period of delay, the 
paclitaxel will be discontinued and treatment will be allowed with 
ifosfamide dose reduced one level. 
 
6.46 
Grade 3 (or greater) hepatic toxicity with elevations in SGOT (AST), 
SGPT (ALT), alkaline phosphatase or bilirubin requires reduction of one 
dose level of the agent felt to be responsible for the elevation (usually 
paclitaxel) and delay in subsequent therapy for a maximum of  2 weeks 
until recovered to Grade 1.  Patients whose treatment is delayed > 14 days 
because of such toxicity should have protocol therapy discontinued.  
Bilirubin must return to within normal limits prior to further therapy. 
  
6.47 
There will be no dose modifications for alopecia, fatigue, or myalgias.  
Myalgias in the several days following paclitaxel treatment may be severe, 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
and should receive aggressive symptomatic treatment, including narcotics 
or steroids as required.  They are not, however, an indication for dose 
reduction or lack of dose escalation. (11/19/2012) 
 
6.48 
It is expected that patients with nausea, emesis, diarrhea, or constipation 
will receive appropriate medical management without dose modification.  
However, patients with persistent (greater than 24 hours) Grade 3 (or 
greater) toxicity, in spite of optimal medical management, require 
reduction of one dose level of both ifosfamide and paclitaxel and delay in 
subsequent therapy for a maximum of 2 weeks until recovered to Grade 1. 
 
6.49 
Paclitaxel hypersensitivity reaction: If hypersensitivity reactions to 
paclitaxel or its vehicle (Cremophor) occur, it will usually be during the 
first few minutes of infusion.  Appropriate symptomatic therapy should be 
given.  Continued 
treatment may be considered if the reaction is not life threatening; 
however, patients must be cautioned about 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.  A 
suggested procedure would be to administer the drug first with 1 cc of the 
original IV solution diluted in 100 ml over one hour, then 5 cc in 100 ml 
over one hour, then 10 cc in 100 ml over one hour, and finally, the original 
solution at the original speed.  Patients who elect not to have continued 
treatment with paclitaxel after experiencing a hypersensitivity reaction 
may continue on protocol therapy with ifosfamide only.  
 
6.410 Supportive Care: In addition to other aspects of supportive care, particular 
attention should be paid to the likely development of non-hemolytic 
anemia after several cycles of treatment.  The patient should be transfused 
as necessary while continuing therapy.  No treatment delays are permitted 
for anemia.  Erythropoietin therapy in addition to iron supplementation is 
permitted to ameliorate anemia, at the investigator’s discretion.  
 
6.411 Other non-hematologic toxicities with an impact on organ function of 
Grade 2 (or greater) require reduction of one dose level and delay in 
subsequent therapy for a maximum of 2 weeks until recovered to Grade 1, 
or pre-therapy baseline.
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7.0 
STUDY PARAMETERS   
 
7.1 
Observations and Tests 
 
The following observations and tests are to be performed and recorded on the 
appropriate form(s).  See Section 7.2 and 10.2 for a description of the stained 
pathology slides that are required for central review by the GOG Pathology 
Committee to confirm eligibility and for instructions for shipping that 
material to the GOG Statistical and Data Center.  See Section 7.3 for a 
description of the specimen requirements for translational research for this 
study. (06/1/10)  
 
PARAMETER 
 
 
Pre-
Treatment 
 
Weekly 
 
 
Prior to 
Each 
Cycle 
Disease 
Surveillance  
Follow-up, 
Post 
Therapy 
 
History & Physical, including 
pelvic examination   
1 
 
X 
 
9 
Toxicity Assessment* 
1 
 
X 
 
 
CBC/Differential/Platelets, 
Creatinine 
3 
4 
5 
 
 
Urine Analysis (U/A) 
3 
 
5 
 
 
Bilirubin, SGOT, Alkaline 
Phosphatase, Electrolytes, BUN, 
Ca, Mg, PO4, Albumin 
3 
 
5 
 
 
CA-125 
1 
 
 
6, 8 
 
6, 8 
 
Chest, Abdomen and Pelvic 
Imaging (CT scan or MRI) 
1 
 
 
6, 8 
6, 8 
Pregnancy test (if childbearing 
potential exists) 
2 
 
 
 
 
Electrocardiogram (EKG) 
1 
 
 
 
 
Audiogram 
X7 
 
 
 
 
Clinical and/or Radiographic 
Tumor Measurement 
1,8 
 
 
 
6, 8 
 
QOL Evaluations: FACT TOI-En, 
FACT/GOG-Ntx Subscale 
1 
 
10 
 
10 
* Including neurotoxicity assessment 
Notes:  
1. Must be obtained within 28 days prior to initiating protocol therapy.  
2. Must be obtained within 72 hours of initiating protocol therapy if childbearing potential exists.  
3. Must be obtained within 14 days prior to initiating protocol therapy.  
4. If Grade 4 neutropenia is documented (ANC < 500/mcl), obtain twice per week until resolved to Grade 3.  
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NCI Protocol #: GOG-0261 
 
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5. CBC/Differential/Platelets, creatinine, and U/A (U/A for patients receiving ifosfamide only) must be 
obtained within 4 days of re-treatment with protocol therapy.  Calcium, Magnesium, PO4 and Albumin 
within 7 days of re-treatment.  
6.  For patients who do not have measurable disease (NON-MEASURABLE) at study entry, they will be 
imaged by CT or MRI (for contrast allergy patients if non-contrast CT is inadequate to assess) scan of 
the chest/abdomen/pelvis within 4 weeks before starting protocol therapy.  CT or MRI scans and CA-
125 will be repeated prior to every three cycles for 6 cycles (baseline, then after cycles 3, and 6) to rule 
out progression.  After the 6th cycle of therapy, patients with no evidence of progression will obtain a 
CA-125 every 3 months for the next 1 year, then every 6 months for three years, then annually, up 
until disease progression is documented.  Imaging will be performed every 6 months for 2 years then 
annually thereafter until disease progression is documented or if there is clinical concern based on a 
clinically significant rise (above institutional normal) in the CA-125, or symptoms develop.  
(04/02/2012)   
7.  Audiogram is necessary if there is a history of hearing loss or new onset hearing loss. Audiograms 
should be repeated at the physician’s discretion.   
8.  For patients with MEASURABLE DISEASE at study entry, they will be imaged by CT or MRI (for 
contrast  allergy patients if non-contrast CT is inadequate to assess) scan of the chest/abdomen/pelvis 
within 4 weeks of starting protocol therapy.  CT or MRI scans and CA-125 will be repeated every 
other cycle until protocol chemotherapy is completed at a maximum of 10 cycles (baseline, then after 
cycles 2, 4, 6, 8, 10) to rule out progression.  After the final protocol cycle of therapy, patients with no 
evidence of progression will undergo imaging and obtain CA-125. Tumor imaging, clinical 
examination and CA-125 will be repeated every 3 months for the next 2 years, and then every 6 
months for 3 years, and then annually, up until disease progression is documented.  Imaging will be 
performed if there is clinical concern based on a clinically significant rise (above institutional normal) 
in the CA-125 or symptoms develop.  (06/1/10) 
9.  Every 3 months x 2 years, then every 6 months x 3 years, then every year until death; all subsequent    
      antitumor therapies administered must be reported. 
10.  Patients will complete the QOL Survey at FOUR times 
      1)  Baseline (within 28 days prior to initiation of therapy) 
      2)  Prior to Cycle 3 (week 6) 
      3)  Prior to Cycle 6 (week 15) 
      4)  30 weeks following initiation of therapy 
NOTE:  QOL assessments should be administered at ALL 4 assessment times, REGARDLESS 
of whether the patient progresses or is removed from study therapy for any reason.  If there are 
treatment delays, the QOL assessment timing should be adjusted to follow the timing of the cycles 
 
7.2 
Stained Pathology Slide Requirements for Central Review to Confirm Protocol 
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 and histologic cell types 
including the presence of heterologous elements will be required. In addition, at 
least one representative H&E stained slide documenting the most advanced stage 
of disease will be required if the most advanced stage is documented by histology 
or cytology.  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 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
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, two 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 4.8 and 10.2 for additional 
requirements and instructions. 
 
7.3 
Translational Research (04/02/2012) 
 
 
7.31 
Specimen Requirements (04/02/2012) 
 
If the patient gives permission for her specimens to be collected and used 
for this optional translational research component, then participating 
institutions within the United States are required to submit the patient’s 
specimens as outlined below (unless otherwise specified). 
 
A detailed description of the specimen requirements can be found in 
Appendix III. 
 
Required Specimen 
(Specimen Code) 
Collection Time Point 
Ship To 
FFPE Primary, Metastatic, or 
Recurrent Tumor  (FT01) 
1st Choice: block 
2nd Choice: 10 unstained slides 
(charged, 5µm) 
Prior to initiating chemotherapy 
GOG Tissue Bank within 8 weeks of 
registration1 
Whole Blood (WB01) 
7-10mL drawn into a purple 
top (EDTA) tube 
Prior to or after initiating 
chemotherapy 
GOG Tissue Bank the day the 
specimen is collected1 
1 
Ship specimens to: GOG Tissue Bank / Protocol GOG-0261, Nationwide Children’s Hospital, 700 Children’s 
Drive, WA1340, Columbus, OH 43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: 
GOGBanc@nationwidechildrens.org 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
 
7.32 
Laboratory Testing (04/02/2012) 
 
 
FFPE tumor and DNA extracted from whole blood will be banked for 
future research. 
 
7.33 
Future Research (04/02/2012) 
 
Details regarding the banking and use of specimens for future research can 
be found in Appendix III. 
 
7.4 
Quality of Life 
 
7.41    Patients will complete the QOL Survey at FOUR times 
                                    1)  Baseline (within 28 days prior to initiation of therapy) 
                                    2)  Prior to Cycle 3 (week 6) 
                                    3)  Prior to Cycle 6 (week 15) 
                                    4)  30 weeks following initiation of therapy 
                                     
 
NOTE: QOL assessments should be administered at all 4 assessment 
times,  REGARDLESS of whether the patient progresses or is removed 
from study for any reason. 
                                                                                                    
 7.42 The QOL Survey is also available in French and Spanish.  Requests for the 
translated versions should be made to the GOG Statistical and Data Center. 
 
7.43 
Whenever possible the QOL Survey should be administered at the clinic 
visit before the patient is seen by the physician, before evaluations are 
performed and before test results are shared with her.  In the event that the 
questionnaires are not administered at the clinic visit, the QOL data can be 
collected by telephone or mail as backup methods, with telephone data 
collection being the preferred back-up method. 
 
7.44     The Quality of Life Liaison (GOG Nurse/Data Manager) at each 
institution has overall responsibility for the administration of the study 
questionnaires. 
 
7.45     The GOG Nurse/Data Manager should read the instructions printed on the 
questionnaire to the patient and ensure the patient understands the 
instructions.  It is important to assure the patient that all material on the 
questionnaire is confidential, and will not be shared with the health care 
team and that it will not become part of the medical record. 
 
7.46     Assistance in reading the questionnaire is permitted if the patient is unable 
to complete the questionnaire on her own (e.g., difficulty in reading, 
elderly).  It is important not to influence the response of the patient.  Note 
why the patient required assistance and what assistance was given. 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
 
7.47     Patients should be instructed to answer all the questions regardless of 
whether the symptoms or conditions asked about are related to the cancer 
or cancer treatment.  Discourage family members from being present 
during questionnaire completion or from influencing the patient’s 
response. 
 
7.48     Review the questionnaire for completeness before the patient leaves. 
                                     
7.481   If the patient has marked more than one answer per question, ask 
the patient which answer best reflects how she is feeling 
 
7.482   If the patient has skipped a question or questions, assure that she 
noted in the space provided that she has chosen not to answer those 
questions. 
             
7.49 
It is essential that the questionnaires be completed according to the 
schedule described in Section 7.41. 
 
7.410 If the patient refuses or cannot complete the questionnaire at any time 
point, she should be asked to do so at the next scheduled administration 
time. 
 
7.411 The patient may withdraw from the Quality of Life portion of the protocol 
for any reason.  The reason must be documented on the form. 
 
7.412 Prior to submitting the QOL Scantron to the GOG Statistical and Data 
Center, be sure the following information is recorded and coded in: 
a)  patient’s complete GOG number 
b)  date of form completion 
c)  study time point for which the form is being completed
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
 
8.0 
EVALUATION CRITERIA 
 
8.1 
Parameters of Outcome – GOG RECIST Criteria 
 
8.11 
Measurable disease is defined as at least one lesion that can be accurately 
measured in at least one dimension (longest dimension to be recorded).  
Each lesion must be ≥ 20 mm when measured by conventional techniques, 
including palpation, plain x-ray, CT, and MRI, or ≥ 10 mm when 
measured by spiral CT.   
 
8.12 
Baseline documentation of “Target” and “Non-Target” lesions 
 
All measurable lesions up to a maximum of 5 lesions per organ and 10 
lesions in total representative of all involved organs should be identified 
as target lesions and will be recorded and measured at baseline.  Target 
lesions should be selected on the basis of their size (lesions with the 
longest dimension) and their suitability for accurate repetitive 
measurements by one consistent method of assessment (either by imaging 
techniques or clinically).  A sum of the longest dimension (LD) for all 
target lesions will be calculated and reported as the baseline sum LD.  
The baseline sum LD will be used as reference to further characterize the 
progression of the measurable dimension of the disease.  Tumor 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. 
 
All other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not 
required and each of these lesions should be followed as stable (the 
persistence of a non-target lesion), complete response (the disappearance of a 
non-target lesion) or progressive disease (the unequivocal progression of a 
non-target lesion). 
 
All baseline evaluations of disease status should be performed as close as 
possible to the start of treatment and never more than 4 weeks before the 
beginning of treatment. 
 
Measurement of the longest dimension of each target lesion size is 
required for follow-up.  Change in the sum of these dimensions affords 
some estimate of change in tumor size and hence therapeutic efficacy.  All 
disease must be assessed using the same technique as baseline.  
 
 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
8.13 
Definition of disease progression 
 
 
Progression for patients with measurable disease at baseline is defined as 
ANY of the following: 
 
• At least a 20% increase in the sum of LD target lesions taking as 
reference the smallest sum LD recorded since study entry  
• In the case where the ONLY target lesion is a solitary pelvic mass 
measured by physical exam which is not radiographically measurable, 
a 50% increase in the LD is required taking as reference the smallest 
LD recorded since study entry 
• The appearance of one or more new lesions   
• Death due to disease without prior objective documentation of 
progression 
• Global deterioration in health status attributable to the disease 
requiring a change in therapy without objective evidence of 
progression  
• Unequivocal progression of existing non-target lesions, other than 
pleural effusions without cytological proof of neoplastic origin, in the 
opinion of the treating physician (in this circumstance an explanation 
must be provided) 
 
 
Progression for patients with non-measurable disease at baseline is defined 
as increasing clinical, radiological, or histological evidence of disease 
since study entry.   
 
 
 
 
8.14 
Survival is the observed length of life from entry into the study to death or 
the date of last contact. 
 
8.15 
Progression-Free Survival is the period from study entry until disease 
progression, death, or date of last contact. 
 
8.16 
Subjective Parameters including performance status, specific symptoms, 
and side effects are graded according to the CTCAE. 
 
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NCI Protocol #: GOG-0261 
 
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9.0 
DURATION OF STUDY 
 
9.1 
A total of 6 cycles of chemotherapy is planned for all patients in the absence of 
disease progression or unacceptable toxicity.  Patients who entered the study with 
measurable disease and meet the criteria for a partial response at the end of 6 
cycles may continue on therapy up to a maximum of 10 cycles in the absence of 
disease progression or unacceptable toxicity. 
 
9.2 
Follow-up is required as outlined in Section 7.0.  In brief, patients will be 
followed (with physical exams and histories) every three months for the first two 
years and then every six months for the next three years, then annually.  
Scheduled imaging varies based on patients having measurable or non-measurable 
disease at enrollment (see Section 7.0)  Patients will be monitored for progression, 
delayed toxicity, non-protocol therapy and survival for this 5-year period with 
D2M and Q forms submitted to the GOG Statistical and Data Center, unless 
consent is withdrawn. 
 
9.3 
A patient is considered off study therapy when the patient has either completed 
the prescribed number of cycles of study therapy, has progressed or died prior to 
completion of study therapy, a non-protocol drug or therapy (directed at the 
disease) is initiated or all study therapy is totally discontinued.  Report all 
treatment received on Form D2R and adverse events on Form T up until the 
patient qualifies as being off study therapy. 
 
 
 
 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
 
10.1 
ADVERSE EVENT REPORTING FOR A COMMERCIAL AGENT 
(05/05/2014) 
   
10.11 Definition of Adverse Events (AE) (09/06/2011) 
 
An adverse event (AE) is any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease that occurs in a 
patient administered a medical treatment, whether the event is considered 
related or unrelated to the medical treatment.  
 
10.12 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 Adverse 
Event Reporting System (CTEP-AERS).  All CTEP-AERS submissions 
are reviewed by GOG before final submission to CTEP. CTEP staff will 
not be evaluating submissions to these databases.  Submitting a report 
through CTEP-AERS serves as notification to GOG, and satisfies the 
GOG requirements for expedited AE reporting.  All adverse reactions will 
be immediately directed to the Study Chair for further action. 
 
The requirement for timely reporting of AEs to the study sponsor is 
specified in the Statement of Investigator, Form FDA-1572.  In signing the 
FDA-1572, the investigator assumes the responsibility for reporting AEs 
to the NCI.  In compliance with FDA regulations, as contained in 21 CFR 
312.64, AEs should be reported by the investigator. 
 
10.13 Phase 2 and 3 Trials Utilizing a Commercial Agent:  CTEP-AERS 
Expedited Reporting Requirements for Adverse Events That Occur Within 
30 Days of the Last Dose of Any Commercial Study Agent  
 
 
From the period of protocol activation through September 30, 2011, 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 
(CTCAE v3.0) are utilized for defining and grading specific adverse 
events reported through the CTEP-AERS system. (09/06/2011) 
 
Beginning October 1, 2011, the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) v 4.0 will be utilized for AE reporting 
through the CTEP-AERS system. CTCAE v 4.0 is located on the 
CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ct
c.htm. All appropriate treatment areas should have access to a copy of 
this Version of CTCAE.  CTCAE v 4.0 definition is also available on 
- 44 - 

NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
the GOG member web site (https://gogmember.gog.org under 
MANUALS). (09/06/2011) 
 
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: 
CTEP-AERS 24-hour notification followed by complete report within 3 calendar days for: 
• Grade 4 and Grade 5 unexpected events  
      CTEP-AERS 7 calendar day report: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• Grade 5 expected events 
 
2 Although a CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full 
report is required as outlined in the table. 
 
 Please see exceptions below under the section entitled, “Additional Instructions or Exceptions to CTEP-AERS 
Expedited Reporting Requirements for Phase 2 and 3 Trials Utilizing a Commercial Agent.”          March 2005 
 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
• 
Expedited AE reporting timelines defined: 
 “24 hours; 3 calendar days” – The investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete CTEP-AERS 
report within 3 calendar days of the initial 24-hour report. 
“7 calendar days” – A complete CTEP-AERS report on the AE must be submitted within 
7 calendar days of the investigator learning of the event. 
 
• 
Any medical event equivalent to CTCAE Grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of 
attribution and designation as expected or unexpected with the exception of any 
events identified as protocol-specific expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
anomalies, or birth defects must be reported to GOG via CTEP-AERS if the event occurs 
following treatment with a commercial agent. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing a Commercial Agent: 
 
• There are no additional instructions or exceptions to CTEP-AERS expedited reporting 
requirements for this protocol. 
 
10.14 Procedures for Expedited Adverse Event Reporting: 
 
10.141 CTEP-AERS Expedited Reports: Expedited reports are to be 
submitted using CTEP-AERS available at http://ctep.cancer.gov.  
The NCI guidelines for expedited adverse event reporting 
requirements are also available at this site.   
 
Up until September 30, 2011, AML/MDS events must be reported 
via CTEP-AERS (in addition to your routine AE reporting 
mechanisms).  In CTCAE v3.0, the event can be reported as:  
“Secondary malignancy-Other (specify)”. (09/06/2011) 
 
Starting October 1, 2011 when use of CTCAE v4.0 begins: 
AML/MDS events must be reported via CTEP-AERS (in addition 
to your routine AE reporting mechanisms). In CTCAE v4.0, the 
event(s) may be reported as either: 1) Leukemia secondary to 
oncology chemotherapy, 2) Myelodysplatic syndrome, or 3) 
Treatment related secondary malignancy. (09/06/2011) 
 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made to GOG by telephone at: 215-854-0770. 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection.  Please note that all paper 
CTEP-AERS forms have been removed from the CTEP website 
and will NO LONGER be accepted. (12/20/2010) 
 
 
 
 
 
 
 
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NCI Protocol #: GOG-0261 
 
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10.2 
GOG DATA MANAGEMENT FORMS 
 
The following forms must be completed for all patients registered and submitted 
to the GOG Statistical and Data Center (SDC) in accordance with the schedule 
below.  Use the SDC Electronic Data Entry System (SEDES) online application 
found at the GOG Web Menu page, to view and print a copy of each form along 
with instructions, and to submit forms electronically.  All amendments to forms 
submitted through SEDES must also be submitted through SEDES.  The original 
form and required copies for forms NOT submitted online must be mailed to the 
GOG SDC.  Note:  Pathology material (Form F, path report and slides) may 
be submitted together via postal mail.  The GOG Uploader Application in 
SEDES is an alternate method for submitting Form F and pathology reports 
to the GOG SDC (stained slides must be shipped via postal mail).See Sec. 4.8 
and 7.2 for additional requirements and instructions. (06/1/10) (3/21/2011) 
 
Form± 
Due within 
Copies* 
Comments 
Weeks 
Event 
Form R (Registration 
Form) 
 
2 
 
Registration 
 
1 
 
Mandatory submission via 
SEDES 
Specimen Consent 
Application 
1 
Registration 
N/A 
Complete online 
Form OSR (Recurrent 
Gynecologic Cancer On-
Study Form) or Form 
OSU (Uterine Cancer On-
Study Form) or Form 
OSO (Primary Ovarian 
Cancer- On Study 
Form)  
2 
Registration 
1 
Mandatory submission via 
SEDES 
Form DR (Treatment 
Summary Form) 
Operative Report 
Discharge Summary 
2 
 
6 
6 
Registration 
 
Registration 
Registration 
1 
 
2 
2 
Mandatory submission via 
SEDES 
Submit via postal to SDC or 
upload via SEDES 
Form BMR (Biomarker 
Reporting Form) 
2 
Registration 
1 
Mandatory submission via 
SEDES; report CA-125 
Form D2M (Solid Tumor 
Reporting Form) - 
baseline assessment) 
2 
Registration 
1 
Mandatory submission via 
SEDES 
Quality of life: ***   
Scantron Form – baseline 
Scantron Form-6 weeks 
Scantron Form-15 weeks 
Scantron Form-30 weeks 
 
2 
8 
17 
34 
 
Start of study therapy 
Start of study therapy 
Start of study therapy 
Start of study therapy 
 
1 
1 
1 
1 
 
Submit Scantron from by 
postal mail***  
Primary disease**: 
Form F (Pathology 
Form) 
 
6 
 
 
Registration 
 
 
2 
 
 
Available in SEDES for print 
only 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
  Pathology Report 
Stained Path Slides to 
confirm eligibility 
 
Recurrent or Persistent 
Disease**: 
Form F (Pathology 
Form) 
Pathology Report 
Stained Path Slides to 
confirm eligibility, if 
histologically-
documented 
6 
6 
 
 
 
 
6 
 
6 
6 
Registration 
Registration 
 
 
 
 
Registration 
 
Registration 
Registration 
2 
** 
 
 
 
 
2 
 
2 
** 
Submit via postal mail to 
GOG SDC in Buffalo, New 
York or submit using the 
report upload of SEDES  
 
 
Available in SEDES for print 
only. Submit via postal mail 
to GOG SDC in Buffalo, 
New York or submit using 
the report upload of SEDES 
Form D2R (Cycle Dose 
Drug Form) 
 
2 
Completion of each 
cycle of therapy 
1 
Mandatory submission via 
SEDES 
Form BMR (Biomarker 
Reporting Form) 
2 
Completion of study 
treatment; each required 
follow-up CA-125 
assessment 
1 
Mandatory submission via 
SEDES; report CA-125 
Form D2M (Solid Tumor 
Reporting Form) 
2 
Every 
clinical/radiographic 
disease assessment 
1 
Mandatory submission via 
SEDES 
Form SP-FT01-0261  
for FFPE tumor  
(04/02/2012) 
8 
Registration 
1 
Mandatory submission via 
SEDESƒ (04/02/2012) 
Form SP-WB01-0261  
whole blood  
(04/02/2012) 
26 
(04/02/2012) 
Registration 
(04/02/2012) 
1 
Mandatory submission via 
SEDESƒ (04/02/2012) 
 
Form T (Common 
Toxicity Form) 
2 
Beginning of each 
subsequent treatment 
cycle and 3 weeks after 
final treatment cycle 
1 
 
Mandatory submission via 
SEDES 
 
Form Q0 (Treatment 
Completion Form) 
 
2 
Completion of study 
treatment and change in 
treatment 
1 
Mandatory submission via 
SEDES 
Form Q (Follow-Up 
Form) 
 
2 
Disease progression; 
death; normal follow-up; 
change in treatment 
1 
Mandatory submission via 
SEDES 
quarterly for 2 years, semi-
annually for 3 more years 
* 
The number of required copies including the original form, which must be sent to the Statistical and Data 
Center. 
** 
Stained pathology slides are required for central review by the GOG Pathology Committee to confirm 
eligibility.  See Sections. 4.8 and 7.2 for additional requirements and instructions.  All stained slides must be 
submitted via postal mail.  
ƒ         Form SP must be submitted regardless of whether the specimen is submitted for research. (04/02/2012) 
 ***     The schedule in Section 10 provides the time that forms are due in the SDC.  See Section 7.4 for the times 
that each QOL assessment should be completed by the patient.  Use only Scantron forms with the header of 
“GOG Protocol 0261.”  Quality of life forms will be provided by the SDC upon request.  If the assessment is 
not performed, submission of the form is still required documenting the reason the assessment was not 
performed. 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
 
Form OSR is required for all patients with measurable or persistent or recurrent disease; Form OSU is 
required for patients with non-measurable and primary uterine carcinosarcoma and Form OSO is required for 
patients with non-measurable and primary ovarian carcinosarcoma. (06/1/10) 
 
This study will be monitored by the Abbreviated Clinical Data System (CDUS) Version 3.0 
CDUS data will be submitted quarterly to CTEP by electronic means. 
 
This study utilizes the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE 
v3.0) for defining and grading adverse events to be reported on GOG case report forms. A GOG 
CTCAE v3.0 Manual is available on the GOG member web site (http://www.gog.org under 
MANUALS) and can be mailed to the institution registering a patient to this study if requested.  
(09/06/2011) 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
11.0 
STATISTICAL CONSIDERATIONS  
 
11.1 
Study design overview and registration: 
 
This study is designed as a randomized open-label Phase III clinical trial.  This 
design will provide a direct assessment of the null hypothesis that survival among 
patients with uterine or ovarian carcinosarcoma treated with paclitaxel and 
carboplatin chemotherapy is not inferior to survival among patients treated with 
ifosfamide, mesna, and paclitaxel chemotherapy.  Prior to activation of Revision 2 
of this study, patients were registered to this study and obtained random treatment 
assignment centrally at the GOG Statistical and Data Center.  Following the 
effective date of Revision 2, patients are to be registered to this study through 
OPEN and treatment randomization will be carried out centrally by the GOG 
Statistical and Data Center.  Prior to registration, eligibility will be reviewed via 
Fast Fact Sheet verification.  The sequence of treatment assignments will be 
concealed from institutions and patients until registration with verification of 
eligibility.  Treatment randomization is to be carried out following study 
registration.  A minimization procedure will be used that tends to balance the 
treatment allocation equally within patient-level stratification factors.  
Stratification is defined by three factors; disease status or stage at entry (recurrent, 
Clinical FIGO Stage I or II, surgical FIGO Stage I or II with or without pelvic 
nodal assessment, surgical FIGO Stage III or IV) and tumor status at entry 
(measurable or non-measurable) and pelvic radiation history (any or none).  All 
interim and final reports will include a complete accounting of all patients 
registered to this protocol. (06/1/10) (10/21/2013) 
   
11.2 
Data collection:  
 
The principal parameters to be collected, analyzed and reported to determine the 
relative therapeutic effect of the two treatment regimens are: 
 
11.21 Outcome measures:  Primary:  Duration of overall survival; Secondary:  
Duration of progression-free survival. 
 
11.22 Tumor characteristics:  Stage or status of disease (persistent, recurrent, 
Stage I-IV), tumor status at entry (measurable or non-measurable), 
primary site of disease (uterine vs ovarian). (06/1/10) 
 
11.23 Host characteristics:  Age at entry, performance status, prior treatment 
(pelvic, vaginal, and extended field radiation, hormonal) and racial/ethnic 
designation. 
 
11.24 Adverse effects:  The frequency and severity of acute and late adverse 
effects graded by CTCAE version 3.0. 
 
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Version Date: 12/19/2014 
11.25 Treatment:  The number of cycles of study therapy administered; for 
those not completing the prescribed study therapy, and the reason for 
discontinuation of assigned therapy. 
 
11.26 Quality of life:  FACT TOI-En and FACT/GOG-Ntx subscale (11 items). 
 
11.3 
Accrual rate, sample size, and study duration:  
 
 
 Based upon accrual to GOG-0161 (a Phase III randomized trial of ifosfamide and 
mesna and ifosfamide, mesna, paclitaxel and G-CSF) and GOG-0232B (a Phase II 
study of carboplatin and paclitaxel), the anticipated accrual for the 
advanced/recurrent measurable disease population for this study is 48 patients per 
year.  Based upon accrual to GOG-0150 (a Phase III randomized trial of radiation 
and ifosfamide, cisplatin and mesna) the anticipated accrual for the non-
measurable Stage I-IV population for this study is 30 patients per year; an 
expected 50% increase over what was observed in GOG-0150.      
 
Based upon previous GOG experience with studies involving uterine 
carcinosarcoma, it is expected that 14% of patients registered to this study will be 
deemed ineligible.  The planned sample size for this study is 364 eligible patients 
with uterine carcinosarcoma; a minimum of 424 total study registrants.  Starting 
with the implementation of Revision #2, patients with ovarian carcinosarcoma 
will be eligible.  The accrual rate for ovarian carcinosarcoma is not well defined 
but is expected to be very low.  Therefore, the current study size will be 
determined strictly by uterine carcinosarcoma accrual.  The ovarian 
carcinosarcoma accrual will be monitored for 24 months to determine the impact 
on the total sample size.  It is anticipated that this study will require 
approximately 5.5 years of accrual assuming a uniform accrual rate of 78 patients 
with uterine carcinosarcoma per year.  It is estimated that 24 months of post 
accrual follow-up will be necessary to observe the minimum number of events 
required for the final primary analysis. (09/07/2009) (06/1/10) 
 
Revision 9:  This study was initially developed to include only uterine 
carcinosarcoma patients and the design parameters were based on data from GOG 
0150 and 0161.  The study was activated in September 2009.  In June 2010, the 
study was amended to include patients with ovarian carcinosarcoma.  
Subsequently the study was open to fallopian tube and peritoneal carcinosarcoma; 
however these cases are even rarer than ovarian carcinosarcoma.  At the time of 
the June 2010 amendment, it was not known how many patients with non-uterine 
carcinosarcoma would be enrolled and to what degree it would impact the design 
of GOG-0261.  There remains very little data in the literature regarding ovarian, 
fallopian tube and peritoneal carcinosarcoma.  
 
As of August 15, 2013 there are 92 patients with ovarian carcinosarcoma and 
three patients with fallopian tube or peritoneal carcinosarcoma enrolled.   Accrual 
rates within subgroups of uterine and ovarian carcinosarcoma can now be 
- 51 - 

N CI Pr ot oc ol #: G O G- 0 2 6 1  
 
Versi o n D ate: 1 2/ 1 9/ 2 0 1 4  
acc o u nte d f or i n t he statistical st u d y desi g n  i n re visi o n 9.  A d diti o nall y, t he 
ori gi nal desi g n ass u m pti o ns ha ve bee n re vie we d.  S pecificall y, t he pr o p orti o n of 
earl y sta ge or l o wer ris k patie nts is m uc h hi g her t ha n ori gi n all y a ntici pate d.  T h us, 
at re visi o n 9, t he sa m ple size has bee n u p war dl y a dj uste d t o acc o u nt f or t his.  
( 1 0/ 2 1/ 2 0 1 3) 
 
1 1. 4 
Pri mar y h y p ot hes es, pla n ni n g para meters, a n d sa m ple size j ustificati o n: 
 
If osfa mi de h as bee n a sta n dar d treat me nt i n t he G O G f or w o me n wit h a d va nce d 
or rec urre nt meas ura bl e uteri ne carci n osarc o ma .  Rece ntl y, res ults fr o m G O G-
0 1 6 1 ha ve s h o w n a s ur vi val a d va nta ge fa v ori n g t h e c o m bi nati o n of if osfa mi de, 
mes na a n d paclita x el ( TI M) o ver if osfa mi de al o ne ( deat h hazar d rati o = 0. 6 9; t w o-
tail test p = 0. 0 3).  T he c o m bi nati o n of car b o plati n a n d paclita x el ( T C) has b ee n a 
sta n dar d treat me nt f or o v aria n ca ncer a n d is n o w b ei n g use d i n t he c o m m u nit y f or 
treati n g m a n y ot her g y n ec ol o gic m ali g n a ncies.  It is c urre ntl y bei n g teste d i n 
a d va nce d or r ec urre nt uteri ne carci n o ma.  T his c o m bi nati o n, T C, has ne ver bee n 
st u die d i n a P hase III s etti n g i n a d va n ce d or rec urre nt uteri ne carci n osarc o ma.  
T here a p pears t o be a n o b vi o us prefere nce f or T C i n ter ms of ease of 
a d mi nistrati o n si nce T C ca n be gi ve n i n a matter of a fe w h o urs, w hereas TI M 
re q uires a t w o-da y a d mi nistrati o n f oll o we d b y 1 0 da ys of G-C S F (fil grasti m) or a 
si n gle da y d os e of pe gfil grasti m o n Da ys 4 t o 6.  Si nce gr o wt h fact or is gi ve n as 
part of t he TI M re gi me n, differe n ces i n ne utr o p e ni a are n ot e x pecte d t o be 
si g nifica nt. 
 
Pri m ary Hy p ot hesis:  T his st u d y will e val uate t he effect of 6 c ycl es of 
car b o plati n a n d p aclita x el relati ve t o 6 c ycles of if osfa mi de, mes na a n d p aclita x el 
wit h G - C S F s u p p ort.  T he pri mar y e n d p oi nt f or t his e val uati o n is o verall s ur vi val.  
T he p ur p ose of t his st u d y is t o deter mi ne w het her T C ca n be c o nsi dere d n ot 
i nferi or a n d p ote ntiall y s u peri or t o TI M wit h re gar d t o o verall s ur vi val d urati o n.  
T o war d t his e n d, t he fi n al a nal ysis will e val u ate t he h y p ot h esis:  
0 : 
1. 2 *
T C
TI M
H
λ
λ
≥
 
w here 
( )
λ is t he tr ue deat h rate f or eac h treat me nt.  Alter natel y, a tra nslati o n of 
t he h y p ot hesis i n ter ms of pr o p orti o n s ur vi vi n g at ti me t ca n be writte n as: 
1. 2
0 : 
( ) ( 
( ))
T C
TI M
H
p
t  
p  t
≤
 
w here 
( )
p is t he tr ue pr o p orti o n s ur vi vi n g at ti me t i n eac h treat me nt ar m.    
 
Pl a n ni n g p ar a m eters:   Data are a v aila ble fr o m G O G - 01 6 1 t o esti mate t h e o verall 
s ur vi val distri b uti o n a m o n g w o me n wit h a d va nce d or rec urre nt uteri ne 
carci n os arc o ma.  T he me dia n s ur vi val ti me fr o m G O G - 0 1 6 1 o n t he TI M re gi me n 
is 1 3. 5 m o nt hs.  T he perce nta ges of p atie nts e nr oll e d o n G O G- 0 1 6 1 assi g n e d t o 
recei v e TI M ali ve at 1, 2 a n d 3 years are 5 5 %, 2 2 % a n d 1 0 %, res pecti vel y.  
K n o w n pr o g n ostic fact ors i ncl u de perf or ma nce stat us rec or d e d at e ntr y.  
 
Si milarl y, d ata fr o m G O G - 0 1 5 0 are use d t o esti mate t he o verall s ur vi val ti me 
distri b uti o n a m o n g w o me n wit h o pti mall y de b ul k e d Sta ges I- I V carci n osarc o ma.  
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
The percentages of patients with Stage I or II disease enrolled on GOG-0150 alive 
at 1, 2 and 5 years are 86%, 76% and 59%, respectively.  The percentages of 
patients with Stage III or IV disease enrolled on GOG-0150 alive at 1, 2 and 5 
years are 64%, 46% and 26%, respectively.  Known prognostic factors include 
surgical stage and age at study entry. 
 
Initial sample size justification:  Originally, this trial was to be considered 
sufficiently mature for a final analysis when there were at least 264 deaths 
reported among all eligible patients (combining uterine and ovarian 
carcinosarcomas together).  If the true death rate on TIM is 13% greater than the 
death rate associated with TC then this study provides 80% chance of rejecting H0 
and concluding that TC is not inferior to TIM when Type I error is limited to 5% 
for a one-tail test.  If the true death rates are equal on both arms then there is a 
45% chance of concluding that TC is not inferior to TIM.24  A stratified log rank 
test will be used to assess the null hypothesis, stated above, between the two 
regimens with the assumption that the hazards are proportional.  A graph of the 
power curve for possible alternatives in terms of the hazard ratio and a graph of 
the absolute differences in the proportion surviving among treatment arms within 
each population for possible alternatives in terms of hazard ratio are provided 
below.  
 
 
 
Figure 11.A 
 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
 
Solid line:  measurable Stages III, IV or recurrent population; short dashed line:  non-
measurable Stages III or IV population; long dashed line:  non-measurable Stages I or II 
population 
Figure 11.B 
 
Assuming a decrease in the hazard of death, it is anticipated that 73% of patients 
will have died at the time of planned analysis.  The sample size necessary to 
observe 264 deaths is estimated to be 364 eligible uterine carcinosarcoma patients 
or a minimum of 424 enrolled patients.  These assumptions and the impact of 
ovarian carcinosarcoma eligibility on accrual were assessed prior to the first 
interim analysis and reported to the GOG Data and Safety Monitoring Board 
(DSMB). The DSMB approved the changes to the statistical considerations 
included in revision 9 on 10/17/2013.  (09/07/2009) (06/1/10) (10/21/2013) 
 
Revised target accrual goal  - revision 9: (10/21/2013) 
Maintaining the same characteristics used above and using the same failure rates 
assumed at the original study design, the target accrual was recalibrated based on 
the current distribution of risk groups (see Table 11.A) and the proportion of cases 
with uterine carcinosarcoma (80%).  The study will target 437 patients with 
uterine carcinosarcoma deemed eligible following central review (508 total 
patients with uterine carcinosarcoma); anticipated total enrollment accounting for 
both uterine and non-uterine carcinosarcoma will be approximately 603 
participants.  The accrual rate was much faster than originally expected (see Table 
11.B).  The accrual duration from study activation is estimated to be 56 months 
and the total study duration is expected to be 80 months; 10 months shorter than 
originally expected (see Table 11.C).   
 
 
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NCI Protocol #: GOG-0261 
 
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Table 11.A  Risk Group Distribution 
 
 
Risk Group  
Original study 
design 
proportion 
Revised proportion 
among uterine 
carcinosarcoma 
Optimal, Stage I or II 
16.7% 
39% 
Optimal, Stage III or IV 
21.3% 
26% 
Measurable, recurrent or 
persistent 
62.0% 
35% 
 
Table 11.B Current Average Accrual Rates 
Average accrual  
Uterine 
Carcinosarcoma 
9.07/month or 
108.8/year 
 
Table 11.C Revised Accrual and Study duration in months 
 
 
Study population 
Revised 
total 
accrual 
 
Revised accrual 
duration (original) 
Revised 
follow-up 
duration 
Revised study 
duration 
(original) 
All carcinosarcoma 
603 
56 (66) 
24 
80 (90) 
Uterine 
Carcinosarcoma 
508 
 
Uterine carcinosarcoma design summary 
Group 
Months of 
accrual 
Expected 
Sample size 
Months of 
follow-up 
Expected 
number of 
events 
Stage I/II optimal 
56 
170 
24 
57 (33%) 
Stage III/IV optimal 
56 
114 
24 
73 (64%) 
Measurable or 
Recurrent 
56 
153 
24 
133 (87%) 
Total eligible 
56 
437 
24 
263 (60%) 
Total enrolled 
508 
patients 
 
Study duration 
80 
months 
 
 
 
Final Analysis:  Originally, a pragmatic approach to the comparison of planned 
therapeutic regimens will be carried out.  All eligible enrolled patients will be 
included in the primary analysis, regardless of the amount of study treatment 
received or, after the addition of other tumor sites, primary tumor site; that is, the 
primary analysis will be an intention-to-treat analysis among eligible patients.  
The approach taken in re-designing this study was to leave the original study 
objectives intact and restrict the primary hypothesis test to include only 
participants with uterine carcinosarcoma.  Since the original study was open only 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
to those with a diagnosis of uterine carcinosarcoma and they now represent 
roughly 80% of the current accrual, the accrual goal will be set to allow for 80% 
power for hypothesis testing within this specific subgroup.  
 
The primary analysis will be stratified by disease status, tumor status, and history 
of pelvic radiation.  Potential confounders, including performance status, age, and 
racial designation will be considered in a final exploratory model.  A forest plot of 
treatment hazard ratios with confidence intervals within subgroup determined by 
primary site (uterine and ovarian, assuming estimation is possible) and other 
covariates will also be reported.  (06/1/10) (10/21/2013) 
 
11.5 
Interim Analyses: 
 
An initial interim analysis of survival data will occur when at least 132 deaths 
have been reported among all eligible patients with uterine carcinosarcoma 
enrolled.  The results of interim analyses are scheduled to be reviewed by the 
GOG DSMB at its meetings in January and July each year.  Approximately eight 
weeks prior to each of these meetings, the study database is locked in order to 
prepare a progress report.  If the prerequisite number of events has been attained, 
an interim analysis report is also prepared and presented to the DSMB at their 
next scheduled meeting.  Overall survival, the accrual rate, adverse events of 
treatment, treatment compliance, the frequency of treatment termination due to 
toxicity, non-protocol therapy, the PFS relative hazard estimate, potential 
confounders and results of external studies will be included in the interim analysis 
report to the DSMB to be taken into consideration when reaching a decision.  It is 
essential to assess adverse events of treatment at the interim and final analyses 
since this is a non-inferiority design. (06/1/10) (04/02/2012) (10/21/2013) 
 
Interim analysis for efficacy (non-inferiority):  The hypothesis testing strategy 
using the log rank test as described above will be used to test the null hypothesis 
of inferiority of TC relative to TIM with respect to overall survival.  The nominal 
p-value to stop for efficacy at the interim analysis will be 0.001.  If the null 
hypothesis can be rejected in the test involving the uterine subgroup, terminating 
accrual will be considered given that the study has not yet reached the target 
accrual goal.  Consideration may also be given to continue accrual in order to test 
the hypothesis 
02 :
TC
TIM
H
λ
λ
≥
.  If the study is closed to accrual early, an 
additional period of follow-up for data maturity will also be considered prior to 
releasing the final report.  This will require evaluating the benefit of observing 
additional events with the cost of postponing the release of the final report to 
observe these events.  If additional interim analyses are warranted, then the 
nominal p-value used to stop for efficacy at each interim analysis will be 0.001.  
There will be no correction to the nominal p-value in the final report. 25 (06/1/10) 
(10/21/2013) 
 
Interim analysis for futility (inferiority):  Additionally, a futility analysis will be 
carried out in the uterine carcinosarcoma subgroup.  If the observed estimate of 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
the stratified ratio of the death rate of the experimental arm to the death rate of the 
control arm equals or exceeds 1.2, then accrual termination will be considered (if 
still active) with a conclusion that it is unlikely that the experimental arm will be 
shown to be not inferior to the control arm.  The increase in Type II error due to 
this interim analysis is negligible.  Under the null hypothesis, this procedure has a 
50% chance of resulting in early termination. (10/21/2013) 
 
Safety monitoring:  The GOG  Safety Review Committee (SRC) reviews 
accumulating summaries of toxicities and all serious adverse event (SAE) reports 
on an ongoing basis (not efficacy results).  This committee also reviews those 
deaths in which study treatment may have been a contributing cause.  The SRC 
reports to the DSMB and it may recommend study amendments pertaining to 
patient safety. (04/02/2012) 
 
11.6 
Secondary endpoints, hypotheses or analyses: (10/21/2013) 
 
Progression-free Survival:  Progression-free survival (PFS) will be analyzed as a 
secondary endpoint.  All eligible patients will be included in the intent-to-treat 
analysis of progression-free survival in the subgroup of uterine carcinosarcoma.  
A stratified Cox proportional hazards model will be used to assess the treatment 
comparison with respect to PFS in the uterine subgroup.  Potential confounders 
will also be assessed in exploratory analyses.  The same null hypothesis that is 
used to assess survival will be used to assess PFS.  
 
Toxicity:  The maximum grade over the entire course of therapy for any 
individual effect will be used as a summary of acute toxicity.  The Kruskal-Wallis 
test corrected for ties will be used to compare the maximum grade of acute 
adverse effects of therapy by treatment arm.  The CTCAE v3.0 grading system 
will be used (i.e., scale from 0 for none to 5 for death).  A significance level of 
0.01 will be used for each tested AE term or category.  No correction for multiple 
testing will be employed since it is very important to identify moderate increases 
in the severity of toxicity at the risk of increasing the Type I error.  Since some of 
these toxicities are correlated, the overall type I error is less than calculations 
would indicate when assuming complete independence.  Toxicity is assumed to be 
independent of primary site of disease.   
 
Quality of Life:  The following assessment tools will be used to measure the 
quality of life prior to and following treatment (baseline, prior to Cycle #3 or 6 
weeks following  initiation of treatment, prior to Cycle #6 or approximately 15 
weeks following initiation of treatment, and 30 weeks following initiation of 
treatment): 
 
• 
FACT-G Physical Well-being (PWB) and Functional Well-being (FWB) 
subscales (14 items),  
• 
FACT-En additional concerns subscale (16 items), and 
• 
FACT/GOG-NTtx subscale (11 items)  
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Each item in the subscales listed above are scored using a 5-point scale (0=not at 
all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much).  Within an individual 
assessment, one or more items may not be answered.  A subscale score will be 
computed as long as more than 50% of subscale items have been answered.  A 
subscale score Si with Ni items will be calculated as:  
 
(
)
∑
∑
=
=
×
×
=
1
1
j
ij
j
ij
ij
i
i
s
N
S
δ
δ
 
 
Where δij is equal to 1 when the jth item has a valid response, otherwise it is equal 
to 0 and sij is the response score of the jth item.  The total score for the PWB and 
FWB is the sum of the two subscale scores if at least 80% of PWB and FWB 
items have been answered.  The total score for the TOI-En is the sum of the FWB, 
PWB, and En subscale if at least 80% of TOI-En items have been answered.  
 
The QOL objectives in this study are to compare treatment regimens with respect 
to the patient-reported quality of life as measured with PWB+FWB score, and 
patient-reported neurotoxicity as measured with FACT/GOG-Ntx-11 subscale.  It 
has been suggested by the FACIT author 26, 27,28, 29 that the Trial Outcome Index 
(TOI) which is the sum of the PWB, FWB, and “additional concerns” of a specific 
cancer is more responsive to change in QOL outcomes in cancer clinical trials 
than the FACT-G plus the disease specific concerns.  However, limited data are 
available on the validation of the FACT TOI-En in terms of psychometric 
properties.  For the purposes of this study, the FACT TOI-En will be assessed as 
an exploratory endpoint.  Currently, the FACT TOI-En scale is being used in 
GOG-0209 and will be validated once the study is completed.  By the time of the 
final QOL report, if the FACT TOI-En is validated to be a reliable scale and 
sensitive to treatment and change over time, it will be assessed as a definitive 
endpoint in place of PWB+FWB to measure the quality of life.    
 
A difference of 2-3 points is considered the minimally clinically important 
difference (MCID) for PWB and FWB respectively and a difference of 6-9 points 
is considered the MCID for FACT TOI-En scale.29 For this study, an observed 
difference of 5.2 points for the total score of PWB and FWB and 7.7 points for 
TOI-En will be considered as the MID in terms of QOL between the treatment 
groups.  This magnitude of difference is equivalent to an effect size of 0.5 
assuming that the standard deviation (SD) is 10.4 for the total score of PWB and 
FWB and 15.4 for TOI-En as currently observed in GOG-0209.  A difference of 
3.8 points in FACT-GOG/Ntx subscale (11 items) is considered the MCID 
between the treatment groups for this study.  This difference is approximately 
equivalent to an effect size of 0.5 assuming a SD of 7.6 as observed in GOG-
0184.   
 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
 
MCID 
Estimated SD 
Effect size 
Study or 
reference 
PWB+FWB 
5.2 
10.4 
0.5 
GOG-0209 
TOI-En 
7.7 
15.4 
0.5 
GOG-0209 
FACT-GOG/Ntx 
subscale 
3.8 
7.6 
0.5 
GOG-0184 
 
With the multiple QOL measures, the Type I error is set at 0.025=1-(1-0.05)1/2 for 
each two-tail comparison between treatments to ensure the overall Type I error to 
be 0.05.  To evaluate the primary endpoint (overall survival) this study will enroll 
603 patients, of which 437 patients with uterine carcinosarcoma are assumed to be 
eligible  with roughly 218 patients in each randomized group.  However, death, 
illness, non-compliance, and missed appointments can lead to missing 
information that increases over time.  Assuming the completion rates of QOL 
assessments are 90% at 6 weeks, 80% at 15 weeks, and 70% at 7 months, there 
will be 196 eligible patients at 6 weeks, 174 at 15 weeks, 152 at 7 months in each 
treatment group for QOL analyses.  These sample sizes provide at least 98% 
power to detect the MCIDs or effect sizes listed above and in the table above at α 
of 0.025 (two-sided).30  The statistical power will be higher than the estimated if 
the correlations among repeated measures are taken into account.  
 
Linear mixed models adjusted for baseline score, age, and performance status at 
enrollment will be used to test the hypothesis of no difference in PWB+FWB 
scores (or FACT TOI-En), and in FACT-GOG/Ntx subscale score between 
assigned treatment arms in an intent-to-treat analysis of all enrolled eligible 
patients. Since the En subscale in the FACT TOI En is designed specifically for 
patients with endometrial cancer, the analysis for FACT TOI En will be limited to 
patients with uterine carcinosarcoma only. These models will account for the 
correlation between scores measured over time and the compound symmetry 
correlation is assumed for the repeated measures in this study.  The interaction 
between treatment and assessment time on QOL scores will be tested initially in 
each model.  If this interaction is found to be statistically significant at level of 
0.05, treatment comparisons for each assessment tool will be carried out 
individually at each time point using the model parameter estimates.  If there is no 
evidence of an interaction, then a weighted average of estimates over the three 
time points will be compared between assigned treatment arms.  The empirical 
sandwich variance will be used to estimate the precision of the parameter 
estimates.  Satterthwaite’s DF approximation will be used in significance testing 
to adjust the degrees of freedom for unequal group variances.  
 
 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
11.7 
Anticipated Gender and Minority Inclusion: (09/07/2009) (10/21/2013) 
 
This study restricts entry to women by nature of the site of disease.  The table 
below lists the projected percentage of patients by racial/ethnic subgroup.  Prior 
GOG studies of uterine carcinosarcoma populations support no differences in the 
intervention effect between racial/ethnic subgroups.  Therefore, the study design 
does not involve race.  However, subsets defined by white, black/African 
American and all others will be analyzed in this study to investigate this important 
question with the current therapies.  Additionally the association of race with 
outcome will be assessed.     
 
 
Ethnic Category 
 
Number of patients 
anticipated 
Hispanic or Latino 
18   (2.9%) 
Not Hispanic or Latino 
566 (93.9%) 
Unknown 
19   (3.2%) 
Total 
603  (100%) 
 
 
Racial Category 
 
Number of patients 
anticipated 
American Indian/Alaskan Native 
4   (0.6%) 
Asian 
5   (0.9%) 
Native Hawaiian or Other Pacific Islander 
2   (0.3%) 
Black or African American 
143  (23.7%) 
White 
442  (73.3%) 
More than one race 
2   (0.4%) 
Unknown 
5   (0.8%) 
Total 
603  (100%) 
 
 
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NCI Protocol #: GOG-0261 
 
Version Date: 12/19/2014 
12.0 
BIBLIOGRAPHY  (06/1/10) 
 
1. 
Olah KS, Gee H, Blunt S, Dunn JA, Kelly K, Chan KK.  Retrospective analysis of 318 
cases of uterine sarcoma.  Eur J Cancer. 1991; 27:1095-1099. 
 
2. 
Zaloudek CJ, Norris HJ.  Mesenchymal tumors of the uterus.  In: Fengolio C, Wolff M, 
Eds.  Progress in Surgical Pathology vol. 3.  New York: Masson: 1-35, 1981. 
 
3. 
F J Major, J A Blessing, S G Silverberg, et al.  Prognostic factors in early-stage uterine 
sarcoma.  A Gynecologic Oncology Group study.  Cancer. 1993; 71:1702–1709. 
 
4. 
Spanos WJ, Peters LJ, Oswald MJ.  Patterns of recurrence in malignant mixed mullerian 
tumor of the uterus.  Cancer. 1986; 57:155-159.  
 
5. 
Nordal RR, Thoresen SO.  Uterine sarcomas in Norway 1956-1992: incidence, survival, 
and mortality.  Eur J Cancer. 1997; 33:907-911. 
 
6. 
Thigpen J, Blessing JA, Orr, Jr, JW, DiSaia PJ.  Phase II trial of cisplatin in the treatment 
of patients with advanced or recurrent mixed mesodermal sarcomas of the uterus: a 
Gynecologic Oncology Group study.  Cancer Treat Rep. 1986;70:271–274. 
 
7. 
Sutton GP, Blessing JA, Rosenshein N, Photopulos G, DiSaia PJ.  Phase II trial of 
ifosfamide and mesna in mixed mesodermal tumors of the uterus (a Gynecologic 
Oncology Group Study).  Am J Obstet Gynecol.  1989;161:309-312. 
 
8. 
Sutton GP, Brunetto, Vl, Kilgore L, et al.  A Phase III trial of ifosfamide with or without 
cisplatin carcinosarcoma of the uterus: A Gynecologic Oncology Group Study.  Gynecol 
Oncol.  200l; 79:147-53. 
 
9. 
Homesley HD, Filiaci V, Markman M, et al.  A Gynecologic Oncology Group Phase III 
trial of ifosfamide versus ifosfamide plus paclitaxel as first-line treatment of advanced or 
recurrent uterine carcinosarcoma (mixed mesodermal tumors): A Gynecologic Oncology 
Group study.  J Clin Oncol.  2007; 25(5):526-31. 
 
10. 
Wolfson AH, Brady MF, Rocereto T, et al.  A Gynecologic Oncology Group randomized 
phase III trial of whole abdominal irradiation (WAI) vs cisplatin-ifosfamide and mesna 
(CIM) as post-surgical therapy in stage I-IV carcinosarcoma (CS) of the uterus.  Gynecol 
Oncol. 2007 ; 107:177-185. 
 
11. 
Toyoshima M, Akahira J, Matsunaga G, et al.  Clinical experience with combination 
paclitaxel and carboplatin therapy for advanced or recurrent carcinosarcoma of the uterus.  
Gynecol Oncol.  2004; 94:774-778. 
 
12 
Hoskins PJ, Le N, Ellard S, Ellard S, Lee U, Martin LA, Swenerton KB, et al.  
Carboplatin plus paclitaxel for advanced or recurrent uterine malignant mixed mullerian 
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tumors.  The British Columbia Cancer Agency experience.  Gynecol Oncol. 2008;108:58-
62. 
 
13. 
Scudder SA, Liu PY, Wilczynski SP, et al.  Paclitaxel and carboplatin with amifostine in 
advanced, recurrent, or refractory endometrial adenocarcinoma: a phase II study of the 
Southwest Oncology Group.  Gynecol Oncol.  2005;96:610-615. 
 
 
14. 
Ozols RF, Bundy BN, Greer BD, et al.  Phase III trial of carboplatin and paclitaxel 
compared with cisplatin and paclitaxel in patients with optimally resected stage III 
ovarian cancer:  a Gynecologic Oncology Group study.  J Clin Oncol. 2003; 21:3194-
3200. 
 
15. 
Curtin JP, Blessing JA, Soper JT, DeGeest K.  Paclitaxel in the treatment of 
carcinosarcoma of the uterus: a gynecologic oncology group study.  Gynecol Oncol. 
2001; 83:268. 
 
16.  
Piura B, Rabinovich A, Yanai-Inbar I, Cohen Y, Glezerman M. Primary sarcoma of the 
ovary: report of five cases and review of the literature. Eur J Gynaecol Oncol. 
1998;19:257–261.  
 
17.   
Sood AK, Sorosky JL, Gelder MS et al. Primary ovarian sarcoma: analysis of prognostic 
variables and the role of surgical cytoreduction. Cancer 1998;82:1731–1737.  
 
18.  
 Le T, Krepart GV, Lotocki RJ, Heywood MS. Malignant mixed mesodermal ovarian 
tumor treatment and prognosis: a 20-year experience. Gynecol Oncol 1997;65:237–240.  
 
19.  
Thigpen J, Blessing JA, DeGeest K, Look KY, Homesley HD; Gynecologic Oncology 
Group. Cisplatin as initial chemotherapy in ovarian carcinosarcomas: a Gynecologic 
Oncology Group study. Gynecol Oncol. 2004;93:336–339.  
 
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Silasi DA, Illuzzi JL, Kelly MG, Rutherford TJ, Mor G, Azodi M, Schwartz PE. 
Carcinosarcoma of the ovary.  Int J Gynecol Cancer. 2008 Jan-Feb;18(1):22-29. Epub 
2007 Apr 19. 
 
21 
Huang HQ, Brady MF, Cella D, Fleming G.  Validation and reduction of FACT/GOG 
Ntx subscale for platinum/paclitaxel-induced neurologic symptoms: a Gynecologic 
Oncology Group study.  Int J Gynecol Cancer 2007;17:387-393. 
 
22. 
Bruner DW, Barsevick A, Tian C, Randall M, Mannel R, Cohn DE, et al. Randomized 
trial results of quality of life comparing whole abdominal irradiation and combination 
chemotherapy in advanced endometrial carcinoma: A Gynecologic Oncology Group 
study.  Qual Life Res. 2007; 16:89-100.  Epub 2006 Oct 11.   
 
23. 
Hensley ML, Schuchter LM, Lindley C, Merepol, NJ, Cohen GI, Broder G et al. for the 
American Society of Clinical Oncology. American Society of Clinical Oncology clinical 
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practice guidelines for the use of chemotherapy and radiotherapy protectants.  J Clin 
Oncol. October 2009;17: 3333-3355. 
 
24. 
Schoenfeld, DA.  Sample size formula for the proportional hazards regression model.  
Biometrics.  1983; 39: 499-503. 
 
25. 
Freidlin, B, Korn EL, George SL.  Data monitoring committees and interim monitoring 
guidelines.  Control Clin Trials. 1999; 20:395-407. 
 
26.  
Cella D, Eton DT, Fairclough DL, et al.  What is a clinically meaningful change on the 
Functional Assessment of Cancer Therapy-Lung (FACT-L) Questionnaire?  Results from 
Eastern Cooperative Oncology Group (ECOG) Study 5592.  J Clin Epidemiol. 2002; 55: 
285-295. 
 
27. 
Cella DF, Bonomi AE, Lloyd SR, et al.  Reliability and validity of the Functional 
Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument.  Lung Cancer.  
1995; 12:199-220. 
 
28.       Webster, K. Cella, D. Yost, K.  The Functional Assessment of Chronic Illness Therapy 
FACIT) Measurement System: properties, applications, and interpretation.  Health Qual 
Life Outcomes 2003;1:79. 
 
29. 
Yost KJ and Eton DT.  Combining distribution- and anchor-based approaches to 
determine minimally important differences: the FACIT experience.  Eval Health Prof.  
2005; 28:172-191. 
 
30. 
Hintze  J.   NCSS and PASS: Number cruncher statistical systems.[computer program] 
Kaysville, Utah; 2001.  www.ncss.com 
 
 
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Version Date: 12/19/2014 
 
APPENDIX I (12/20/2010) 
FIGO STAGING FOR UTERINE CARCINOSARCOMA 
 
Uterine Carcinosarcoma FIGO Surgical Stage Classification 
based on the Carcinoma of the Endometrium FIGO Classification 2009 1-3 
 
Stage I* 
Tumor confined to the corpus uteri 
IA* 
No or less than half myometrial invasion 
IB* 
Invasion equal to or more than half of the myometrium 
Stage II* 
Tumor invades cervical stroma, but does not extend beyond the uterus** 
Stage III* 
Local and/or regional spread of the tumor 
IIIA* 
Tumor invades the serosa of the corpus uteri and/or adnexae# 
IIIB* 
Vaginal and/or parametrial involvement# 
IIIC* 
Metastases to pelvic and/or para-aortic lymph nodes# 
IIIC1* 
Positive pelvic nodes 
IIIC2* 
Positive para-aortic lymph nodes with or without positive pelvic lymph         
nodes 
Stage IV* 
Tumor invades bladder and/or bowel mucosa, and/or distant metastases 
IVA* 
Tumor invasion of bladder and/or bowel mucosa 
IVB 
Distant metastases, including intra-abdominal metastases and/or inguinal 
lymph nodes 
*  Either Grade 1, Grade 2, or Grade 3. 
**Endocervical glandular involvement only should be considered as Stage I and no longer as Stage II. 
#   Positive cytology has to be reported separately without changing the stage. 
 
FIGO Clinical Staging for Uterine Corpus Cancer (1971) 4 
To be used only for patients who have not had a hysterectomy 
 
Stage I 
Tumor is limited to the uterine body 
IA 
Uterine cavity measures 8 cm or less 
IB 
Uterine cavity measures greater than 8 cm 
Stage II 
Tumor extends to the uterine cervix 
Stage III 
Tumor has spread to the adjacent pelvic structures 
Stage IV 
Bulky pelvic disease or distant spread 
IVA 
Tumor invades the mucosa of the bladder or rectum 
IVB 
Distant metastasis is present. 
 
 
References 
1. Int J of Gynaecol Obstet. 2009; 106:277. 
2. Int J of Gynaecol Obstet. 2009; 104:179. 
3. Int J of Gynaecol Obstet. 2009; 105:103-104. 
4. Zaino, RJ.  FIGO Staging of endometrial adenocarcinoma: A critical review and proposal.  Int J Gynecol 
Pathol. 2009; 28: 1-9. 
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APPENDIX II 
OVARIAN CARCINOSARCOMA 
FIGO STAGING CRITERIA 
Based on 
FIGO STAGE GROUPING FOR PRIMARY CARCINOMA OF THE OVARY 
 
(1985) 
 
These categories are based on findings at clinical examination and/or surgical exploration.  The 
histologic characteristics are to be considered in the staging, as are results of cytologic testing as 
far as effusions are concerned.  It is desirable that a biopsy be performed on suspicious areas 
outside the pelvis. 
 
Stage I  
Growth limited to the ovaries. 
 
Stage IA 
Growth limited to one ovary; no ascites.   
 
 
 
 
No tumor on the external surface; capsule intact. 
 
Stage IB 
Growth limited to both ovaries; no ascites. 
 
 
 
 
No tumor on the external surfaces; capsules intact. 
 
Stage IC* 
Tumor either Stage IA or IB but with tumor on the surface of one 
or both ovaries; or with capsule ruptured; or with ascites present 
containing malignant cells or with positive peritoneal washings. 
 
Stage II 
 
Growth involving one or both ovaries with pelvic extension. 
 
Stage IIA 
Extension and/or metastases to the uterus and/or tubes. 
 
Stage IIB 
Extension to other pelvic tissues. 
 
Stage IIC* 
Tumor either Stage IIA or IIB but with tumor on the surface of one 
or both ovaries; or with capsule(s) ruptured; or with ascites present 
containing malignant cells or with positive peritoneal washings. 
 
 
Stage III 
Tumor involving one or both ovaries with peritoneal implants outside the pelvis 
and/or positive retroperitoneal or inguinal nodes.  Superficial liver metastasis 
equals Stage III.  Tumor is limited to the true pelvis but with histologically 
verified malignant extensions to small bowel or omentum. 
 
Stage IIIA 
Tumor grossly limited to the true pelvis with negative nodes but 
with histologically confirmed microscopic seeding of abdominal 
peritoneal surfaces. 
 
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Stage IIIB 
Tumor of one or both ovaries with histologically confirmed 
implants of abdominal peritoneal surfaces, none exceeding 2 cm in 
diameter.  Nodes negative. 
 
Stage IIIC 
Abdominal implants >2 cm in diameter and/or positive 
retroperitoneal or inguinal nodes. 
 
Stage IV 
Growth involving one or both ovaries with distant metastasis.  If pleural effusion 
is present there must be positive cytologic test results to allot a case to Stage IV.  
Parenchymal liver metastasis equals Stage IV. 
 
* 
In order to evaluate the impact on prognosis of the different criteria for allotting cases to 
Stage IC or IIC, it would be of value to know if rupture of the capsule was (1) 
spontaneous or (2) caused by the surgeon and if the source of malignant cells detected 
was (1) peritoneal washings or (2) ascites.
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APPENDIX III 
Specimen Procedures 
 
I.  
Summary of Specimen Requirements 
 
Required Specimen 
(Specimen Code) 
Collection Time Point 
Ship To 
FFPE Primary, Metastatic, or 
Recurrent Tumor (FT01) 
1st Choice: block 
2nd Choice: 10 unstained slides 
(charged, 5µm) 
Prior to initiating chemotherapy 
Ship to the GOG Tissue Bank within 
2 week(s) of registration1 
Whole Blood (WB01) 
7-10mL drawn into a purple top 
(EDTA) tube 
Prior to or after initiating 
chemotherapy 
Ship to the GOG Tissue Bank the 
day the specimen is collected1 
1 
Ship specimens to: GOG Tissue Bank / Protocol GOG-0261, Nationwide Children’s Hospital, 700 
Children’s Drive, WA1340, Columbus, OH 43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: 
GOGBanc@nationwidechildrens.org 
 
II. 
Obtaining a GOG Bank ID 
 
Only one GOG Bank ID (# # # # - # # - G # # #) is assigned per patient. All specimens 
and accompanying paperwork must be labeled with this coded and confidential tracking 
number.  A GOG Bank ID can be obtained online via the Tissue Bank Portal on the GOG 
website (under Tools on the Web Menu page).  
 
Obtain the GOG patient study ID for any GOG protocol with specimen requirements 
before requesting a GOG Bank ID from the Tissue Bank Portal. 
 
Please contact GOG User Support at the GOG Statistical and Data Center if you need 
assistance (Email: support@GOGStats.org; Phone: 716-845-7767). 
 
III.  
Requesting Specimen Kits 
 
 
Specimen kits are not provided for this protocol. 
 
IV. 
 Submitting Formalin-Fixed, Paraffin-Embedded (FFPE) Tissue 
 
A. 
Requirement 
 
If the patient gives permission for her specimens to be used for this optional 
translational research component, then participating institutions within the United 
States are required to submit specimens as outlined in Section I. 
 
Every attempt should be made to provide a block; however, if a block cannot be 
provided, please submit 10 unstained slides, 5 micrometers in thickness on 
charged slides suitable standard immunohistochemistry. 
 
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The type of specimen (block or slides) should be specified on Form SP. 
 
B. 
Purpose 
 
 
FFPE primary, metastatic, and/or recurrent tumor will be banked for future 
research. 
 
C. 
Time Point 
 
 
FFPE tumor should be collected prior to initiating chemotherapy. 
 
D. 
Format for Labeling the Specimen 
 
 
Label FFPE tissue specimens with the GOG protocol number (GOG-0261), GOG 
Bank ID (# # # # - # # - G # # #), specimen code (FT01), and collection date 
(mm/dd/yyyy). This specimen may also be labeled with the pathology accession 
number and block identifier, but must not be labeled with personal identifiers like 
patient name or initials. 
 
V.  
Submitting Whole Blood  
 
A. 
Requirement 
 
 
If the patient gives permission for her specimens to be used for this optional 
research component, then participating institutions within the United States are 
required to submit specimens as outlined in Section I. 
 
B. 
Purpose 
 
 
DNA will be extracted from whole blood specimens. DNA will be banked for 
future research. 
 
C. 
Time Point 
 
Whole blood can be collected prior to or after initiating chemotherapy. 
 
D. 
Format for Labeling the Specimen 
 
 
Label the specimen with the GOG protocol number (GOG-0261), GOG Bank ID 
(# # # # - # # - G # # #), specimen code (WB01), and collection date 
(mm/dd/yyyy). 
 
E. 
Instructions for Submitting Whole Blood 
 
1.  
Label the purple top whole blood collection tube(s) (containing EDTA) as 
described above.  
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2. 
Draw 7-10mL of blood into the labeled purple top tube(s).  
 
3.  
Mix the blood with the EDTA by gently inverting the tube 5-10 times. 
   
4. 
Ship the whole blood specimen to GOG Tissue Bank the day the specimen is 
collected*.  Whole blood specimens should be stored at room temperature until 
the specimens can be shipped. 
 
 
* If the whole blood absolutely cannot be shipped the day it is collected, the tube 
may be placed in the refrigerator overnight.  Please note that the blood was 
refrigerated overnight in the comment box on Form SP (item 15). 
 
VI. 
Submitting Form SP 
 
A. 
Form SP Requirements 
 
 
 
Form SP must be submitted online via SEDES for each specimen regardless of 
specimen submission status. Retain a printout for your records. 
 
 
Include hard copy of the electronically-completed form should be included with 
the specimen when shipped to the GOG Tissue Bank or alternate laboratory. Form 
SP does not need to be sent to the GOG Tissue Bank when specimens are not 
collected. 
 
B. 
Instructions for Submitting Form SP Online   
 
Specific instructions for completing Form SP are available on SEDES. Questions 
should be directed to User Support at the GOG Statistical and Data Center (Email: 
support@gogstats.org, Phone: 716-845-7767). 
 
VII.  Shipping Specimens 
 
A.  
Formalin-Fixed, Paraffin-Embedded Tissue 
 
FFPE tissue should be shipped using your own container at your own expense to: 
 
GOG Tissue Bank / Protocol GOG-0261 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
 
Phone: (614) 722-2865 
FAX: (614) 722-2897 
Email: GOGBank@nationwidechildrens.org 
 
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B.  
Whole Blood 
 
 
Whole blood should be shipped to the GOG Tissue Bank (address above) the day 
the specimens are collected*. Please do not ship blood the day before a holiday. 
Use your own shipping container to ship specimens via FedEx using a pre-
paid GOG Tissue Bank FedEx air bill. 
 
 
* If the whole blood absolutely cannot be shipped the day it is collected, the tube 
may be placed in the refrigerator overnight. Please note that the blood was 
refrigerated overnight in the comment box on Form SP (item 15).   
 
  
When shipping whole blood specimens, please be aware that your institution 
must comply with IATA standards (www.iata.org).  If you have questions 
regarding your shipment, contact the GOG Tissue Bank at 
GOGBank@NationwideChildrens.org or by phoning 866-GOG-BANC (866-464-
2262).  
 
 
To ship whole blood specimens you will need (1) a sturdy shipping container 
(e.g., a cardboard or styrofoam box), (2) a leak proof shipping bag with absorbent 
material*, (3) a puncture and pressure resistant envelope (e.g., Tyvek envelope), 
(4) an Exempt Human Specimen Sticker, and (5) a pre-paid FedEx air bill. 
 
 
*If you will be shipping whole blood specimens from more than one patient, 
please put each specimen in a separate plastic zip-lock bag before placing the 
specimens in the shipping bag. 
 
 
If you do not have these materials available at your Institution, you may order 
them from any supplier (e.g., Saf-T-Pak; Phone: 800-814-7484; Website: 
www.saftpak.com). 
 
Instructions for Shipping Whole Blood Using Your Own Shipping 
Container* 
 
*Please note that you can include up to four different blood specimens in one 
biohazard envelope. 
 
1. Place the whole blood specimen in a biohazard envelope containing absorbent 
material. Expel as much air as possible before sealing the bag. 
  
2. Wrap the biohazard envelope in bubble wrap or another padded material. 
 
3. Place the padded tube(s) into a Tyvek envelope.  Expel as much air as possible 
before sealing the envelope. 
 
4. Place the Tyvek envelope in a sturdy shipping contained (e.g., cardboard FedEx 
box). 
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5. Insert a copy of the SP Form(s) into the box.  
 
6. Attach an Exempt Human Specimen Sticker to the outside of the shipping 
container. 
 
7. Print a pre-paid FedEx air bill using the Kit Management application (found 
under Data Entry on the Web Menu page) and attach the air bill. 
 
 
 
Make arrangements for FedEx pick-up through your usual institutional 
procedure or by calling 800-238-5355. Ship the specimens and transmittal 
forms to the GOG Tissue Bank via FedEx Priority Overnight delivery. Please 
ship specimens Monday through Friday for Tuesday through Saturday 
delivery. If the whole blood is collected on a Friday, select “yes” for Saturday 
delivery when completing the FedEx air bill. Saturday delivery is only 
available for the shipment of whole blood. 
 
VIII.  Banking Specimens 
 
The GOG Tissue Bank will be responsible for all activities associated with receiving, 
banking, and distributing clinical specimens. 
 
Upon receipt of specimen shipments, the GOG Tissue Bank will immediately (1) assess 
the type, quantity, and condition of the specimens received, (2) complete the appropriate 
fields on Form SP, (3) enter the specimens into their database system, and (4) store the 
specimens under the appropriate conditions. 
 
As needed, the GOG Tissue Bank will work with the GOG Statistical and Data Center to 
reconcile specimen identifiers, information, condition, and quality. 
 
A. 
FFPE Tissue 
 
 
FFPE tissue will be received as a block or unstained slides. The GOG Tissue 
Bank will make sure that each block, slide, or scroll is labeled appropriately.  
 
B. 
Whole Blood 
 
 
Whole blood will be processed by the Bank to isolate DNA. DNA will be stored 
at the Bank. Bank staff will make sure each whole blood and subsequent DNA 
specimen is labeled appropriately. 
  
IX. 
Distributing Specimens for Laboratory Testing 
 
 
The GOG Statistical and Data Center and GOG Tissue Bank will coordinate the 
distribution of specimens to approved investigators for laboratory testing. Specimen 
selection will be based on information regarding specimen procurement and condition as 
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well as patient eligibility, evaluation criteria, statistical considerations, and relevant 
clinical information. 
 
 
For each shipment, an inventory of all specimens sent will be provided to the investigator 
and the Statistical and Data Center. 
 
Investigators will not be given access to any personal identifiers. 
 
Investigators will be responsible for the direct supervision and oversight of the laboratory 
testing performed and for keeping accurate records of all specimen testing. 
 
Investigators will ensure that the laboratory testing results are linked to the appropriate 
specimen-specific identifiers and are responsible for transferring relevant laboratory data 
to the Statistical and Data Center. 
 
X.  
Banking Specimens for Future Research 
  
Specimens will remain banked at the GOG Tissue Bank and made available only for 
approved research projects if the patient has provided permission for the use of her 
specimens for future cancer and/or non-cancer research. The patient’s choices will be 
recorded on the informed consent document the patient signs and electronically via the 
online Specimen Consent Application. 
GOG Institutions can amend a patient’s choices regarding the future use of her 
specimens at any time if the patient changes her mind. 
 
If the patient does not give permission for the use of her specimens, the GOG Tissue 
Bank will be instructed to destroy (incinerate) any remaining specimens to insure that the 
patient’s wishes are honored. 
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APPENDIX IV 
 
CARBOPLATIN DOSE CALCULATION INSTRUCTIONS (3/21/2011) (04/02/2012) 
1) The Cockcroft-Gault formula will be used in GOG trials.  
2) Conversion of IDMS creatinine levels to “non-IDMS” values will not be permitted.  
3) The carboplatin calculation tool is available on the GOG website (Web Menu, Tools). 
 
Dosing of Carboplatin: 
1) The carboplatin dose will be calculated to reach a target area under the curve (AUC) 
according to the Calvert formula using an estimated glomerular filtration rate (GFR) from 
the Cockcroft-Gault formula. 
 
2) The initial dose of carboplatin must be calculated using GFR. In the absence of renal 
toxicity greater than or equal to CTCAE Grade 2 (serum creatinine >1.5 x ULN) or 
toxicity requiring dose modification, the dose of carboplatin will not need to be 
recalculated for subsequent cycles, but will be subject to dose modification for toxicity as 
noted in the protocol. 
 
3) Carboplatin doses are required to be recalculated if the patient has a weight change of 
greater than or equal to 10%.  Patients are permitted to have chemotherapy doses 
recalculated for <10% weight changes. 
 
4) At the time of dose modification, if the patient’s age had changed (the patient has had a 
birthday), the site can use the current age. 
 
5) In patients with an abnormally low serum creatinine (less than 0.7 mg/dl), the creatinine 
clearance should be estimated using a minimum value of 0.7 mg/dl. 
 
6)   For trials where patients enter and are treated within less than or equal to 12 weeks of 
surgery:  If a more appropriate (higher) baseline creatinine value is available from the 
pre-operative period (within 4 weeks of surgery date), that value may also be used for the 
initial estimation of GFR. 
 
CALVERT FORMULA: 
Carboplatin dose (mg) = target AUC x (GFR + 25) 
NOTE:  the GFR used in the Calvert formula should not exceed 125 ml/min. 
Maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 ml/min. 
The maximum allowed doses of carboplatin are: 
AUC 6 = 900 mg 
AUC 5 = 750 mg 
AUC 4 = 600 mg 
For the purposes of this protocol, the GFR is considered to be equivalent to the estimated 
creatinine clearance. The estimated creatinine clearance (ml/min) is calculated by the method of 
Cockcroft-Gault using the following formula: 
Creatinine Clearance (mL/min) =    [140-Age (years)] x Weight (kg) x 0.85  
                                                             
72 x serum creatinine (mg/dl)  
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Notes: 
1)  Weight in kilograms (kg): 
a. Body Mass Index (BMI) should be calculated for each patient.  A BMI calculator is available at 
the following link:  http://www.nhlbisupport.com/bmi/  
b. Actual weight should be used for estimation of GFR for patients with BMI of less than 25.   
c. Adjusted weight should be used for estimation of GFR for patients with BMI of greater than or 
equal to 25. 
d. Adjusted weight calculation: 
Ideal weight (kg) = (((Height (cm)/2.54) – 60) x 2.3) + 45.5 
Adjusted weight (kg) = ((Actual weight – Ideal weight) x 0.40) + Ideal weight 
 
2)  The Cockcroft-Gault formula above is specifically for women (it includes the 0.85 factor). 
At the time of a dose modification for toxicity:  
 
If the creatinine at the time of a dose modification is lower than the creatinine used to 
calculate the previous dose, use the previous (higher) creatinine; if the creatinine at the time 
of a dose modification is higher than the creatinine used to calculate the previous dose, use 
the current (higher) creatinine.  This will ensure that the patient is actually receiving a dose  
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APPENDIX V (04/02/2012) 
 
General Chemotherapy Guidelines: 
• For 21 or 28 day cycles, a patient will be permitted to have a new cycle of 
chemotherapy delayed up to 7 days (without this being considered to be a 
protocol violation) for major life events (e.g., serious illness in a family member, 
major holiday, vacation which is unable to be re-scheduled).  Documentation to 
justify this decision should be provided. 
• It will be acceptable for individual chemotherapy doses to be delivered within a 
“24-hour window before and after the protocol-defined date” for “Day 1” 
treatment of 21 or 28 day cycles.  If the treatment due date is a Friday, and the 
patient cannot be treated on that Friday, then the window for treatment would 
include the Thursday (1 day earlier than due) through the Monday (day 3 past 
due). 
• For weekly regimens, it will be acceptable for individual chemotherapy doses to 
be delivered within a “24-hour window,” for example; “Day 8 chemotherapy” can 
be delivered on Day 7, Day 8, or Day 9 and “Day 15 chemotherapy” can be given 
on Day 14, Day 15, or Day 16. 
• Chemotherapy doses can be “rounded” according to institutional standards 
without being considered a protocol violation (most institutions use a rule of 
approximately +/- 5% of the calculated dose). 
• Chemotherapy doses are required to be recalculated if the patient has a weight 
change of greater than or equal to 10%.  Patients are permitted to have 
chemotherapy does recalculated for <10% weight changes. 
• Maximum body surface area used for chemotherapy dose calculations will be 2.0 
m2.  For chemotherapy dose calculations that use mg/kg, there will be no 
maximum kilogram amount used (doses will be calculated on actual weight in 
kg). 
 
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