Clinical trial NCT01533207
Conditions: Stage I Uterine Sarcoma AJCC v7 Uterine Corpus Leiomyosarcoma
Sponsor: Gynecologic Oncology Group
Start date: 2012-06-04; Completion date: 2019-02-09
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase III trial studies how well gemcitabine hydrochloride and docetaxel followed by doxorubicin hydrochloride work compared to observation in treating patients with high-risk uterine leiomyosarcoma previously removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride, docetaxel, and doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether combination therapy after surgery is an effective treatment for uterine leiomyosarcoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine whether overall survival of patients with uterus-limited high-grade leiomyosarcoma is superior among patients assigned to treatment with adjuvant gemcitabine hydrochloride (gemcitabine) plus docetaxel followed by doxorubicin hydrochloride compared to patients assigned to observation.

SECONDARY OBJECTIVES:

I. To determine whether treatment with adjuvant gemcitabine plus docetaxel followed by doxorubicin improves recurrence-free survival of patients with uterus-limited high-grade leiomyosarcoma compared to observation.

II. To explore the impact of potential predictors of recurrence or death such as patient age, institution reported tumor size, cervix involvement (yes or no), and mitotic rate.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive adjuvant gemcitabine hydrochloride IV over 70-90 minutes on days 1 and 8 and docetaxel IV over 30-60 minutes on day 8. Patients also receive filgrastim subcutaneously (SC) on days 9-15 or pegfilgrastim SC on day 9 or 10. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo computed tomography (CT) and/or magnetic resonance imaging (MRI). Patients with no evidence of disease receive doxorubicin hydrochloride IV every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients also receive filgrastim SC on days 2-8 or pegfilgrastim SC on day 2 or 3.

Arm II: Patients undergo clinical observation.

After completion of study treatment, patients in both arms are followed up every 4 months for 3 years and then every 6 months for 2 years.

Arms: arm 1: Patients receive adjuvant gemcitabine hydrochloride IV over 70-90 minutes on days 1 and 8 and docetaxel IV over 30-60 minutes on day 8. Patients also receive filgrastim SC on days 9-15 or pegfilgrastim SC on day 9 or 10. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo CT and/or MRI. Patients with no evidence of disease receive doxorubicin hydrochloride IV every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients also receive filgrastim SC on days 2-8 or pegfilgrastim SC on day 2 or 3. arm 2: Patients undergo clinical observation.
Interventions: intervention 1: Clinical Observation intervention 2: Docetaxel intervention 3: Doxorubicin Hydrochloride intervention 4: Filgrastim intervention 5: Gemcitabine Hydrochloride intervention 6: Pegfilgrastim
Intervention descriptions: intervention 1: Patients followed clinically intervention 2: Given IV intervention 3: Given IV intervention 4: Given subcutaneously (SC) intervention 5: Given IV intervention 6: Given SC

Protocol documents:
Prot_SAP_000.pdf: 
 
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SUMMARY OF CHANGES 
 
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NCI Version Date is now 12/07/2017.  No additional changes have been made to 
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PROTOCOL GOG-0277 (IRCI 001) 
 
A PHASE III RANDOMIZED TRIAL OF GEMCITABINE (NSC# 613327) PLUS DOCETAXEL 
(NSC#  628503) FOLLOWED BY DOXORUBICIN (NSC# 123127) VERSUS OBSERVATION FOR 
UTERUS-LIMITED, HIGH-GRADE UTERINE LEIOMYOSARCOMA (10/28/2013) 
NCI Version Date 12/07/2017 
Includes Revisions #1-3 
POINTS: 
PER CAPITA - 20 
MEMBERSHIP -6 
Lead Organization: NRG/NRG Oncology (02/16/2015) 
STUDY CHAIR: GOG (10/28/2013) 
STUDY CO-CHAIR 
MARTEE L. HENSLEY, M.D. 
JAMES HOFFMAN, MD. 
MEMORIAL SLOAN-KETTERING CANCER CENTER 
See GOG Website Directory 
300 E. 66th Street, Suite 1355 
 
NEW YORK, NY 10065 
PATHOLOGIST 
646-888-4222 
HELEN E. MICHAEL, M.D. 
FAX: 212-717-3272 
See GOG Website Directory 
hensleym@mskcc.org  
 
 
STATISTICIAN 
NURSE CONTACT (10/28/2013) 
DANIELLE ENSERRO, Ph.D. 
KATHLEEN O’CONNOR, RN 
NRG ONCOLOGY SDMC-BUFFALO 
MEMORIAL SLOAN-KETTERING CANCER CENTER 
ELM AND CARLTON STREETS 
1275 YORK AVE, H907 
BUFFALO, NY 14263 
NEW YORK, NY 10065 
716-845-5702 
212-639-2252 
FAX: 716-845-8393 
FAX: 212-639-8895 
enserrod@nrgoncology.org  
oconnor@mskcc.org 
 
 
STUDY CHAIR: NCRN (10/28/2013) 
 
HELEN HATCHER, M.D. 
 
UNIVERSITY OF CAMBRIDGE 
 
ONCOLOGY DEPARTMENT 
 
BOX 193 (R4) 
 
ADDENBROOKE'S HOSPITAL 
 
HILLS ROAD 
 
CAMBRIDGE CB2 0QQ. 
 
ENGLAND, UNITED KINGDOM 
 
T: +44 01223 769309 
 
hh321@medschl.cam.ac.uk  
 
OPEN TO PATIENT ENTRY JUNE 4, 2012 
REVISED OCTOBER 28, 2013  
REVISED FEBRUARY 16, 2015 
CLOSED TO PATIENT ENTRY SEPTEMBER 20, 2016 
 


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PROTOCOL GOG-0277 (IRCI 001) 
 
A PHASE III RANDOMIZED TRIAL OF GEMCITABINE (NSC# 613327) PLUS 
DOCETAXEL (NSC#  628503) FOLLOWED BY DOXORUBICIN (NSC# 123127) VERSUS 
OBSERVATION FOR UTERUS-LIMITED, HIGH-GRADE UTERINE LEIOMYOSARCOMA 
NCI Version Date 12/07/2017 
Includes Revisions #1-3 
 
 
STUDY CHAIR: EORTC Gynecological Cancer 
Group (GCG) (10/28/2013) 
STUDY CHAIR: EORTC  (Soft Tissue Bone Sarcoma 
Group (STBSG) (10/28/2013) 
PETRONELLA BEATRIX OTTEVANGER 
ANDERS KRARUP-HANSEN 
RADBOUD UNIVERSITY NIJMEGEN  
HERLEV HOSPITAL –UNIVERSITY COPENHAGEN 
MEDICAL CENTRE 
HERLEV RINGVEJ 
PO BOX 9101-GEERT GROOTEPLEIN 10 
2730 HERLEV 
6500 HB NIJMEGEN 
DENMARK 
NETHERLANDS 
+45 44535300 
+31 243610353 
Anders.Krarup-Hansen@regionh.dk 
FAX: +31 243540788 
 
E-MAIL: p.ottevanger@onco.umcn.nl 
PATHOLOGIST: EORTC (10/28/2013) 
 
CYRIL FISHER 
 
DEPT OF HISPATHOLOGY 
 
ROYAL MARSDEN HOPSITAL-CHELSEA, LONDON 
 
FULHAM ROAD 203 
 
GB LONDON SW3 6JJ 
 
UNITED KINGDOM 
 
+44 2078082631 
 
FAX: +44 2078082578 
 
E-MAIL: Cyril.fisher@rmh.nhs.uk 
 
 
 
 
 
 
 
 
 
 
 
 
OPEN TO PATIENT ENTRY JUNE 4, 2012 
REVISED OCTOBER 28, 2013 
REVISED FEBRUARY 16, 2015 
CLOSED TO PATIENT ENTRY SEPTEMBER 20, 2016 
 


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PROTOCOL GOG-0277 (IRCI 011) 
A PHASE III RANDOMIZED TRIAL OF GEMCITABINE (NSC# 613327) PLUS 
DOCETAXEL (NSC#  628503) FOLLOWED BY DOXORUBICIN (NSC# 123127) VERSUS 
OBSERVATION FOR UTERUS-LIMITED, HIGH-GRADE UTERINE LEIOMYOSARCOMA 
NCI Version Date 12/07/2017 
Includes Revisions #1-3 
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
 
 
 
 
 
OPEN TO PATIENT ENTRY JUNE 4, 2012 
REVISED OCTOBER 28, 2013 
REVISED FEBRUARY 16, 2015 
CLOSED TO PATIENT ENTRY SEPTEMBER 20, 2016 
 
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 
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 
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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SCHEMA (10/28/2013) 
 
ATTENTION: EORTC and NCRN Sites:  Please refer to your site-specific appendices 
(Appendices III and IV) for important site-specific protocol information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enroll Patients with 
1) High-grade uterine LMS 
2) FIGO Stage I (uterus +/- cervix) 
3) Hysterectomy +/- BSO 
RANDOMIZE 
Regimen I*: 
Gemcitabine 900 mg/m2 IV days 1 and 8 
Docetaxel 75 mg/m2 IV day 8  
GCSF 5 micrograms/kg days 9-15 or pegfilgrastim  6 mg 
day 9 or 10 
 
Every 21 days for  4 cycles 
 
CT/MRI imaging to confirm disease-free 
 
Doxorubicin 60 mg/m2 IV every 21 days for 4 cycles 
 
*Please see Section 5.2 for Regimen modifications for 
patients with ejection fraction <50% or below institution 
normal limits 
 
Regimen II: 
Observation 


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TABLE OF CONTENTS 
1.0 
OBJECTIVES 
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1.1 
Primary Objectives 
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1.2 
Secondary Objectives 
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2.0 
BACKGROUND AND RATIONALE 
- 7 - 
2.1 
Rationale for a randomized trial of adjuvant systemic therapy in uterine LMS 
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2.2 
Rationale for gemcitabine + docetaxel followed by doxorubicin as the experimental arm of an 
adjuvant treatment trial 
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2.3 
Rationale for observation as the control arm of an adjuvant treatment trial 
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2.4 
Rationale for every 4 month imaging 
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2.5 
Rationale for international collaboration with EORTC and Cancer Research-NCRN (UK) - 10 - 
2.6 
Rationale for primary endpoint of overall survival 
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2.7 
Inclusion of Women and Minorities 
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3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS 
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3.1 
Eligible Patients 
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3.2 
Ineligible Patients 
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4.0 
STUDY MODALITIES 
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4.1 
Docetaxel (Taxotere® RP-56976, NSC #628503) 
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4.2 
Gemcitabine, Gemzar ® (NSC #613327) 
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4.3 
Filgrastim (G-CSF), Neupogen® (NSC #614629) 
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4.4 
Pegfilgrastim (Neulasta) (NSC #725961) 
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4.5 
Doxorubicin (Adriamycin) NSC #123127) 
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4.6 
Pathology Requirements 
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5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 
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5.1 
Patient Entry and Registration 
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5.2 
Treatment Plan 
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5.3 
Criteria for removal from treatment 
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6.0 
TREATMENT MODIFICATIONS 
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6.1 
Gemcitabine Dose level definitions 
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6.2 
Doxorubicin Dose level definitions: 
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6.3 
Hematologic toxicity during EITHER gemcitabine + docetaxel OR doxorubicin 
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6.4 
Hepatic Dysfunction during gemcitabine + docetaxel 
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6.5 
Hepatic Dysfunction during doxorubicin 
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6.6 
Hypersensitivity reactions to Docetaxel 
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6.7 
Other Non-hematologic toxicity likely attributable to gemcitabine and/or docetaxel or 
doxorubicin 
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7.0 
STUDY PARAMETERS 
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7.1 
Observations and Tests 
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7.2 
Stained Pathology Slide Requirements for Central Review to Confirm Eligibility 
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7.3 
Translational Research 
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7.4 
Quality of Life (  ) 
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8.0 
EVALUATION CRITERIA 
- 42 - 
8.1 
Antitumor Effect – Solid Tumors 
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9.0 
DURATION OF STUDY 
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10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
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10.1 
ADVERSE EVENT REPORTING FOR A COMMERCIAL AGENT 
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10.2  GOG DATA MANAGEMENT FORMS 
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11.0 
STATISTICAL CONSIDERATIONS 
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11.1 
Study Design and Treatment Randomization 
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11.2 
Efficacy and toxicity measures 
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11.3 
Statistical study design and planned analyses of therapeutic efficacy 
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11.4 
Safety analyses 
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11.5 
Anticipated distribution of patients’ race and ethnicity (all are female) for GOG credited 
enrollment (  ) 
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12.0 
BIBLIOGRAPHY 
- 59 - 
APPENDIX I 
- 61 - 
APPENDIX II 
- 62 - 
APPENDIX III 
- 63 - 
APPENDIX IV 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.11 
To determine whether overall survival of patients with uterus-limited 
high-grade leiomyosarcoma is superior among patients assigned to 
treatment with adjuvant gemcitabine plus docetaxel followed by 
doxorubicin compared to patients assigned to observation. 
 
1.2 
Secondary Objectives 
 
1.21 
To determine whether treatment with adjuvant gemcitabine plus docetaxel 
followed by doxorubicin improves recurrence-free survival of patients 
with uterus-limited high-grade leiomyosarcoma compared to observation. 
 
1.22 
To explore the impact of potential predictors of recurrence or death such 
as patient age, and institution reported tumor size, cervix involvement (yes 
or no), and mitotic rate. 
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1 
Rationale for a randomized trial of adjuvant systemic therapy in uterine LMS 
 
Patients with early-stage, high-grade uterine leiomyosarcoma (LMS) have a 50-
70% chance of relapse/recurrence of disease.  Recurrences may be distant or local 
or both.  In one GOG study of prognostic factors for recurrence of LMS, only 
14% of patients with stage I or II disease had isolated pelvic recurrences as the 
site of first recurrence.  Adjuvant pelvic radiation can decrease local recurrence 
rates, but has not been shown to increase overall survival.  In the EORTC 
randomized trial of adjuvant whole pelvic radiation v. observation for FIGO stage 
I and II uterine sarcomas, the recurrence rates were approximately 50% in both 
arms of the study.  The percentage of leiomyosarcoma patients remaining 
progression-free at 2 years in that study was approximately 58%, and the 
percentage of all patients (both uterine LMS and uterine carcinosarcoma) that 
remained progression-free at 3 years was 52%. 
 
A recent prospective phase II study of adjuvant gemcitabine plus docetaxel 
followed by doxorubicin for women with uterus-limited high-grade LMS was 
conducted by the Sarcoma Alliance for Research through Collaboration (SARC) 
and the results were presented at the American Society of Clinical Oncology 
(Hensley, ASCO 2010).  In that study (SARC005), 47 women with uterus-limited 
high-grade LMS were enrolled over 3 years' time.  All patients were treated with 
adjuvant gemcitabine + docetaxel for four cycles.  Provided that repeat CT 
imaging showed no evidence of disease, patients then received four cycles of 
doxorubicin.  All patients were followed with CT imaging every 3 months for 2 
years, then every 6 months for 3 years.   


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The primary endpoint of that study was the progression-free survival at 2 years.  
12/46 evaluable patients recurred (26%) at a median time of 12.6 months (range 
3-39). Recurrence sites:  lung-5, liver-1, pelvis-4, both-1, bone+liver-1.  With 
median follow-up of 27.3 months, 78.4% of women remain progression-free at 2 
years from diagnosis (95% confidence interval 67-99%).  Median progression-
free survival (PFS) is 39.3 months (95% confidence interval 31.6-not yet 
reached). The probability that 2-year PFS is ≥50% is > 0.999. The probability that 
2-year PFS is ≥70% is 0.855.  The conclusion was that 78% of women with 
uterus-limited LMS treated with adjuvant GT followed by D remain progression-
free at 2 years, with median follow-up of 27.3 months.  This compares favorably 
with historical estimates of PFS.  The updated results of this study have been 
submitted to the Connective Tissue Oncology Society (CTOS, annual meeting 
October 2011).  Although these data are not yet published, the principal 
investigator (Hensley) provided personal communication that the 3 year PFS is 
about 52%. 
 
Despite these promising data, SARC005 is still, at best, a single-arm study 
without a control group, and the 3-year disease-free survival rate does not appear 
to be substantially better than the outcomes observed in the EORTC adjuvant 
radiation study.  The research question of whether adjuvant chemotherapy 
improves survival for women with early stage high grade LMS remains 
unanswered.  The ideal strategy for answering this research question is with a 
randomized trial with observation as the control arm. 
 
2.2 
Rationale for gemcitabine + docetaxel followed by doxorubicin as the 
experimental arm of an adjuvant treatment trial 
 
Doxorubicin remains a standard first-line treatment for patient with advanced soft 
tissue sarcoma.  Because of its proven activity in metastatic disease, doxorubicin 
has been studied as adjuvant therapy.  Adjuvant doxorubicin or epirubicin-based 
chemotherapy has been beneficial in some trials of soft-tissue sarcomas, but these 
studies have included patients with differing histologies and differing disease 
sites.  Adjuvant chemotherapy with doxorubicin (60 mg/m2 every 3 weeks for 8 
cycles) has been studied in one randomized trial that enrolled patients with either 
carcinosarcoma of the uterus or leiomyosarcoma of the uterus.  Patients enrolled 
on the study may have had pelvic radiation at physician discretion.  In this study, 
adjuvant doxorubicin did not improve survival in the total patient population.  
However, among the subgroup of patients with leiomyosarcoma, adjuvant therapy 
with doxorubicin decreased the risk of relapse (44% v. 61%).  The sample size 
was not large enough for this difference in this subgroup to be statistically 
significant.  These data may, however, be used to support the inclusion of 
doxorubicin in an adjuvant therapy strategy for LMS. 
 
The rationale for testing gemcitabine and docetaxel as part of an adjuvant strategy 
for uterus-limited LMS is that gemcitabine-docetaxel achieves moderately high 


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objective response rates in patients with measurable metastatic disease.  The 
Gynecologic Oncology Group conducted a phase II trial for women with 
advanced, unresectable uterine leiomyosarcoma who had progressed after one 
prior cytotoxic regimen (gemcitabine-docetaxel as second-line therapy).  Ninety 
percent of the patients had received prior doxorubicin-based therapy.  Three of 48 
patients (6.3%) achieved complete responses, and 10 (20.8%) achieved partial 
responses (assessed by RECIST) for an overall objective response rate of 27%.   
An additional 50% of women had stable disease lasting a median duration of 5.4 
months.  The median number of cycles per patient was 5.5 (range 1-22).  The 
percentage of patients remaining progression-free at 3 months was 73%, and the 
percentage progression-free at 6 months was 52%.  Median progression-free 
survival was 5.6+ months (range 0.7 – 27+ months).  The median duration of 
objective response was 9+ months (range 3.9 – 24.5+ months).  
 
The Gynecologic Oncology Group subsequently conducted a prospective phase II 
trial to assess the efficacy of fixed dose-rate gemcitabine plus docetaxel in women 
with advanced uterine leiomyosarcoma who had received no prior cytotoxic 
treatment (first-line treatment).  Objective responses were observed in 35.8% of 
patients with complete responses in 4.8%, and partial responses in 31%, (90% 
confidence interval for the overall response rate, 23.5 to 49.6%).  An additional 
26.2% had stable disease.  Half of the patients received six or more cycles of 
study treatment.  The median progression-free survival was 4.4 months (range 0.4 
to 37.2+ months).  Among the patients with objective response, median response 
duration was six months (range 2.1 to 33.4+ months).  Median overall survival 
was 16+ months (range 0.4 - 41.3 months). 
 
2.3 
Rationale for observation as the control arm of an adjuvant treatment trial 
 
The current standard of care for management of women with completely resected, 
uterus-limited, high grade LMS is observation.  No intervention has been proven 
in a prospective, randomized trial to improve recurrence-free or overall survival.  
In a discussion among potential international collaborators (EORTC and Cancer 
Research-NCRN (UK), the consensus of the group was that the scientifically 
correct control arm is observation. (10/28/2013) 
 
2.4 
Rationale for every 4 month imaging 
 
With a secondary endpoint of recurrence-free survival (RFS), we will need to 
image patients in order to determine whether there is evidence of recurrence.  
Although SARC005 had patients undergo imaging every 3 months, an increase in 
the imaging interval to every 4 months to decrease resource use and radiation 
exposure is reasonable.  Surveillance imaging for soft tissue sarcoma is in 
accordance with published guidelines from the American College of Radiology 
(http://www.acr.org/SecondaryMainMenuCategories/quality_safety/app_criteria.a
spx).  Patients on this study will have approximately 16 CT scans over 5 years.  
This level of radiation exposure is not expected to significantly increase the risk 


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of cancer, particularly in a population that is at high risk to die of the existing 
cancer (Zondervan, Lee, 2011)1. 
 
Provided that imaging occurs at the same time point in both arms, RFS will be a 
reliable endpoint.   
 
While it has traditionally been thought that most recurrences of LMS happen 
within the first 2 years of diagnosis, we have observed a shift in the timing of 
recurrences among patients treated on SARC005.  There were few recurrences in 
years 1 and 2, but more recurrences in year 3.  Thus, every 4 month imaging for 3 
years, then every 6 months for 2 additional years (total of 5 years of required 
imaging) is a reasonable schedule.  This schedule was agreed upon among the 
international collaborators at the June 2011 meeting. 
 
International collaborators requested the flexibility of using MRI of the abdomen 
and pelvis plus CT of the chest as a surveillance strategy.  Thus, the surveillance 
imaging on this study will be either CT chest/abdomen/pelvis or MRI 
abdomen/pelvis + CT chest. 
 
2.5 
Rationale for international collaboration with EORTC and Cancer Research-
NCRN (UK)  (10/28/2013) 
 
Although there are some concerns about whether a phase III trial with observation 
as the control arm may be difficult to accrue, discussion with international 
collaborators led to the consensus that observation as the control arm is the best 
scientific design, and that most patients, when told that chemotherapy has not 
been shown to benefit in terms of either disease-free or overall survival, would be 
comfortable enrolling on a trial that has an observation arm.  The group discussed 
that in order to facilitate accrual, it is useful to reassure patients that if there is 
evidence of recurrence then chemotherapy or resection or other appropriate 
therapy would be offered at that time.   
 
International collaboration raises some logistical issues, which were discussed at 
the June 2011 meeting.  We plan to allow each group (GOG, EORTC, and 
NCRN) to use their current standards for review of eligibility criteria, histologic 
review, and imaging for both eligibility and evidence of recurrence. We do not 
plan for central review of imaging studies.  RECIST will be used for 
determination of recurrence.   
 
We do plan for central histologic review: each group will assign a pathologist to 
be a co-investigator for the group for this study.  The three pathologists will set up 
a mechanism for review of slides or digital images of slides among the 
pathologists of the three groups.  This could be done with digital images or in 
person in conjunction with a meeting.  We will not plan on real-time review of 
pathology slides prior to enrollment. Each group will follow its current standards 
for pathology review.  On a once or twice a year basis, designated pathologists 


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from each group will arrange to review representative patient slides from the 
already-enrolled patients.  This cross-group pathology review may be done in 
person or with digital images.   
 
2.6 
Rationale for primary endpoint of overall survival 
 
Many recurrences among patients with uterine LMS are not accompanied or 
signaled by symptoms and only detected on scans.  This suggests that patient 
benefit may be more appropriately measured by survival.  Relative activity of the 
combination arm can be evaluated by recurrence-free survival assuming 
surveillance is standardized across arms.  In the observation control arm, 
treatment will be delayed until recurrence is documented.  In the absence of a 
survival benefit with multi-agent chemotherapy, with or without a RFS benefit, 
adjuvant treatment of all patients upfront with such chemotherapy would be called 
into question.  This would be even more so if the recurrences on the observation 
arm were treated with the study regimen.  Treatment at the time of recurrence 
may be highly variable: some patients have late, isolated recurrences which are 
resectable; other patients may recur quickly but respond well to treatment with 
chemotherapy; and still others will have rapidly progressive-treatment-refractory 
disease.  In this rare tumor, we would not be able to control for the down-stream 
management of recurrences. 
 
While a RFS endpoint requires smaller sample size and study duration, with 
international collaboration, overall survival will be the primary endpoint.  The 
study is designed to detect an increase in overall survival to 48 months with 
adjuvant chemotherapy versus 30 months without.  It is thought that living an 
average of eighteen months longer is likely to be worth the six months spent on 
chemotherapy for most women.  The RFS endpoint will help us estimate the 
difference between treatment arms in the median number of months alive and 
recurrence-free. 
 
Uterine leiomyosarcoma is a rare disease with a high risk of recurrence.  
Currently, the standard of care after complete resection of uterus-limited disease 
is observation, although it is recognized that the recurrence rate is 50-70%.  No 
adjuvant intervention has been shown in a prospective randomized trial to 
diminish this risk.  Adjuvant whole pelvic radiation was no better than 
observation in a prospective phase III trial 4. Adjuvant chemotherapy as delivered 
in the prospective phase 2 trial SARC005 showed a promising 2-year progression-
free survival rate but in the absence of a control arm we cannot conclude that 
adjuvant chemotherapy improves recurrence-free or overall survival.   
 
The proposed trial would establish the standard of care for adjuvant treatment of 
high-risk uterus-limited LMS.  If the study shows a clinically meaningful 
improvement in overall survival with chemotherapy compared with observation, 
adjuvant chemotherapy can be recommended to women after resection of uterus-
limited disease.  If chemotherapy shows no improvement in overall survival, then 


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women can be spared the toxicities of chemotherapy in the adjuvant setting, with 
subsequent treatment delayed until recurrence. 
 
2.7 
Inclusion of Women and Minorities 
 
The Gynecologic Oncology Group and GOG participating institutions will not 
exclude potential subjects from participating in this or any study solely on the 
basis of ethnic origin or socioeconomic status.  Every attempt will be made to 
enter all eligible patients into this protocol and therefore address the study 
objectives in a patient population representative of the entire high grade uterine 
leiomyosarcoma population treated by participating institutions. 
 
 
 


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3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS  
 
3.1 
Eligible Patients  
 
3.11 
Patients with high risk uterine LMS, FIGO stage I (confined to corpus +/- cervix).  
Patients with known uterine serosa involvement are not eligible.  Patients should 
have had, at least, a complete hysterectomy (including removal of the cervix).   
Bilateral salpingo-oophorectomy is not required.   
 
3.111 Institutional pathology review calls the uterine leiomyosarcoma “high 
grade.” 
 
3.112 Additionally, if the pathology report indicates a mitotic rate, the mitotic 
rate should be greater than or equal to 5 mitoses/10 high power field.   
 
 
All patients must be no longer than 12 weeks (3 months) from surgical 
resection of cancer at the time of enrollment on study.  If a patient requires 
a second operation to complete her surgery, i.e. trachelectomy to remove 
the cervix and/or BSO, the 12 weeks may be counted from the time of the 
second operation. 
 
Patients who had a “morcellation” hysterectomy procedure that involved 
morcellation within the peritoneal cavity are eligible IF a second operation 
is performed and biopsies from the second procedure show no evidence of 
leiomyosarcoma. (10/28/2013) 
 
3.12 
All patients must have no evidence of persistent or metastatic disease as 
documented by a post-resection CT of the chest/abdomen/pelvis or by CT chest + 
MRI abdomen/pelvis.  The post-resection imaging studies should be performed 
within 4 weeks of registration on study. 
 
 
 
3.13 
Patients must have adequate: 
 
3.131 Bone marrow function: Absolute neutrophil count (ANC) greater than or 
equal to 1,500/mcl (ANC 1.5 x 109/liter (L). 
 
Platelets greater than or equal to100,000/mcl  (Platelets 100 x 109/L). 
Hemoglobin greater than 8.0 g/dl (= 80 g/L; or 4.9 mmol/L). 
 
3.132 Renal function:  creatinine less than or equal to 1.5 x institutional upper 
limit normal (ULN.)  
 
3.133 Hepatic function: Bilirubin within normal range. SGOT (AST), SGPT 
(ALT), and alkaline phosphatase less than or equal to 2.5 x ULN.  
 
Patients with a history of Gilbert’s syndrome may be eligible provided 
total bilirubin is less than or equal to 1.5 x ULN and the AST, ALT, 
Alkaline phosphatase meet the criteria detailed. 


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3.134 Neurologic function: Neuropathy (sensory and motor) less than or equal to 
CTCAE grade 1. 
 
3.14 
Patients with GOG performance status of 0 or 1; ECOG performance status of  0 
or,1; or KPS >= 80%. 
 
3.15 
Patients who have met the pre-entry requirements specified in Section 7.0. 
 
3.16 
Patients must have signed an approved informed consent. 
 
3.17 
Patients participating through U.S. sites must sign an approved and authorization 
permitting release of personal health information.  
 
3.18 
Patients must be a minimum of 18 years of age. 
 
3.19 
Patients should be free of active infection requiring antibiotics (with the exception 
of an uncomplicated UTI). 
 
3.2 
Ineligible Patients 
 
3.21 
Patients who have had prior therapy with docetaxel or gemcitabine or doxorubicin 
at any time in their history. 
 
3.22 
Patients with a history of other invasive malignancies, with the exception of non-
melanoma skin cancer, are ineligible 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 with a history of severe hypersensitivity reaction to Taxotere® 
(docetaxel) or other drugs formulated with polysorbate 80. 
 
3.24 
Patients with GOG performance status of 2, 3 or 4; or ECOG performance status 
of 2, 3 or 4. 
 
3.25 
Patients who are breast-feeding. 
 
3.26 
Patients with a known history of congestive heart failure or cardiac ejection 
fraction < 50% (or less than institutional normal limits).  ECHO or MUGA is not 
required prior to enrollment.  For patients assigned to the chemotherapy arm, an 
ECHO or MUGA must have been done within 6 months of day 1 of gemcitabine-
docetaxel treatment. 
 
Patients who enroll on study and are randomized to Regimen I (chemotherapy ) 
and then are found on baseline ECHO or MUGA to have cardiac ejection fraction 
<50% or below institutional normal will remain ON study.  Such patients will 


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receive gemcitabine + docetaxel for 4 cycles, as detailed in Section 5.2, but will 
NOT receive any doxorubicin treatment.  They will continue treatment follow-up 
as outlined for all patients assigned to Regimen I. (10/28/2013) 
 
3.27 
Patients with a history of prior whole pelvic radiation. 
 
3.28 
Concurrent treatment with hormone replacement therapy is permitted at the 
discretion of the treating physician.  Patients who have been taking 
hormonal/hormone blocking agents for breast cancer or breast cancer prevention 
or other indication are eligible.  Use of anti-hormonal agents (tamoxifen, 
medroxyprogesterone, aromatase inhibitors) is permitted at the discretion of the 
treating physician.  Documentation of concurrent medications is required. 
 
3.29 
Patients with recurrent uterine LMS. 
 
3.210 Patients who are known to be HIV (human immunodeficiency virus) positive are 
not eligible due to the high risk for infectious complications of the 
myelosuppressive therapy used in the experimental arm of this study.  
 
3.211 Patients with gross residual or metastatic tumor findings following complete 
surgical treatment for uterine LMS. 
 


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4.0 
STUDY MODALITIES   
 
4.1 
Docetaxel (Taxotere® RP-56976, NSC #628503) 
 
4.11 
Formulation:  Docetaxel is supplied as a sterile, non-pyrogenic, non-
aqueous viscous solution in single dose vials containing 20mg/0.5mL or 
80mg/2mL of docetaxel.  Each mL contains 40mg docetaxel (anhydrous) 
and 1040mg polysorbate 80. 
 
4.12 
Docetaxel requires dilution prior to use.  A sterile, non-pyrogenic, single 
dose diluent is supplied for this purpose.  The diluent for docetaxel 
contains 13% (w/w) ethanol in water for injection and is supplied in vials. 
 
4.13 
Storage:  Unopened vials of docetaxel are stable to the date indicated on 
the package when stored between 2 and 25°C (36 and 77°F).  Protect from 
light. 
 
4.14 
Preparation:  Docetaxel must be combined with its supplied diluent (final 
concentration = 10mg/mL) and then further diluted prior to infusion.  
Docetaxel should be diluted in 0.9% Sodium Chloride for Injection, USP 
or 5% Dextrose Injection, USP to produce a final concentration of 0.3 to 
0.74mg/mL.  The fully prepared docetaxel infusion solution should be 
used within 4 hours (including the infusion duration).NOTE:  In order to 
minimize patient exposure to the plasticizer DEHP, which may be leached 
from PVC infusion bags or sets, the final docetaxel dilution for infusion 
should be stored in bottles (glass, polypropylene) or plastic 
(polypropylene, polyolefin) bags and administered through polyethylene-
lined administration sets. 
 
4.15 
Administration: Docetaxel is given intravenously as a one-hour infusion. 
All patients should be pre-medicated with oral corticosteroids ( for 
example:   dexamethasone 16 mg per day (8 mg BID)) for three days 
starting one day prior to docetaxel administration in order to reduce the 
incidence and severity of fluid retention as well as the severity of 
hypersensitivity reactions 
 
4.16 
Adverse Effects:  Consult the package insert for the most current and 
complete information. 
 
4.17 
Supplier:  Docetaxel is commercially available.  Consult the American 
Hospital Formulary Service Drug Information guide, Facts and 
Comparisons, or the package insert for additional information. 
 
4.2 
Gemcitabine, Gemzar ® (NSC #613327) 
 
 


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4.21  Formulation: Gemcitabine HCl is a nucleoside analog that exhibits anti-
tumor activity.  
 
4.22 
Supplier/How Supplied: Gemcitabine HCl is commercially available. 
Gemcitabine is supplied as a white lyophilized powder in sterile single use 
vials containing 200mg (10 ml) or 1000 mg (50 ml) of gemcitabine as the 
hydrochloride salt.  
 
4.23 
Stability/Storage:  Unopened vials of gemcitabine are stable until the 
expiration date indicated on the package when stored at controlled room 
temperature between 20 to 25°C (68 to 77° F).  
 
4.24 
Preparation:  To reconstitute, add 5 ml of 0.9% Sodium Chloride Injection 
to the 200 mg vials or 25 ml to the 1000 mg vial. Shake to dissolve. These 
dilutions each yield a gemcitabine concentration of 38 mg/ml which 
includes accounting for the displacement volume of the lyophilized 
powder. The total volume upon reconstitution will be 5.26 ml or 26.3 ml, 
respectively. Complete withdrawal of the contents will provide 200 mg or 
1 g of gemcitabine, respectively. The appropriate amount of drug may be 
administered as prepared or further diluted with 0.9% Sodium Chloride 
Injection to concentrations as low as 0.1 mg/ml. The solution should be 
clear, colorless to slightly straw colored. Do not administer if discoloration 
or particulate matter is found. Once the drug has been reconstituted, it 
should be stored at controlled room temperature and used within 24 hours.  
 
4.25 
Administration: The mixed solution will be continuously infused over 70-
90 minutes, depending on the dose (See Section 5.2 and Section 6.1). 
 
4.26 
Adverse effects: 
 
Hematologic: The following Grade 3 and 4 toxicities can be expected after 
single agent therapy with doses between 800 and 1250 mg/m2: neutropenia 
25%, leukopenia 9%, anemia 8%, and thrombocytopenia 5%. Infection 
occurred in 16% of patients; sepsis occurred in less than 1%. 17% of 
patients experienced hemorrhage of Grade 2 or less.  
Gastrointestinal:  Nausea and vomiting is frequent, up to 69%, but usually 
mild to moderate. Grade 3 and 4 nausea and vomiting were noted in 14%. 
Diarrhea was seen in 19%, stomatitis in 11%, and constipation in 23%. 
Pulmonary: Dyspnea was seen in 23%, severe in 3%. Rarely parenchymal 
toxicity including pneumonitis has been reported. Treatment should be 
discontinued immediately, if suspicious symptoms occur. 
Hepatic:  Transient elevation of hepatic enzymes was seen in 70%, 
however, this was not dose dependent and no increase was noted during 
prolonged therapy. Serious hepatotoxicity, including liver failure and 
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Fever: This is seen in up to 41%, but usually of a mild degree. Fever may 
be accompanied by flu-like symptoms in 19%.  
Renal: Reversible proteinuria, hematuria are frequent; increased BUN and 
creatinine in 16% and 8% of patients, respectively. However, renal 
insufficiency or hemolytic uremic syndrome is very rare. If suspicious 
symptoms are noted therapy should be discontinued immediately. 
Dermatologic/Skin:  Alopecia is seen in 15%; a reversible macular or 
macular-papular rash is seen in 30%; pruritus occurs in 13%. Peripheral 
edema is seen in up to 20% of the patients treated. Infusion site reactions 
occurred in 4% of patients. 
Neurologic: There was a 10% incidence of mild paresthesias; somnolence 
occurred in 11% of patients.   
Pain at the site of injection: Seen in 48% of patients; Grade 3 in 9%.   
Other: Cardiovascular or allergic reactions are seen very rarely.  
 
*See FDA-approved gemcitabine package insert for a comprehensive list 
of adverse events associated with gemcitabine. 
 
4.3 
Filgrastim (G-CSF), Neupogen® (NSC #614629)  
 
4.31 
Formulation:  Filgrastim (G-CSF), Neupogen® (recombinant granulocyte-
colony stimulating factor) is a protein produced by E. Coli into which has 
been inserted the human G-CSF gene.  Filgrastim differs from the natural 
protein in that the N-terminal amino acid is a methionine and it is not 0-
glycosylated.  G-CSF functions as a hematopoietic growth factor; it 
increases the proliferation, differentiation, maturation and release of 
precursor cells into mature blood cells of the neutrophil lineage.  G-CSF 
has demonstrated in vitro effects on mature neutrophils, including an 
increase expression of chemotactic receptors, enhanced phagocytosis and 
intracellular killing of certain organisms, as well as enhanced killing of 
target cells that are bound by antibodies. 
Approximately 6,400 patients in US and international based trials have 
participated in clinical trials of filgrastim to date, and the worldwide 
commercial populations receiving filgrastim totaled approximately 
190,000.  The drug has been found to be well tolerated at dosages up to 69 
mcg/kg/d given IV or subcutaneously, with no toxic effects attributable to 
filgrastim.  A maximum tolerated dose has not yet been determined. 
4.32 
Supplier/How Supplied:  Filgrastim is commercially available.  Filgrastim 
is supplied as a clear, colorless preservative-free liquid for parenteral 
administration.  The product is available in single use vials and pre-filled 
syringes. 
Single use vials: Single use vials contain filgrastim 300 mcg/ml in a preservative-
free solution with 0.59 mg/ml acetate, 50 mg/ml sorbitol, 0.004% Tween 
80, 0.035 mg/ml sodium, and water for injection, USP, pH 4.0 to make 1 


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ml filgrastim.  Filgrastim (G-CSF) is commercially available in two vial 
sizes: 300 mcg/1ml and 480 mcg/1.6 ml. 
Single use pre-filled syringes: Single use pre-filled syringes contain either 
300 mcg or 480 mcg of filgrastim at a fill volume of 0.5 ml or 0.8 ml, 
respectively.  
4.33 
Storage and Stability: Filgrastim should be stored in the refrigerator at 2 - 
8°C (36 to 46° F).  Avoid shaking.  Prior to injection, filgrastim may be 
allowed to reach room temperature for a maximum of 24 hours.  Any vial 
or pre-filled syringe left at room temperature for greater than 24 hours 
should be discarded.  Parenteral drug products should be inspected 
visually for particulate matter and discoloration prior to administration, 
whenever solution and container permit; if particulates or discoloration are 
observed, the container should not be used.    
4.34 
Administration: Filgrastim is administered as a single daily injection by 
subcutaneous bolus injection, by short IV infusion (15-30 minutes), or by 
continuous subcutaneous or continuous IV infusion. Because of the 
potential sensitivity of rapidly dividing myeloid cells to cytotoxic 
chemotherapy, do not use filgrastim in the period 24 hours before through 
24 hours after the administration of cytotoxic chemotherapy. 
4.35 
Dilution:  If required, filgrastim may be diluted in 5% dextrose.  
Filgrastim diluted to concentrations between 5 and 15 mcg/ml should be 
protected from adsorption to plastic materials by addition of albumin 
(human) to a final concentration of 2 mg/ml.  When diluted in 5% dextrose 
or 5% dextrose plus albumin, filgrastim is compatible with glass bottles, 
PVC and polyfilm IV bags, and polypropylene syringes.  Dilution of 
filgrastim to a final concentration of less than 5 mcg/ml is not 
recommended at any time.  Do not dilute with saline at any time; product 
may precipitate. 
4.36 
Precautions: Filgrastim should be used with caution in patients with pre-
existing cardiac conditions such as hypertension, angina pectoris and 
cardiac dysrhythmias.  Until further data become available, precaution 
should be exercised if filgrastim is administered to those patients with 
myeloid malignancies. 
4.37 
Pregnancy and lactation:  No clinical trials have been performed in 
pregnant or lactating women.  Therefore, administration of filgrastim 
during pregnancy or lactation is not recommended until further data are 
available. 
4.38 
Contraindications: Filgrastim is contraindicated in these patients with 
known hypersensitivity to E. coli -derived proteins.  
4.39 
Adverse Effects: 
 
Medullary bone pain: Occurring in 20-25% of patients in phase II and III 
trials.  When bone pain was reported it often preceded a rise in the 


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circulating neutrophil count; it occurred more frequently in patients treated 
with 20-100 mcg/kg/d of intravenously administered filgrastim, and less 
often in lower subcutaneous doses.  The pain was generally mild to 
moderate in severity, and usually controlled with non-narcotic analgesics 
such as acetaminophen.   
Other side effects include transient but reversible increases of alkaline 
phosphatase, lactate dehydrogenase, and uric acid levels.  These occurred 
in 27-58% of patients, without clinical sequelae observed.  Transient 
decreases in blood pressure that did not require clinical treatment were 
reported in 7/176 patients in Phase III clinical studies following 
administration of filgrastim. Cardiac events (myocardial infarctions, 
arrhythmias) have been reported in 11/375 cancer patients receiving 
filgrastim in clinical studies but the relationship to filgrastim therapy is 
unknown.  
Less frequently reported adverse events related to filgrastim 
administration include subclinical splenomegaly, exacerbation of pre-
existing skin rashes, alopecia, and thrombocytopenia, and cutaneous 
vasculitis.  Ischemic or infarcted colon, sometimes with involvement of 
other parts of the gastrointestinal tract, has been seen in patients receiving 
paclitaxel and G-CSF therapy.  Patients reporting abdominal discomfort 
should be monitored closely. The specific etiologic role of paclitaxel, other 
chemotherapeutic agents, or G-CSF is not entirely defined.  It is 
conceivable that the high doses of chemotherapy used in these studies 
induced sufficiently severe neutropenia that these patients were at risk for 
complications based on the myelotoxicity alone.  If this is the case, then 
the use of G-CSF may actually assist in preventing this occurrence in other 
patients receiving high-dose paclitaxel chemotherapy.  A review of the 
Amgen database of over 10,000 patients treated on company-sponsored 
trials revealed the occurrence of only one case of typhlitis, two instances 
of intestinal ischemia, and six occurrences of intestinal perforation.  
However, it is remotely possible that the G-CSF may have contributed in 
some unforeseen way to these events.  
Adult respiratory distress syndrome (ARDS) has been reported in 
neutropenic patients with sepsis receiving filgrastim, and is postulated to 
be secondary to an influx of neutrophils to sites of inflammation in the 
lungs. Neutropenic patients receiving filgrastim who develop fever, lung 
infiltrates, or respiratory distress should be evaluated for the possibility of 
ARDS. In the event that ARDS occurs, filgrastim should be discontinued 
until resolution of ARDS and patients should receive appropriate medical 
management for this condition.  
Rare cases of splenic rupture have been reported following the 
administration of filgrastim in both healthy donors and patients with 
cancer. Some of these cases were fatal. Patients who report left upper 


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abdominal and/or shoulder tip pain should be evaluated for an enlarged 
spleen or splenic rupture.  
Rarely, allergic-type reactions have occurred.  Since the commercial 
introduction of filgrastim there have been reports (< 1 in 4,000 patients) of 
symptoms suggestive of an allergic-type reaction, but in which an immune 
component has not been demonstrated.  These have generally been 
characterized by systemic symptoms involving at least two body systems, 
most often skin (rash, urticaria, edema), respiratory (wheezing, dyspnea), 
and cardiovascular (hypotension, tachycardia).   Some reactions occurred 
on initial exposure.  Reactions tended to occur within the first thirty 
minutes after administration and appeared to occur more frequently in 
those patients who received filgrastim intravenously.  Rapid resolution of 
symptoms occurred in most cases after administration of standard 
supportive care, and symptoms recurred in more than half the patients 
when re-challenged. 
*Please see the FDA-approved filgrastim package insert for a 
comprehensive list of adverse events associated with filgrastim.   
4.4 
Pegfilgrastim (Neulasta) (NSC #725961) 
 
4.41 
Formulation:  Pegfilgrastim is a covalent conjugate of recombinant 
methionyl human G-CSF (filgrastim) and monomethoxypolyethylene 
glycol. To produce pegfilgrastim, a 20 kD monomethoxypolyethylene 
glycol molecule is covalently bound to the N-terminal methionyl residue 
of filgrastim. The average molecular weight of pegfilgrastim is 
approximately 39 kD. 
4.42 
Supplier/How Supplied: Pegfilgrastim is commercially available. 
Pegfilgrastim is supplied in 0.6 ml pre-filled syringes for subcutaneous 
injection. Each syringe contains 6 mg pegfilgrastim (based on protein 
weight), in a sterile, clear, colorless, preservative-free solution (pH 4.0) 
containing acetate (0.35 mg), sorbitol (30.0 mg), polysorbate 20 (0.02 
mg), and sodium (0.02 mg) in water for injection, USP.  
4.43 
Storage and Stability: Pegfilgrastim should be stored refrigerated at 2 to 8° 
C (36 to 46° F); syringes should be kept in their carton to protect from 
light until time of use. Shaking should be avoided. Before injection, 
pegfilgrastim may be allowed to reach room temperature for a maximum 
of 48 hours but should be protected from light. Pegfilgrastim left at room 
temperature for more than 48 hours should be discarded. Freezing should 
be avoided; however, if accidentally frozen, pegfilgrastim should be 
allowed to thaw in the refrigerator before administration. If frozen a 
second time, it should be discarded.   
4.44 
Administration: Pegfilgrastim is a single subcutaneous injection of 6 mg 
administered once per chemotherapy cycle.  


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Because of the potential sensitivity of rapidly dividing myeloid cells to 
cytotoxic chemotherapy, do not use pegfilgrastim for 24 hours after the 
administration of cytotoxic chemotherapy. 
4.45 
Precautions: Pegfilgrastim should be visually inspected for discoloration 
and particulate matter before administration and should not be 
administered if discoloration or particulates are observed.  
4.46 
Pregnancy and lactation:  No clinical trials have been performed in 
pregnant or lactating women.  Therefore, administration of pegfilgrastim 
during pregnancy or lactation is not recommended until further data are 
available. 
4.47 
Contraindications: Pegfilgrastim is contraindicated in patients with known 
hypersensitivity to E. coli -derived proteins, pegfilgrastim, filgrastim, or 
any other component of the product.  
4.48 
Adverse Effects:  
 
Medullary bone pain: The most common adverse event attributed to 
pegfilgrastim in clinical trials was medullary bone pain, reported in 26% 
of subjects. This bone pain was generally reported to be of mild-to-
moderate severity. Approximately 12% of all subjects utilized non-
narcotic analgesics and less than 6% utilized narcotic analgesics in 
association with bone pain.  
 
Other side effects include reversible elevations in LDH, alkaline 
phosphatase, and uric acid, which did not require treatment intervention.  
 
One case of splenic rupture has been reported following the administration 
of pegfilgrastim. Patients who report left upper abdominal and/or shoulder 
tip pain should be evaluated for an enlarged spleen or splenic rupture. 
 
Adult respiratory distress syndrome (ARDS) has been reported in 
neutropenic patients with sepsis receiving filgrastim, the parent compound 
of pegfilgrastim, and is postulated to be secondary to an influx of 
neutrophils to sites of inflammation in the lungs. Neutropenic patients 
receiving pegfilgrastim who develop fever, lung infiltrates, or respiratory 
distress should be evaluated for the possibility of ARDS. In the event that 
ARDS occurs, pegfilgrastim should be discontinued until resolution of 
ARDS and patients should receive appropriate medical management for 
this condition. 
 
Allergic-type reactions, including anaphylaxis, skin rash, and urticaria, 
occurring on initial or subsequent treatment have been reported with 
filgrastim. In some cases, symptoms have recurred with re-challenge, 
suggesting a causal relationship. Allergic-type reactions to pegfilgrastim 
have rarely been reported in post-marketing experience. If a serious 
allergic reaction or an anaphylactic reaction occurs, appropriate therapy 
should be administered and further use of pegfilgrastim should be 
discontinued.  


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In subjects receiving pegfilgrastim in clinical trials, the only serious event 
that was not deemed attributable to underlying or concurrent disease or to 
concurrent therapy was a case of hypoxia.  
 
*Please see the FDA-approved pegfilgrastim package insert for a 
comprehensive list of adverse events associated with pegfilgrastim. 
4.5 
Doxorubicin (Adriamycin) NSC #123127) 
 
4.51 
Formulation: Doxorubicin is supplied as a sterile, red-orange, freeze-dried 
powder in 10, 20 and 50 mg single dose vials and a 150 mg multidose vial 
as doxorubicin hydrochloride for injection only. Doxorubicin is also 
available as a sterile parenteral, isotonic solution for intravenous injection 
only, containing no preservative, available in 10, 20, 50 and 75 mg single 
dose vials and a 200 mg multidose vial.  
 
4.52 
Preparation: Doxorubicin hydrochloride for injection 10, 20,50 and 150 
mg vials should be reconstituted with 5, 10, 25 and 75 ml respectively, of 
sodium chloride injection, USP (0.9%) to give a final concentration of 2 
mg/dl of doxorubicin hydrochloride.  An appropriate volume of air should 
be withdrawn from the vial during reconstitution to avoid excessive 
pressure build-up.  Bacteriostatic diluents are not recommended. After 
adding the diluent, the vial should be shaken and the contents allowed to 
dissolve.  
 
4.53 
Storage: The reconstituted solution is stable for 7 days at room 
temperature and normal light and 15 days under refrigeration (2° to 8°C). 
It should be protected from sunlight. Discard any unused solution. 
 
4.54 
Adverse Events: Severe local tissue necrosis will occur if there is 
extravasation during administration. Doxorubicin must not be given by the 
intra-muscular or subcutaneous route.  
 
 
Dose-limiting toxicities are myelosuppression and cardiotoxicity.  Serious 
irreversible myocardial toxicity with delayed congestive heart failure often 
unresponsive to any cardiac supportive therapy may be encountered as 
total dosage approaches 550 mg/m2.  This toxicity may occur at lower 
cumulative doses in patients with prior mediastinal irradiation or on 
concurrent cyclophosphamide therapy. 
 
 
Adverse reactions may include: acute nausea, vomiting, mucositis, and 
reversible and complete alopecia. Facial flushing may occur if the 
injection is given too rapidly. Severe cellulitis, vesication and tissue 
necrosis will occur if doxorubicin is extravasated during administration. 
Fever, chills and urticaria have been reported occasionally. 
 
 
Doxorubicin imparts a temporary red coloration to the urine. 


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4.55 
Supplier: Commercially available. 
 
4.56 
Administration:  Doxorubin is administered by slow IV push through a 
free-running intravenous access.  It is recommended but not required that 
doxorubicin be given through a central access device in order to decrease 
the risk for extravasation injury. 
 
 
It is recommended that doxorubicin be slowly administered by IV push 
into the tubing of a freely running intravenous infusion of sodium chloride 
injection, USP or 5% dextrose injection, USP.  The tubing should be 
attached to a Butterfly® needle inserted preferably into a large vein.  If 
possible, avoid veins over joints or in extremities with compromised 
venous or lymphatic drainage.  Doxorubicin should not be mixed with 
heparin or fluorouracil since it has been reported that these drugs are 
incompatible to the extent that a precipitate may form. 
 
 
*Refer to Package Insert for additional information 
 
4.6 
Pathology Requirements 
 
4.61 
Eligibility Criteria: Patients must have “high grade” leiomyosarcoma of 
the uterus diagnosed on the institutional pathology report. The tumor must 
be FIGO stage I (confined to the uterus with or without involvement of the 
cervix.) Patients with involvement of the uterine serosa are not eligible.  If 
the mitotic rate is reported, it must be at least 5 mitotic figures/10HPF. 
Patients must have had a complete hysterectomy with removal of the 
uterine cervix (trachelectomy after supracervical hysterectomy is 
acceptable if needed to remove the cervix). 
 
 
The following patients are not eligible: Patients with recurrent uterine 
leiomyosarcoma, patients with residual, persistent or metastatic 
leiomyosarcoma after hysterectomy, and patients with a history of other 
invasive malignancies within the past 5 years (with the exception of non-
melanoma skin cancer). 
 
4.62 
Requirements: Stained pathology slides are required for central review by 
the GOG pathology committee to confirm eligibility. At least one H&E 
stained slide is required to demonstrate the primary high grade uterine 
leiomyosarcoma with adequate mitotic rate (>5 MF/10 HPF), nuclear 
atypia and tumor necrosis (if present). 
 
4.63 
See Section 7.2 and 10.2 for additional instructions for submitting the 
stained pathology slides to the GOG Statistical and Data Center in 
Buffalo, NY. 


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5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE     
 
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.    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-0277 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) 
Suite 1100 
1818 Market Street 
Philadelphia, PA 19103 
FAX: 1-215-569-0206 
CTSURegulatory@ctsu.coccg.org 
 
5.1 
Patient Entry and Registration 
 
When a suitable candidate has been identified for protocol entry, the following 
steps should be taken: 


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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 
CTSU RSS.  Patients must have signed and dated all applicable consents and 
authorization forms.   
 
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. 
 
OPEN Registration: All site staff 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: 
  
• 
All eligibility criteria have been met within the protocol stated 
timeframes. Site staff should use the registration forms provided on the 
group web site as a tool to verify eligibility. 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
  
Access requirements for OPEN: 
  
• 
Site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account. This is the same account (user id and password) used 
for the CTSU members' web site.  
• 
To perform registrations, the site user must have been assigned the 
'Registrar' role on the GOG or CTSU roster.  
• 
To perform registrations 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.  
  
Further instructional information is provided on the CTSU members' web 
site OPEN tab or within the OPEN URL. For any additional questions 


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contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com.  
 
5.2 
Treatment Plan 
 
5.21 
Randomization will be stratified by country of treating site. 
 
 
Patients diagnosed with high grade uterine LMS and who have had a 
hysterectomy will be randomized into one of the two management arms: 
 
REGIMEN I: (10/28/2013) 
 
Patients randomly assigned to Regimen I will be treated as follows: 
 
Gemcitabine 900 mg/m2 IV over 90 minutes on days 1 and 8 
 
Docetaxel 75 mg/m2 IV day 8 (pre-medication dexamethasone 4-8 mg p.o. 
bid for 3 days, starting 12-24 hours prior to docetaxel) 
 
(Gemcitabine is administered prior to docetaxel on day 8) 
 
Filgrastim (GCSF) 5 micrograms/kg (may round to nearest vial size of 300 
micrograms or 480 micrograms) subcutaneously days 9-15 or 
pegfilgrastim 6 mg subcutaneously day 9 or 10 
 
Each cycle is 21 days 
Treat for 4 cycles 
 
Repeat CT chest/abdomen/pelvis (or CT chest + MRI abdomen/pelvis) 
imaging after 4 cycles (no sooner than 3 months from start of study 
treatment, but no later than 4 months from start of study treatment) of 
gemcitabine plus docetaxel to confirm continued no evidence of disease 
(NED). 
 
If NED, no sooner than 3 weeks, but no longer than 8 weeks from cycle 4 
day 1 of  gemcitabine/docetaxel start: 
 
Doxorubicin 60 mg/m2 IV every 21 days for 4 cycles (use of central 
venous catheter access recommended, but not required).  
 
Filgrastim (GCSF) 5 micrograms/kg (may round to nearest vial size of 300 
micrograms or 480 micrograms) subcutaneously days 2-8 or pegfilgrastim 
6 mg subcutaneously day 2 or 3 is OPTIONAL. 
 
NOTE:  Patients who are found, after enrollment, to have a cardiac 
ejection fraction of <50% or below institutional normal limits will 


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conclude their adjuvant chemotherapy at the completion of 4 cycles of 
gemcitabine + docetaxel.  They will NOT receive any doxorubicin.  
They will remain ON STUDY and proceed with follow-up as detailed 
for all patients assigned to Regimen I. 
 
Follow-up: 
Follow patients for recurrence by physical examination and CT 
chest/abdomen/pelvis (or CT chest +MRI abdomen/pelvis) every 4 months 
from study entry until 3 years out from the start of study treatment, then 
every 6 months for the next 2 years.  There is a maximum of 5 years of 
imaging for initial recurrence. 
 
At time of documented recurrence:  management of recurrent disease will 
be at the discretion of the treating physician.  Documentation of the site(s) 
of recurrence and management plan will be required (surgical resection, 
chemotherapy, radiation, best supportive care, etc). 
 
Chemotherapy administration:  See Appendix II for GOG General 
Chemotherapy Guidelines. 
 
 
The initial recommended pre-medication for the docetaxel is:  
dexamethasone 8 mg orally X 2 doses the day prior to chemotherapy (Day 
7), and 8 mg orally twice daily for the next 2 days (Days 8-9).  The 
dexamethasone dosing schedule may be adjusted at the discretion of the 
treating physician. 
 
Patients who develop peripheral edema as a side effect of docetaxel 
and/or gemcitabine may be treated with diuretics at the discretion of the 
treating physician.  Recommended treatment for edema includes starting 
with Hydrochlorothiazide/triamterene (25/37.5) or (25/50) up to 3 times a 
day, or hydrochlorothiazide (HCTZ) 25-50 mg once or twice daily.  
Furosemide may be used if Hydrochlorothiazide/triamterene or HCTZ 
does not adequately control the edema. 
 
REGIMEN II: (10/28/2013) 
Observation only 
 
RN (nurse) or MD (physician) telephone call every 3-4 weeks for 
approximately 24 weeks to document patient-reported toxicities or adverse 
events (see Section 7.1, Regimen II table). 
 
CT chest/abdomen/pelvis (or CT chest +MRI abdomen/pelvis) imaging 
after 3 to 4 months from study entry to confirm continued no evidence of 
disease. 
 
Continue with observation if there is no evidence of disease. 


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Follow-up: 
Follow patients for recurrence by physical examination and CT 
chest/abdomen/pelvis (or CT chest +MRI abdomen/pelvis) imaging every 
4 months from study entry until 3 years out from the start of study 
treatment, then every 6 months for the next 2 years.  There is a maximum 
of 5 years of imaging for detection of first recurrence. 
 
At time of documented recurrence:  management of recurrent disease will 
be at the discretion of the treating physician.  Documentation of the site(s) 
of recurrence and management plan will be required (surgical resection, 
chemotherapy, radiation, best supportive care, etc). 
 
5.3 
Criteria for removal from treatment 
 
5.31 
Inability to tolerate the lowest doses because of toxicity. 
 
5.32 
Disease recurrence which is defined by RECIST in section 8. 
 
5.33 
Patients may refuse further intervention or completely withdraw consent 
from the study at any time for any reason.  If a patient elects to discontinue 
further study treatment and/or intervention prior to documentation of 
recurrent disease and elects to receive alternate therapy, this information 
should be specifically documented as consent allows. 
 
 
 
 


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6.0 
TREATMENT MODIFICATIONS    
 
Note: Version 4.0 of the NCI Common Terminology for Adverse Events (CTCAE) is the 
reference for all grade specifications included in this study’s dose modification sections.  
 
6.1 
Gemcitabine and Docetaxel Dose level definitions  
 
 
 
 
 
 
 
 
6.2 
Doxorubicin Dose level definitions: (10/28/2013) 
 
 
 
 
 
 
Note: Patients who require a dose reduction because of a toxicity meeting criteria 
below are permitted ONE dose reduction.  If toxicity recurs of a severity that 
would require another dose reduction, a second dose reduction is NOT permitted.  
Instead, treatment with the regimen that caused the additional toxicity should be 
discontinued. 
 
6.3 
Hematologic toxicity during EITHER gemcitabine + docetaxel OR doxorubicin 
(10/28/2013) 
 
6.31 
Initial treatment modifications will consist of cycle delay and/or dose 
reduction as indicated below.  The use of hematopoietic cytokines and 
protective reagents are restricted as noted: 
 
6.311 Patients will receive prophylactic growth factors [filgrastim (G-
CSF), or pegfilgrastim (Neulasta)] on Day 9 of each cycle of 
treatment with gemcitabine + docetaxel as detailed in Section 5.2. 
Use of [filgrastim (G-CSF), or pegfilgrastim (Neulasta)] on Day 2 
of treatment with doxorubicin is optional. 
 
6.312 Patients will NOT receive prophylactic thrombopoietic agents 
unless they experience recurrent Grade 4 thrombocytopenia after 
treatment modifications as specified below. 
 
6.313 Patients may receive erythropoietin (EPO), iron supplements, and/or 
transfusions as clinically indicated for management of anemia. 
Study Drug                     1 Level reduction                  Initial dose level 
 
Gemcitabine 
675 mg/m2over 70-90  
minutes  
900 mg/m2 over  90  minutes   
Docetaxel 
60 mg/m2 
75 mg/m2 
Study Drug    1 Level reduction Initial dose level 
 
Doxorubicin 45 mg/m2 
60 mg/m2 


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Treating physicians should be aware of the recent changes in 
prescribing information for the erythropoiesis stimulating agents 
(including Aranesp, Epogen and Procrit); this information notes a 
potential risk of shortening the time to tumor progression or disease-
free survival and recommends that these agents be administered only 
to avoid red blood cell transfusions. They do not alleviate fatigue or 
increase energy. They should not be used in patients with 
uncontrolled hypertension. They can cause an increased incidence of 
thrombotic events in cancer patients on chemotherapy. The updated 
package inserts should be consulted.  
 
6.314 Patients may NOT receive amifostine or other protective reagents, 
as this would be considered a protocol violation.  
 
6.32 
Treatment decisions will be based on the absolute neutrophil count (ANC) 
rather than the total white cell count (WBC). 
 
6.33 
Subsequent cycles of therapy will not begin until the ANC is ≥ 1000 /mcl 
(ANC ≥ 1.0 x 109/liter (L). and the platelet count is ≥ 100,000/mcl (100 x 
109/L) Gemcitabine and docetaxel, or doxorubicin (whichever is 
applicable) will be delayed for a maximum of two weeks until these values 
are achieved.  Patients whose counts fail to recover adequately within a 
two week delay will not receive further study treatment with that regimen.  
If the patient was on the gemcitabine + docetaxel section of the adjuvant 
treatment, and the ANC and platelets recover after no longer than a 3 week 
delay, the patient may proceed on to the doxorubicin portion of the study.  
If again there is a failure to recover ANC and platelets within a 2 weeks 
delay during treatment with doxorubicin, then study treatment will be 
discontinued. 
 
6.34   For first occurrence of febrile neutropenia (ANC < 1,000/mcl and fever > 
38.5 C), and/or documented Grade 4 neutropenia persisting ≥ 7 days, OR 
Grade 3 thrombocytopenia (platelet count 25,000 to < 50,000/mcl) that is 
associated with bleeding or need for transfusion, OR Grade 4 
thrombocytopenia (platelet count < 25,000/mcl), reduce the doses of both 
gemcitabine and docetaxel, or doxorubicin (whichever is applicable), by 
one dose level on all subsequent cycles.   For a second episode of febrile 
neutropenia occurring despite dose reduction with the current regimen, 
treatment with that regimen should be discontinued. As in section 6.23, if 
the febrile neutropenia events occurred during treatment with gemcitabine 
+ docetaxel, and patient has recovered from the toxicity after no longer 
than a 3 week delay, the patient may proceed on to the doxorubicin portion 
of the study.  If the patient experiences a febrile neutropenia event during 
doxorubicin, study treatment should be discontinued. 
 


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If treatment with gemcitabine + docetaxel is stopped for toxicity, the 
patient may proceed on to treatment with doxorubicin provided blood 
counts, liver function, and other toxicities permit chemotherapy treatment 
with doxorubicin within 3 weeks of the discontinuation of the gemcitabine 
+ docetaxel. 
 
There will be no dose modifications on the basis of uncomplicated 
granulocyte nadirs lasting less than 7 days. 
 
6.35 
In addition to the dose modifications listed above Day 8 Gemcitabine 
and Docetaxel dose adjustments should be made according to the table 
below: 
 
Study Drug 
ANC ≥ 1000/mcl AND 
Plt ≥ 100,000/mcl 
ANC 500-999/mcl 
OR Plt 50,000-
99,000/mcl 
ANC < 500/mcl 
OR  
Plt < 50,000/mcl 
Gemcitabine 
100% of dose 
For patients at the 
initial dose level of 
Table 6.1, give 675 
mg/m2 over 70-90 
minutes. 
For patients at the 1 
level dose reduction 
dose of Table 6.1, 
give 500 mg/m2   
Omit on day 8 
Docetaxel 
100% of dose 
For patients at the 
initial dose level of 
Table 6.1, give 60 
mg/m2.   
For patients at the 1 
level dose reduction 
dose of Table 6.1, 
give 50 mg/m2  
Omit on day 8 
 
Note:  ANC (absolute neutrophil count) >1000/mcl = ANC 1.0 x 109/liter (L). 
Plt (platelets) ≥ 100,000/mcl = Plt 100 x 109/L. 
 
Dose reduction on Day 8 does not count as one of the two permitted 
protocol dose reductions for toxicity.  The next cycle may be started at 
previous doses, provided that blood counts have recovered as detailed in 
6.23.  If a dose reduction is required on Day 8 of a cycle, subsequent Day 
8 doses should only be reduced in subsequent cycles if the criteria for 
reduction or omission of the day 8 doses are met on that cycle’s Day 8 of 
treatment. 
  


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6.4 
Hepatic Dysfunction during gemcitabine + docetaxel (10/28/2013) 
 
6.41 
If bilirubin increases to greater than institutional upper limits of normal 
when checked on Day 1, repeat the bilirubin on or prior to Day 8, prior to 
giving the docetaxel.  If the bilirubin has returned to normal, proceed with 
docetaxel on Day 8.  If the bilirubin remains greater than institutional 
normal limits on Day 8, give only gemcitabine on Day 8.  The patient will 
thus receive no docetaxel that cycle.  If the bilirubin does not recover by 
Day 8 of the next cycle, study treatment may be continued but will 
continue without docetaxel until the bilirubin returns to within institutional 
normal limits.  If the bilirubin returns to within institutional normal limits, 
the docetaxel may be added back to the regimen.     
 
6.42 
Elevations of 5 x ULN or higher in SGOT (AST), SGPT (ALT), or 
alkaline phosphatase requires delay in subsequent study treatment for a 
maximum of 2 weeks until recovered to less than or equal to 2.5 x ULN, 
AND reduction of one dose level for all subsequent cycles.  Treatment 
with gemcitabine and docetaxel will be discontinued in patients whose 
SGOT (AST), SGPT (ALT), or alkaline phosphatase elevations fail to 
recover to less than or equal to 2.5 x ULN within 2 weeks.   
 
6.5 
Hepatic Dysfunction during doxorubicin (10/28/2013) 
 
If bilirubin increases to greater than 1.5 x institutional upper limits of normal, 
delay the doxorubicin by up to 2 weeks.  If the bilirubin does not recover after 
two weeks delay, the patient will be removed from study treatment. 
6.6 
Hypersensitivity reactions to Docetaxel (10/28/2013) 
 
There are no dose reductions for hypersensitivity reactions. 
 
MANAGEMENT OF ACUTE HYPERSENSITIVITY TO DOCETAXEL 
Severity of Symptoms 
Treatment Guidelines 
Mild symptoms: localized cutaneous reactions 
such as mild pruritus, flushing, rash 
Consider decreasing the rate of infusion until recovery from 
symptoms, stay at bedside and monitor patient; 
then, complete docetaxel infusion at the initial planned rate 
Moderate symptoms: any symptom that is not 
listed above (mild symptoms) or below (severe 
symptoms) such as generalized pruritus, 
flushing, rash, dyspnea, hypotension with 
systolic BP > 80 mm Hg 
 
Interrupt docetaxel infusion 
Give diphenhydramine 50 mg IV with or without dexamethasone 10 
mg IV; monitor patient until resolution of symptoms  
Resume docetaxel infusion after recovery of symptoms; depending 
on the physician’s assessment of the patient, docetaxel infusion 
should be resumed at a slower rate, then increased incrementally to 
the initial planned rate, (e.g. infuse at an 8 hour rate for 5 minutes, 
then at a 4-h rate for 5 minutes, then at a 2-h rate for 5 minutes, 
then finally, resume at the initial planned rate. 
Depending on the intensity of the reaction observed, additional oral 
or IV pre-medication with an antihistamine should also be given for 
the next cycle of treatment, and the rate of infusion should be 
decreased initially and then increased back to initial planned rate, 
(e.g. infuse at an 8 hour rate for 5 minutes, then at a 4-h rate for 5 


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minutes, then at a 2-h rate for 5 minutes, and finally, administer at 
the initial planned rate.) 
Severe symptoms: any reaction such as 
bronchospasm, generalized urticaria, systolic BP 
≤ 80mm Hg, angioedema 
Immediately discontinue docetaxel infusion  
Give diphenhydramine 50 mg IV with or without dexamethasone 10 
mg IV and/or epinephrine as needed; monitor patient until 
resolution of symptoms 
The same treatment guidelines outlined under moderate symptoms 
(i.e. the third and fourth bullets) should be followed. 
Anaphylaxis (NCI grade 4 reaction) 
NO FURTHER DOCETAXEL THERAPY.  Patients can continue 
gemcitabine on study. 


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6.7 
Other Non-hematologic toxicity likely attributable to gemcitabine and/or 
docetaxel or doxorubicin (10/28/2013) 
 
6.71 
In the event of Grade 3 or 4 neurotoxicity, treatment will be delayed 1 
week.   
      
If neurotoxicity has resolved to less than or equal to Grade 1, then the 
patient may continue on study with docetaxel dose reduction of one dose 
level in the current and all subsequent cycles (no dose adjustment is 
required for gemcitabine).   
 
If the Grade 3 or 4 neurotoxicity has not resolved to less than or equal to 
Grade 1 after a two-week delay, the docetaxel will be discontinued.  
Patients will continue to receive gemcitabine.  
 
A patient who presents with Grade 2 peripheral neuropathy requires a 
docetaxel dose reduction of one dose level and delay in subsequent 
therapy for a maximum of 2 weeks until recovery to Grade 1.  If the 
patient is re-treated with a docetaxel dose reduction after recovery from a 
Grade 2 peripheral neuropathy, the dose reduction should remain in the 
current and all subsequent cycles. 
 
6.72 
Grade 2 (or greater) renal toxicity requires reduction of one dose level for 
gemcitabine and for docetaxel and delay in subsequent therapy for a 
maximum of 2 weeks until recovered to Grade 1.  Discontinue both 
gemcitabine and docetaxel (or doxorubicin, if applicable) when Grade 2 or 
worse renal toxicity does not recover to Grade 1 or less.  Since renal 
toxicity is generally not considered a toxicity of doxorubicin, no dose 
reduction for doxorubicin is required, unless, in the judgment of the 
treating physician, the doxorubicin was considered the cause of the renal 
toxicity. (10/28/2013) 
 
HUS (hemolytic uremic syndrome):  The diagnosis of HUS should be 
considered if the patient develops hemolytic anemia with evidence of 
microangiopathic hemolysis as indicated by elevation of indirect bilirubin 
or LDH, reticulocytosis, severe thrombocytopenia, and/or evidence of 
renal failure (elevation of serum creatinine of BUN). Gemcitabine therapy 
should be discontinued immediately. Renal Failure associated with HUS 
may not be reversible even with discontinuation of therapy and dialysis 
may be required.  Patients who develop HUS requiring intervention should 
be removed from study treatment. 
6.73 
There will be no dose modifications for alopecia or fatigue. 
 
6.74 
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 


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of one dose level for both gemcitabine and docetaxel if the toxicity occurs 
during the gemcitabine + docetaxel treatment, and for doxorubicin if the 
toxicity occurs during the doxorubicin treatment, and delay in subsequent 
study treatment for a maximum of 2 weeks until recovered to Grade 1. 
 
6.75 
Other non-hematologic toxicities (including mucositis) with an impact on 
organ function of Grade 2 (or greater) require reduction of one dose level 
for both gemcitabine and docetaxel if the toxicity occurs during the 
gemcitabine + docetaxel treatment, and for doxorubicin if the toxicity 
occurs during the doxorubicin treatment, and delay in subsequent study 
treatment for a maximum of 2 weeks until recovered to Grade 1, or pre-
therapy baseline. 
 
6.76 
In patients who develop Grade 4 edema considered likely related to 
gemcitabine and/or docetaxel, gemcitabine and docetaxel will be 
discontinued.  
 
 


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7.0 
STUDY PARAMETERS   
 
7.1 
Observations and Tests 
 
For patients on REGIMEN I Gemcitabine + Docetaxel x 4 cycles, followed by 
Doxorubicin x 4 cycles:   
The following observations and tests are to be performed and recorded on the appropriate 
form(s)  
 
PARAMETER 
 
 
Baseline, 
pre- 
treatment 
(10/28/2013) 
Day 8 of 
treatment 
with 
Gemcitabine
/docetaxel 
 
Prior to each 
cycle of 
chemotherapy  
After 4 
cycles 
Gemcitabine/
docetaxel  
Follow up (until 
evidence of disease 
recurrence) every 4 
months for 3 yrs, then 
every 6 months for 2 
years]† 
History & Physical 
1 
 
X 
 
5 
Review of 
concurrent 
medications 
1 
 
X 
 
 
Serum Pregnancy 
Test (for patients of 
childbearing 
potential) 
6 
 
 
 
 
Electrocardiogram 
1 
 
 
 
 
Toxicity Assessment 
3 
 
X 
 
 
CBC/Diff/ platelets 
3 
X 
X 
 
 
Albumin, Total 
Bilirubin, AST, 
ALT, Alkaline 
Phosphatase 
3,7 
7 
X 
 
 
Electrolytes, BUN, 
creatinine) 
3 
 
X 
 
 
CT chest/abdomen/ 
pelvis or CT chest + 
MRI 
abdomen/pelvis  
2 
 
 
8 
5 
ECHO/MUGA scan 
(10/28/2013) 
4 
 
 
 
 
†       Protocol-specified imaging studies should continue until disease progression or until patient is 
put on non-protocol cancer therapy.  Follow-up for SURVIVAL status should continue for a 
minimum of 5 years from time of study entry, regardless of whether patient has recurred or 
not. 
 
1. Must be obtained within 28 days prior to initiating protocol therapy. 


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2.   CT c/a/p is preferred as there is less reader variation among centers.  Baseline imaging to confirm no 
evidence of disease prior to enrollment should be done within 4 weeks of enrollment. 
3. Must be obtained within 14 days prior to initiating protocol therapy. 
4. Documentation of  cardiac ejection fraction is only required for patients assigned to the chemotherapy 
arm and may have been done up to six months prior to initiation of study treatment. (10/28/2013) 
5. Follow patients by physical examination and CT chest/abdomen/pelvis (or CT chest +MRI 
abdomen/pelvis) imaging every 4 months from study entry until 3 years out from the start of study 
treatment, then every 6 months for the next 2 years.  There is a maximum of 5 years of imaging for 
detection of first recurrence.  Patients who stop study treatment prior to completion of all planned 
chemotherapy for reasons of toxicity or for any reason (other than withdrawal of consent) should 
continue with every 4 month imaging to determine date of first recurrence. 
6.  Obtain within 48 hours prior to patient enrolling into study. 
7. Bilirubin should be repeated on or before Day 8 if abnormal on Day 1 of the 4 cycles of 
Gemcitabine/ docetaxel. 
8.   The CT scan that occurs after the 4th cycle of gemcitabine + docetaxel should occur approximately 4 
months from study enrollment.  If a patient stops gemcitabine + docetaxel prior to cycle 4, and plans 
to proceed on to doxorubicin treatment, no CT is needed until approximately 4 months from study 
enrollment. 
 
 


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For patients on REGIMEN II-observation: 
The following observations and tests are to be performed and recorded on the appropriate 
form(s)
PARAMETER 
 
 
Baseline, 
pre-
enrollment 
Every 3 -4 
weeks for  
months 1-3 
on study 
At 
approximately 
4 months from 
enrollment 
Every 3 -4 
weeks for  
months 3-6 on 
study 
Follow up (until 
evidence of disease 
recurrence) every 4 
months for 3 yrs, then 
every 6 months for 2 
years]† 
History & 
Physical 
1 
 
X 
 
5 
Review of 
concurrent 
medications 
1 
 
X 
 
 
Serum Pregnancy 
Test (for patients 
of childbearing 
potential) 
6 
 
 
 
 
 
Electrocardiogram 
1 
 
 
 
 
Toxicity 
Assessment 
3 
4 
X 
4 
 
CBC/Diff/ 
platelets 
3 
 
X 
 
 
Albumin, Total 
Bilirubin, AST, 
ALT, Alkaline 
Phosphatase 
3 
 
X 
 
 
Electrolytes, 
BUN, creatinine) 
3 
 
X 
 
 
CT 
chest/abdomen/ 
pelvis or CT chest 
+ MRI 
abdomen/pelvis  
2 
 
X 
 
5 
MD or RN 
telephone call  
 
4 
 
4 
 
†       Protocol-specified imaging studies should continue until disease progression or until patient is put on 
non-protocol cancer therapy.  Follow-up for SURVIVAL status should continue for a minimum of 5 
years from time of study entry, regardless of whether patient has recurred or not. 
 
1. Must be obtained within 28 days prior to initiating protocol therapy. 
2.   CT c/a/p is preferred as there is less reader variation among centers.  Baseline imaging to confirm no evidence 
of disease prior to enrollment should be done within 4 weeks of enrollment. 
3. Must be obtained within 14 days prior to initiating protocol therapy. 
4. Approximately every 3 to 4 weeks, for the first 6 months from enrollment, an RN or MD should obtain vital 
status, and report of any toxicities from patient by phone or by office visit evaluation. 
 
 


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5. Follow patients by physical examination and CT chest/abdomen/pelvis (or CT chest +MRI abdomen/pelvis) 
imaging every 4 months from study entry until 3 years out from the start of study treatment, then every 6 
months for the next 2 years.  There is a maximum of 5 years of imaging for detection of first recurrence. 
6.  Obtain within 48 hours prior to patient enrolling into study. 


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7.2 
Stained Pathology Slide Requirements for Central Review to Confirm Eligibility 
 
NOTE: The following details about GOG review of pathology apply to GOG 
participants.  For details about submission of slides and pathology review for EORTC 
and NCRN participants, please see the EORTC and NCRN specific appendices. 
 
Stained pathology slides are required for central review by the GOG pathology 
committee to confirm eligibility.  At least one H&E stained slide is required: 1) at least 
one representative H&E stained slide demonstrating the primary high grade uterine 
leiomyosarcoma with adequate mitotic rate, nuclear atypia and tumor necrosis (if 
present),  
 
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 stained slides, pathology reports and Form F to the GOG 
Statistical and Data Center.  Please see sections 4.6 and 10.2 for additional requirements 
and instructions. 
 
7.3 
Translational Research 
 
 
Not Applicable 
 
7.4 
Quality of Life (10/28/2013) 
 
 
 
 
Not Applicable 
 
 


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8.0 
EVALUATION CRITERIA   
 
8.1 
Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (Version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
8.11 Disease Parameters 
 
 
This is a study of adjuvant therapy.  All patients must have no evidence of 
measurable disease on baseline imaging in order to be eligible for this study.   
 
 
Malignant lymph nodes:  To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
 
 
 
Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts.   
 
8.12 
Methods for Evaluation of Disease 
 
All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.  In this study of adjuvant therapy, baseline imaging should be 
performed no longer than 28 days prior to study enrollment. (10/28/2013) 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
Chest x-ray: Chest CT is required for thoracic disease surveillance on this study.  
 
 


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Conventional CT and MRI: While CT is preferred, MRI is also acceptable in 
certain situations (e.g., for body scans), but NOT lung.   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement.  Furthermore, the availability of MRI is variable globally.  As with 
CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of 
disease.  Furthermore, as with CT, the modality used at follow-up should be the 
same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, 
and diseases.  Ideally, subsequent image acquisitions should use the same type of 
scanner and follow the baseline imaging protocol as closely as possible.  If 
possible, body scans should be performed with breath-hold scanning techniques. 
 
PET-CT: At present, the low-dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  PET-CT scans are not always done with oral and IV 
contrast.  In addition, the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.  For these 
reasons, the GOG will not allow PET-CT use for RECIST 1.1 response 
criteria. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible 
“new” disease).  New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm:  
a. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
b. 
No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.  If the positive FDG-PET at follow-up is not 
confirmed as a new site of disease on CT, additional follow-up CT  scans 
are needed to determine if there is truly progression occurring at that site 
(if so, the date of PD will be the date of the initial abnormal FDG-PET 
scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
 
 Note:  A “positive” FDG-PET scan lesion means one that is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation 
corrected image. 


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Ultrasound: Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken 
from one assessment to the next.  If new lesions are identified by ultrasound in the 
course of the study, confirmation by CT or MRI is advised.  If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected 
instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 
 
Cytology, Histology: It is mandatory to obtain cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment.  This 
confirmation is necessary to differentiate recurrent disease from a side effect of 
the treatment. 
 
8.13 
 
Response Criteria 
 
This is a study of adjuvant therapy and thus, by eligibility criteria, all patients will 
have no evidence of disease at time of enrollment.  There will be no evaluation for 
CR or PR since patients will not have measurable disease.   
 
 
However, RECIST will be used to determine whether there is radiographic 
evidence of recurrence. 
 
8.14 
Recurrence 
 
 
Recurrence is defined as newly evident disease for patients who have no evidence 
of disease at baseline.  
 
 


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8.15 
Recurrence-Free Survival 
 
 
Recurrence-Free Survival (RFS) is defined as the duration of time from study 
entry to time of recurrence or death, whichever occurs first. 
 
8.16 
Survival 
 
 
Survival is defined as the duration of time from study entry to time of death or the 
date of last contact. 
 
8.17 
Adverse Events 
 
 
Adverse events will be categorized and graded according to NCI Common 
Terminology Criteria for Adverse Events version 4.0.   
 
 


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9.0 
DURATION OF STUDY    
 
 
9.1 
Patients on Regimen I will receive therapy for a maximum of 8 cycles (4 cycles of 
gemcitabine + docetaxel, followed by 4 cycles of doxorubicin) or until disease recurrence 
or toxicity intervenes.   
 
9.2 
A patient is considered off study treatment when the patient has recurred or died, 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.  Patients on the observation arm, 
Regimen II, are considered off study treatment at the end of 24 weeks from study entry.  
Patients who are considered off study treatment remain on study in terms of follow-up for 
evidence of recurrence and for survival status. 
 
9.3 
Patients will be followed for recurrence with physical exam, histories and imaging until 
recurrence, death or five years of follow-up is reached.  If there is evidence of disease 
recurrence, patients will continue to be followed for survival for at least 5 years from 
study entry.  Patients will be monitored for non-protocol therapy, serious delayed toxicity 
and survival for this 5 year period with Q forms submitted to the GOG Statistical and 
Data Center, unless consent is completely withdrawn. 
 
9.4 
Patients can refuse study treatment at any time, but can continue to be followed for 
evidence of recurrence or death as consent allows.  
 
 


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10.0 
STUDY MONITORING AND REPORTING PROCEDURES   
 
10.1 
ADVERSE EVENT REPORTING FOR A COMMERCIAL AGENT 
   
10.11 Definition of Adverse Events (AE) 
 
NOTE: The following details about GOG reporting of Adverse Events apply to 
GOG participants.  For details about Adverse Event reporting for EORTC and 
NCRN participants, please see the EORTC and NCRN specific appendices. 
 
An adverse event (AE) is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease that occurs in a patient 
administered a medical treatment, whether the event is considered related or 
unrelated to the medical treatment.  
 
The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized 
for AE reporting. All appropriate treatment areas should have access to a copy of 
the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP web site (http://ctep.cancer.gov). The CTCAE v4.0 Manual is also 
available on the GOG member web site (http://www.gog.org under MANUALS). 
 
10.12 Reporting Expedited Adverse Events 
 
 
Depending on the phase of the study, use of investigational or commercial agents, 
and role of the pharmaceutical sponsor, an AE report may need to reach multiple 
destinations.  For patients participating on a GOG trial, all expedited AE reports 
should be submitted by using the CTEP automated system for expedited reporting 
(AdEERS).  All AdEERS submissions are reviewed by GOG before final 
submission to AdEERS.  Submitting a report through AdEERS serves as 
notification to GOG, and satisfies the GOG requirements for expedited AE 
reporting.  All adverse reactions will be immediately directed to the Study Chair 
for further action. 
 
 
The requirement for timely reporting of AEs to the study sponsor is specified in 
the Statement of Investigator, Form FDA-1572.  In signing the FDA-1572, the 
investigator assumes the responsibility for reporting AEs to the NCI.  In 
compliance with FDA regulations, as contained in 21 CFR 312.64, AEs should be 
reported by the investigator. 
 
10.13 Phase 2 and 3 Trials Utilizing a Commercial Agent:  AdEERS Expedited 
Reporting Requirements for Adverse Events That Occur Within 30 Days of the 
Last Dose of Any Commercial Study Agent (10/28/2013)  


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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 
G
Unexpected  
and Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected E
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 
C
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 
C
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last d
treatment with a commercial agent require reporting as follows: 
AdEERS 24-hour notification followed by complete report within 3 calendar days for: 
• Grade 4 and Grade 5 unexpected events  
      AdEERS 7 calendar day report: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• Grade 5 expected events 
 
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a fu
is required as outlined in the table. 
 
 Please see exceptions below under the section entitled, “Additional Instructions or Exceptions to AdEERS
Expedited Reporting Requirements for Phase 2 and 3 Trials Utilizing a Commercial Agent.”          March 
 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
• 
Expedited AE reporting timelines defined: 
 
“24 hours; 3 calendar days” – The investigator must initially report the AE via 
AdEERS within 24 hours of learning of the event followed by a complete 
AdEERS report within 3 calendar days of the initial 24-hour report. 
“7 calendar days” – A complete AdEERS report on the AE must be submitted within 7 
calendar days of the investigator learning of the event. 
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-
specific expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported to GOG via AdEERS if 
the event occurs following treatment with a commercial agent. 


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• 
Use the NCI protocol number and the protocol-specific patient ID provided 
during trial registration on all reports. 
 
Additional Instructions or Exceptions to AdEERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing a Commercial Agent: 
 
The following events should be excluded from AdEERS reporting although they 
should still be reported on the routine AE CRFs: 
 
Grade 3 or 4 thrombosis/thrombus/embolism that does not require hospitalization 
Grade 3 or 4 neutrophils, anemia, thrombocytopenia that does not require 
hospitalization 
Grade 3 or 4 nausea, diarrhea, fatigue that does not require hospitalization 
Docetaxel hypersensitivity reactions that are mild or moderate (grade 2 or 3) but 
which do not require hospitalization.  Grade 4 (anaphylaxis) reaction DO require 
reporting regardless of whether or not hospitalization is required. 
Grade 3 elevations in AST, ALT, alkaline phosphatase, bilirubin that do not 
require hospitalization. 
 
 
10.14 Procedures for Expedited Adverse Event Reporting: 
 
10.141 AdEERS Expedited Reports: Expedited reports are to be submitted using 
AdEERS available at http://ctep.cancer.gov. The CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements for expedited adverse event 
reporting requirements are also available at this site.  
 
 
AML/MDS events must be reported via AdEERS (in addition to 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. 
 
 
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 AdEERS forms have 
been removed from the CTEP website and will NO LONGER be accepted. 
  
10.15 Automated CDUS reporting  
 
 
This study will be monitored by the Clinical Data Update System (CDUS) version 
3.0. Cumulative CDUS data will be submitted quarterly to CTEP by electronic 
means.  Reports are due January 31, April 30, July 31 and October 31. 
 
 


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10.2  GOG DATA MANAGEMENT FORMS 
 
The following GOG forms must be completed for all patients registered and submitted to 
the GOG Statistical and Data Center (SDC) in accordance with the schedule below.  
GOG Protocol forms and instructions can be submitted through or printed from the SDC 
Electronic Data Entry System (SEDES) online application found at the GOG Web Menu 
page. 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. Pathology material (Form F, pathology reports and 
slides) should be submitted together via mail. The GOG Uploader Application in SEDES 
is an alternate method for submitting Form BDR, operative reports, Form F and 
pathology reports to the GOG SDC. 
Form∆ 
Due within 
Copies* 
Comments 
Weeks 
Event 
Form R (Registration 
Form) 
 
2 
Registration 
1 
Mandatory Submission via SEDES 
Form OSU (Uterine Cancer 
- On Study Form) 
2 
Registration 
1 
Mandatory Submission via SEDES 
Form C (Surgical Reporting 
Form) 
Operative report  
Discharge summary 
6 
 
6 
6 
Registration 
 
Registration 
Registration 
1 
 
2 
2 
Mandatory Submission via SEDES  
Submit via postal mail or upload 
online via SEDES labeled with patient 
identifier 
Form DR (Pre-Treatment 
Summary Form) 
 
2 
Registration 
1 
Mandatory Submission via SEDES 
Form D2M (Solid Tumor 
Evaluation Form) - baseline 
4 
Registration 
1 
Mandatory Submission via SEDES 
Primary disease: 
Form F 
Pathology Report 
Slides   
 
6 
6 
6 
 
Registration 
Registration 
Registration 
 
2 
2 
** 
 
Submit together to SDC via postal 
mail 
 or upload online via SEDES** 
Form D2R (Cycle Dose 
Drug Form) 
2 
Completion of each 
cycle of therapy 
(Regimen I only) 
1 
Mandatory Submission via SEDES 
Form D2M (Solid Tumor 
Evaluation Form) 
2 
each disease 
assessment 
1 
Mandatory Submission via SEDES 
Form T (Common Toxicity 
Reporting Form) 
2 
Beginning of each 
subsequent cycle for 
patients on Regimen I 
(chemotherapy) and 
every 3-4 weeks for 
months 1-6, using 
patient telephone call, 
for patients on 
Regimen II 
1 
 
Mandatory Submission via SEDES 


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(observation) 
Form Q0 (Treatment 
Completion Form) 
2 
Completion of study 
Rx and change in Rx 
1 
Mandatory Submission via SEDES 
Form Q (Follow-Up Form) 
 
2 
Disease progression; 
death; normal follow-
up 
1 
every 4 months for 3 years, then every 
6 months for 2 years or more,  
 
* 
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 4.6 and 7.2 for additional requirements and mailing instructions. 
 
This study will be monitored by the Abbreviated Clinical Data System (CDUS) Version 3.0 CDUS data 
will be submitted by the January 31, April 30, July 31 and October 31 due dates to CTEP by 
electronic means. 
 


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11.0 
STATISTICAL CONSIDERATIONS   
 
11.1 
Study Design and Treatment Randomization   
 
The study is designed as a two arm open label randomized phase III superiority trial with 
an observation only control arm, Regimen II, and experimental arm of multi-agent 
chemotherapy (Regimen I, 4 cycles of gemcitabine and docetaxel followed by 4 cycles of 
doxorubicin).  The design will provide a direct assessment of the null hypothesis that 
multi-agent adjuvant chemotherapy offers no increase in survival when compared with 
observation until recurrence.   
 
Prior to patient registration, eligibility will be reviewed by Fast Fact Sheet verification.  
The sequence of treatment assignments will be concealed from institutions and patients 
until registration with verification of eligibility.   Patients will be registered by the 
participating site through OPEN and randomization will be carried out centrally by the 
GOG Statistical and Data Center.  The randomization will be stratified country of treating 
site using a minimization procedure that tends to allocate two study arms in a ratio of 1 to 
1 within strata. 
 
Reports and publications will include a complete accounting of all patients registered to 
this study.   
 
11.2 
Efficacy and toxicity measures 
 
The principal observations for evaluating the therapeutic efficacy and safety of treatments 
are listed below (see Section 8 for definitions). 
 
11.21 Primary efficacy endpoint: overall survival 
 
11.22 Interim futility endpoint:  recurrence-free survival 
 
11.23 Safety endpoints:  frequency and severity of adverse events 
 
11.3 
Statistical study design and planned analyses of therapeutic efficacy 
 
11.31 Accrual goal:  216 patients are targeted for enrollment on this study. 
 
11.32 Accrual rate:  3 patients per month from GOG sites (10/28/2013) 
 
 
There were 47 patients enrolled on SARC005 (a prospective phase 2 trial of 
adjvant gemcitabine-docetaxel followed by doxorubicin for high-grade, uterus-
limited leiomyosarcoma) in less than 3 years.  It is expected that accrual through 
GOG would potentially be superior to that seen on the SARC trial.  Based on data 
from GOG-0250, a randomized phase III evaluation of docetaxel and gemcitabine 
plus G-CSF with bevacizumab versus docetaxel and gemcitabine plus G-CSF  


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with placebo in the treatment of recurrent or advanced leiomyosarcoma of the 
uterus, the accrual from November 13, 2010 through May 12, 2011 was 23 
patients.  Furthermore, 47% of patients enrolled on GOG-0250 at the time of 
recurrence were originally diagnosed with early stage leiomyosarcoma.  
Assuming that this accounts for 60% of early stage patients, then we can expect at 
least (0.47*3.8*12/.6) 36 patients per year from the GOG.  International 
collaboration with EORTC and NCRN (as agreed at NCI-EORTC-NCRN Rare 
Tumor Initiative meeting, June 2011) will likely increase the accrual rate to over 3 
patients per month.   
 
EORTC estimates their annual accrual to be no more than 30 patients and NCRN 
estimates accrual to be no more than 20 patients per year. (10/28/2013) 
 
11.33 Study duration:   
 
 
With an average accrual rate of 36 patients per year, the study accrual time would 
be 72 months to enroll 216 patients followed by 16 additional months of follow-
up.  Thus the total study duration is planned as 88 months.  If the accrual rate is 
increased to 3.75 patients per month, the study accrual time would be 58 months 
to enroll 216 patients with a maximum study duration of 79 months.   
 
Accrual and Study Duration (10/28/2013) 
For various annual accrual rates and target sample size fixed at 216 
 
 
Annual accrual 
Accrual duration 
in months 
Study duration in 
months 
86 
30 
63 
72 
36 
66 
60 
43 
70 
48 
54 
77 
36 
72 
88 


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11.34 Primary hypothesis:  The null hypothesis to be tested is that multi-agent adjuvant 
chemotherapy offers no increase in survival time when compared with 
observation until recurrence. 
 
H0:  λc / λe  ≤  1 vs. H1:  λc / λe  >  1 
 
In this statistical representation of the primary hypothesis, λc represents the death 
hazard rate on the observation arm; λe represents the death hazard rate on the 
multi-agent adjuvant chemotherapy arm. 
 
11.341 Effect size:  A hazard ratio (HR), control to experimental, of 1.6 would be 
of clinical interest.  This translates to an absolute difference of 15.5% at 3 
years (46% vs. 61.5%) in overall survival.   
 
11.342 Type I error for superiority:  0.05, one tail test. 
 
11.343 Statistical power:  0.80 calculated under the alternative that λc / λe =  1.6 
 
11.344 Additional assumptions:  Overall and recurrence-free survival data from 
patients diagnosed with early stage leiomyosarcoma enrolled on GOG 40 
are used as the basis for determining sample size and duration of follow-
up.  The death rate is initially high but dissipates somewhat over time with 
approximately 23% alive after 6 years and 24% alive, recurrence-free after 
5 years.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall Survival 
 
Cumulative percent of 
patients alive 
Cumulative percent of 
patients alive 
Months 
Control Arm 
Experimental Arm (HR=1.6) 
6 
96 
97 
12 
84 
90 
24 
65 
76 
36 
46 
62 
48 
38 
55 
60 
31 
48 
72 
23 
40 


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11.35 Primary analysis: The intention-to-treat principle will be applied in the primary 
analysis comparing the distribution of time to death with censoring between 
assigned treatment arms.  The logrank test will be used to test the null hypothesis 
of independence between survival and randomized treatment.  Kaplan-Meier 
estimates will be used to graph survival distribution curves for each treatment 
arm.  The death hazard ratio (experimental to control) will be estimated using a 
Cox Proportional Hazards model and a 95% Wald confidence interval will be 
reported.   
 
11.351 Delta value to reject H0 at final analysis of overall survival assuming 
exactly 115 events are observed: λc / λe > 1.37 (≈0.73-1)  
 
11.36 Secondary endpoint analysis: 
Recurrence-free survival is a secondary endpoint.  The intention-to-treat principle 
will be applied in the secondary analysis comparing the distribution of time to 
recurrence or death with censoring between assigned treatment arms.  The 
recurrence or death hazard ratio (experimental to control) will be estimated using 
Cox’s proportional hazards model and a 95% Wald confidence interval will be 
reported.  The logrank test will be used to test the null hypothesis of independence 
between recurrence-free survival and randomized treatment.  It is expected that 
this analysis will have 85% power to detect a 37.5% relative decrease in the 
hazard of recurrence or death (133 events) at the time that overall survival data 
will be mature.  Kaplan-Meier estimates will be used to graph overall survival 
distribution curves for each treatment arm.   
Additional exploratory analyses assessing the univariate and multi-variable 
prognostic significance of baseline clinical, pathologic or demographic factors 
such as patient age, tumor size, cervix involvement (yes or no), and mitotic rate 
will be carried out using proportional hazards models of both survival and 
recurrence.    
 
 
Recurrence-free Survival 
 
Cumulative percent of 
patients alive, recurrence free 
Cumulative percent of 
patients alive, recurrence free 
Months 
Control Arm 
Experimental Arm (HR=1.6) 
6 
83 
89 
12 
66 
77 
24 
45 
61 
36 
32 
49 
48 
26 
43 
60 
24 
41 
72 
23 
40 


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11.37 Interim analysis:   
 
An interim analysis plan is outlined below assuming the interim analyses occur 
exactly at 45% of the information fraction (target number of overall survival 
events).  However the timing of the interim analysis will likely vary from this 
exact schedule for practical reasons.  At the interim analysis, the test statistic for 
the primary analysis will be compared with the critical boundaries defined by the 
statistical design parameters described above.   If a boundary is crossed, 
consideration will be given to terminating study accrual, if still active, and/or 
early release of data.  Additional decisions may include recommendations on 
instructions for patients on study treatment. 
 
One interim analysis of futility and superiority is planned at 45% of information 
time (that is, when at least 52 overall survival events have been reported).  Given 
the rarity of this disease and the disparate treatment arms, stopping early for 
futility is desirable.  Basing the interim futility analysis on recurrence-free 
survival allows for a higher degree of available information (RFS events) at the 
time of the interim analysis.  Using RFS as the endpoint for futility analysis 
assumes that a lack of benefit in RFS translates to a lack of benefit in overall 
survival.  While data for the disease under study are extremely limited, this is a 
likely scenario in gynecologic malignancies in general and a reasonable 
assumption for this study. .  The boundary for futility (rejection of the alternative 
hypothesis, HR=0.625) will be defined by a critical region of values 0.442 or 
lower on the Z scale (0.90 or higher on the hazard ratio scale) provided there are 
exactly 74 RFS events (56% of the RFS information fraction) using linear 
interpolation of a spending function that has a probability of early termination 
under the null hypothesis of no difference of at least 65%.  The actual number of 
RFS events will depend on the timing of the interim analysis of efficacy.  
Assuming equal true hazard ratios for RFS and overall survival under the 
alternative hypothesis, the loss in power at the final analysis of overall survival is 
estimated to be 0.75% or 1.9% where the correlation between RFS at the interim 
analysis and overall survival at the final analysis is 0.8 or 0.6, respectively.  
The interim superiority analysis will be based on overall survival.  An O'Brien 
and Fleming-like spending function is used to define the boundaries for rejecting 
the null hypothesis.  Type I error to be spent at the interim analyis is 0.0035 if 
exactly 52 overall survival events have been reported.        
 
 


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Interim and final analysis plan details for overall survival 
 
Look 
Info 
Event 
Type I Error Spent 
# 
Fraction 
Size 
Alpha 
1 
0.43 
52 
0.0028 
2 
1.000 
115 
0.0500 
 
Other data to be summarized at the interim analysis will include tabulation of 
adverse events, deaths at least partially attributable to protocol treatment, major 
violations (complete refusal of protocol therapy, initiation of non-protocol therapy 
prior to recurrence, etc) and distribution of baseline characteristics.  
 
The results of interim analyses are scheduled to be reviewed by the GOG Data 
Safety and Monitoring Board (DSMB) at its semi-annual meetings. This 
committee meets in January and July each year. The precise dates for these 
meetings are set more than one year in advance by individuals who have no 
knowledge of efficacy results.  Approximately eight weeks prior to each of these 
meetings, the database is locked in order to prepare a progress report. If the 
prerequisite number of patients evaluated for response has been attained, an 
interim analysis is also prepared and presented to the DSMB at their next 
scheduled meeting. The decision to terminate accrual to any particular regimen 
includes consideration of adverse events, treatment compliance, survival data and 
results from external studies. Additionally, 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 the study treatment may have been a contributing 
cause. The SRC reports to the DSMB and may recommend study amendments 
pertaining to patient safety. 
 
11.4 
Safety analyses 
Patients’ adverse events will be captured by individual adverse event terms and grades 
defined by the NCI Common Terminology Criteria for Adverse Events version 4.  The 
maximum grade of any adverse event observed during active treatment period or within 
3-4 weeks of completing study treatment for each eligible patient will be tabulated.  The 
proportion of patients with a serious adverse event or reported grade 3 or worse adverse 
event, regardless of attribution, will be compared between the treatment regimens using a 
chi-squared test.  Additionally, the frequency of hospitalization while on study therapy, 
frequency of early study treatment discontinuation due to adverse events or refusal in the 
absence of disease recurrence, and the number of patients who receive non-protocol 
therapy prior to recurrence will be monitored in each arm.  Additionally, the initial post-
protocol therapy will be tabulated for each arm. 
 
 


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11.5 
Anticipated distribution of patients’ race and ethnicity (all are female) for GOG credited 
enrollment (10/28/2013) 
 
Ethnic Category 
Percent 
Hispanic or Latino 
19 
9.0 
Not Hispanic or Latino 
197 
91.0 
Ethnic Category: Total of all subjects 
216 
100.0 
Racial Category 
 
American Indian or Alaskan Native 
2 
1.0 
Asian 
4 
1.8 
Black or African American 
37 
17.0 
Native Hawaiian or other Pacific Islander 
1 
0.2 
White 
172 
80.0 
Racial Category: Total of all subjects 
216 
100.0 
 


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12.0 
BIBLIOGRAPHY   
 
1. Zondervan RL, Hahn PF, MD, Sadow CA, Liu B, Lee SI, Frequent Body CT Scanning of 
Young Adults: Indications, Outcomes, and Risk for Radiation-Induced Cancer.  J Am 
Coll Radiol. 2011;8:501-507. 
 
2. Major F, Blessing JA, Silverberg SG, Morrow CP, Creaseman WT, Curry JL, Yordon E, 
Brady MF.  Prognostic factors in early-stage uterine sarcoma. A Gynecologic Oncology 
Group study. Cancer. 1993 Feb 15;71(4 Suppl):1702-1709. 
 
3. Gadducci A, Landoni F, Sartori E, Zola P, Maggino T, Lissoni A, Bassurini L, Arisio R, 
Romagnolo C, Cristofani R.  Uterine leiomysarcoma: analysis of treatment failures and 
survival. Gynecol Oncol. 1996;62:25-32. 
 
4. Reed NS, Mangioni C, et al. Phase III randomized study to evaluate the role of adjuvant 
pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: An European 
Organization for Research and Treatment of Cancer Gynaecological Cancer Group Study 
(protocol 55874). Eur J Cancer. 2008. 
 
5. ML Hensley, K Wathen, RG Maki, DM Araujo, G Sutton, DA Priebat, S George, LH 
Baker.  Adjuvant treatment of high risk uterine leiomyosarcoma with 
gemcitabine/docetaxel (GT), followed by doxorubicin (D): results of phase II multi-
center trial SARC 005. ASCO Abstract #10021. 2010. 
 
6. Sarcoma meta-analysis collaboration:  adjuvant chemotherapy for localized resectable 
soft-tissue sarcoma of adults:  meta-analysis of individual data.  Lancet 350. 1997;1647-
1654. 
 
7. Frustaci S, Gherlinzoni G, DePaoli A, Bonetti M, Azzarelli A, Comandone A, Olmi P, 
Buonadonna A, Pignatti G, Barbieri E, Apice G, Zmerly H, Serraino D, Picci P.  
Adjuvant chemtoehrap for adult soft tissue sarcomas of the extremities and girdles: 
results of the Italian randomized cooperative trial.  J Clin Oncol 19. 2001;1238-1247. 
 
8. Omura GA, Blessing JA, Major F, et al.  A randomized clinical trial of adjuvant 
Adriamycin in uterine sarcomas: a Gynecologic Oncology Group study.  J Clin Oncol 3. 
1985:1240-1245. 
 
9. Hensley ML, Blessing J, DeGeest, K, Abulafia O, Rose P, Homesley HD.  Fixed-dose 
rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine 
leiomyosarcoma: a Gynecologic Oncology Group phase II study. Gynecol Oncol 109. 
2008;323-328. 
 
10. Hensley ML, Blessing J, Mannel R, Rose PG.  Fixed-dose rate gemcitabine plus 
docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic 
Oncology Group phase II trial.  Gynecol Oncol 109. 2008;329-324. 


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11. O’Cearbhaill R, Zhou Q, Iasonos A, Soslow RA, Leitao MM, Aghajanian C, Hensley 
ML.  Treatment of Advanced Uterine Leiomyosarcoma with Aromatase Inhibitors.  
Gynecol Oncol. 2010;116:424-429. 
 
12. ML Hensley, K Wathen, RG Maki, DM Araujo, G Sutton, DA Priebat, S George, LH 
Baker,  3-year follow-up of SARC005:  adjuvant treatment of high risk primary uterine 
leiomyosarcoma with gemcitabine/docetaxel (GT), followed by doxorubicin (D).  
Submitted to CTOS, 2011. 
 
 


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APPENDIX I  
Uterine Sarcomas FIGO Classification 2009 
 
 
(1) LEIOMYOSARCOMAS AND ENDOMETRIAL STROMAL SARCOMAS (ESS)* 
Stage 
Definition 
I 
Tumor limited to uterus 
IA 
≤5 cm 
IB 
>5 cm 
II 
Tumor extends beyond the uterus, within the pelvis 
IIA 
Adnexal involvement 
IIB 
Involvement of other pelvic tissues 
III 
Tumor invades abdominal tissues (not just protruding into the abdomen). 
IIIA 
One site 
IIIB 
>one site 
IIIC 
Metastasis to pelvic and/or para-aortic lymph nodes 
IV       IVA 
Tumor invades bladder and/or rectum 
IVB 
Distant metastases 
 
(2) ADENOSARCOMAS 
Stage 
Definition 
I 
Tumor limited to uterus 
IA 
Tumor limited to endometrium/endocervix with no myometrial invasion 
IB 
Less than or equal to half myometrial invasion 
IC 
More than half myometrial invasion 
II 
Tumor extends beyond the uterus, within the pelvis 
IIA 
Adnexal involvement 
IIB 
Involvement of other pelvic tissues 
III 
Tumor invades abdominal tissues (not just protruding into the abdomen). 
IIIA 
One site 
IIIB 
>one site 
IIIC 
Metastasis to pelvic and/or para-aortic lymph nodes 
IV       IVA 
Tumor invades bladder and/or rectum 
IVB 
Distant metastases 
 
(3) CARCINOSARCOMAS 
Carcinosarcomas should be staged as carcinomas of the endometrium. 
 
*Note: 
Simultaneous endometrial stromal sarcomas of the uterine corpus and ovary/pelvis in association 
with ovarian/pelvic endometriosis should be classified as independent primary tumors. 


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APPENDIX II  
 
General Chemotherapy Guidelines 
 
• For 21 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 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. 
• 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 doses 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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APPENDIX III (10/28/2013) 
EORTC Group-Specific Appendix to GOG Protocol GOG-0277 
Intergroup Trial 
 
 
  
EORTC Gynecological Cancer Group EORTC Soft Tissue and Bone Sarcoma 
Group 
  
EORTC protocol 55116-62114 
EORTC Group Specific Appendix to GOG-0277 protocol 
(EudraCT number 2012-002852-17) (NCT01533207) 
  
A Phase III Randomized Trial of Gemcitabine plus Docetaxel followed by 
Doxorubicin v. observation for uterus-limited, High Grade Uterine 
Leiomyosarcoma. 
  
EORTC Study 
Coordinators:   
Petronella Beatrix Ottevanger Phone: +31243610353 Fax:  
+31243540788 E-mail: p.ottevanger@onco.umcn.nl  
  
Anders Krarup-Hansen Phone: +45 44 53 53 30 Fax: +45 44 53 30 77 
E-mail: ankha@heh.regionh.dk  
GSA version  
Date of PRC 
approval/notification  
Amendment 
reference  
Applicable for 
Protocol  
 
 
N°  
Category  
 
1.0  
04 December 2012  
----  ----  
GOG-0277-April 25, 
2012 and subsequent 
versions  
  
Version 1.0 / 04 December 2012     
 
 
  ©Copyright EORTC 2012  
  
Warning:  
The enclosed protocol has not been initiated and written by the EORTC and it does not 
follow the usual sequence of chapters of EORTC protocols.  
  
All practical and administrative aspects of the protocol specific to the EORTC 
(Randomization, data flow, responsibilities, insurance, safety reporting ….) are included 
under this EORTC Group Specific Appendix of the protocol.  


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Contact addresses for the coordinating group  
Study Coordinator:  
Martee L. Hensley (GOG) 
E-mail: hensleym@mskcc.org  
Coordinating Clinical Trial Office:  CANCER TRIALS SUPPORT UNIT 
Phone: +1-888-823-5923 
E-mail: ctsucontact@westat.com  
  
  
 
Contact addresses for EORTC  
EORTC Study Coordinators:  Petronella Beatrix Ottevanger 
Phone: +31243610353 
Fax:  +31243540788 
E-mail: p.ottevanger@onco.umcn.nl 
  
Anders Krarup-Hansen 
Phone: +45 44 53 53 30  
Fax: +45 44 53 30 77  
E-mail: ankha@heh.regionh.dk  
Clinical Research Physician:  Emad Shash  
Phone: +32 2 774 10 59  
Fax: +32 2 774 16 36  
E-mail: emad.shash@eortc.be  
Project Manager:  
Liesbeth Knaepen 
Phone: +32 2 774 10 28  
Fax: +32 2 772 35 45  
E-mail: Liesbeth.kneaepen@eortc.be 
IRCI Project Manager:  
Hilde Breyssens  
Phone: +32 2 774 10 04  
Fax: +32 2 772 35 45  
E-mail: hilde.breyssens@eortc.be  
Data Manager:  
Maarten De Rouck  
Phone: +32 2 774 16 60  
Fax: +32 2 771 38 10  
E-mail: maarten.derouck@eortc.be  
Statistician:  
Corneel Coens   
Phone: +32 2 774 16 32  
Fax: +32 2 771 38 10  
E-mail: corneel.coens@eortc.be  
Pharmacovigilance Unit:  
Phone :+ 32 2 774 16 76  
Fax :  + 32 2 772 80 27  
E-mail: pharmacovigilance@eortc.be  
 
 
 


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Table of contents:  
1 
 Trial organization    
2 
 Forms and procedures for collecting data  
3  Translational research  
 
3.1  General principles for human biological material (HBM) collection  
4  Investigator authorization procedure  
5  Treatment plan and registration/randomization procedure  
 
5.1  Patient registration & randomization procedure  
 
5.2  Treatment plan   
6 
 Reporting of Serious Adverse Events   
 
6.1  Definitions    
 
6.2  Exceptions   
 
6.3  Severity assessment   
 
6.4  Causality assessment   
 
6.5  Expectedness assessment   
 
6.6  Reporting procedure for investigators   
 
6.7  Reporting responsibilities for EORTC   
 
6.8  Pregnancy reporting    
 
6.9  Audits    
 
6.10 External review of histology  
 
 
6.10.1 Local pathologist   
 
 
6.10.2 Reference pathologist  
7 
 Ethical considerations   
 
7.1  Patient protection   
 
7.2 Subject identification   
 
7.3  Informed consent   
8  Administrative responsibilities  
 
8.1  The study coordinator  
 
8.2  The EORTC Headquarters   
 
8.3  The EORTC group   
9 
 Trial sponsorship and financing    
10  Trial insurance   
   
1 Trial organization  
 
This trial is an Intergroup Trial, jointly conducted by the Gynecology Oncology Group 
(GOG) from USA, the EORTC Gynecology Cancer Group, EORTC Soft Tissue Bone 
Sarcoma Group and the National Cancer Research Network (NCRN) from United Kingdom.  
♦ The GOG is the Coordinating Group in this Intergroup trial and therefore is responsible for 
the trial design and activation, data management (including the quality control of data), 
statistical analysis and publication.  
 
♦ The EORTC is Collaborating Group in this trial.   
 
♦ The protocol developed by the Coordinating Group is compliant with specific 
EORTC guidelines for Intergroup trials and will be used by EORTC. The present 
EORTC specific Appendix details the participation of the EORTC institutions in the 
trial. The content of this appendix is therefore applicable only to the EORTC 


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investigators, for whom it supersedes entirely or partially the corresponding 
chapters in the protocol.  
♦ EORTC is the legal sponsor for all EORTC and NCRN participants.   
♦ EORTC will use the standard EORTC SAE definition. EORTC investigators will 
use standard EORTC SAE forms.  
♦ Only the Coordinating Data Center of GOG will code the data, perform 
consistency checks on data and modify them. Only the Coordinating Data 
Center will do the analysis.  
♦ All study drugs will have to be taken from the shelf and should be stored, prepared 
and administered in line with study protocol, normal hospital procedures and 
information contained within the current summary of product characteristics for 
each product.  
♦ This trial is an academic trial without any financial support from the industry.  
2 Forms and procedures for collecting data  
 
♦ EORTC Investigators/ Authorized personnel will enter study data in electronic 
CRFs via GOG Statistical and Data Centre (SDC) Electronic Data Entry System 
(SEDES) online application.  
♦ All queries will be sent from GOG Statistical and Data Centre (SDC) to the 
participating sites via SDC Electronic Data Entry System (SEDES) online 
application.   
♦ The GOG SDC is responsible for raising validation checks and for overall quality 
control of trial data.   
 
 3 Translational research 
  
The translational research program is optional.  
♦ All patients included in the clinical study will be offered to participate to the 
translational research project, at the time they are offered participation to the 
clinical study. Patients will have the possibility to accept or refuse the participation. 
A written informed consent should be given by the patient for inclusion in the 
translational research project.   
♦ For patients who have consented, tumor material sent to the reference pathologist 
for histopathological diagnosis will not be returned to the local pathologists but kept 
for future translational research, unless specifically required otherwise.  
♦ Further practical details will be provided through separate site guidelines. 


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3.1 General principles for human biological material (HBM) collection  
 
Human biological material (HBM) collection involves the collection and storage of biological 
material, residual biological material or derivatives in compliance with ethical and technical 
requirements.   
 
In this study, biological material will be centralized and stored at the site of the reference 
pathologist. From here, the biological material will be used or distributed to the other 
research laboratories involved in the translational research (TR) projects defined in the future.  
  
The following principles apply to storage of HBM:  
 
 
♦ The collected HBM should be documented, i.e. the amount remaining and its 
location.  
The EORTC Gynecology Cancer Group (GCG) and Soft Tissue and Bone Sarcoma Group 
(STBSG) Committees will be responsible for TR project review and prioritization, including 
the consideration of newly proposed TR projects not specified in the protocol. In the absence 
of Group Committees, responsibilities of the GCG and STBSG Committees are transferred to 
the EORTC HQ as applicable.  
 
Final decisions on the use of HBM will be determined by a majority vote of the GCG and 
STBSG Group committees. Additional expertise may be sought through advisory non GCG 
and STBSG Group committees members.  
 
Access to HBM (see EORTC Biobanking Policy POL020): HBM may be used for another 
purpose for which it was originally collected, subject to meeting ethical principles/and is 
covered by informed consent/ethics approval. In the case of secondary use of HBM, (i.e. for 
new TR projects that are not specified in the clinical study protocol and that were not 
foreseen at the time of protocol writing) interested parties may apply for the use of HBM and 
will follow the next steps:   
♦ A short description of the new TR projects will be written and submitted to EORTC 
HQ for coordination with GCG and STBSG Group committees.  
♦ The GCG and STBSG Group committees will prioritize the TR projects. Access 
procedures defined by the Groups committees will build on the following key 
points:   
♦ Project prioritization   
♦ should be strongly based on scientific merit,   
♦ should consider the contribution of the different investigators to the trial and TR 
project,   
♦ will take into consideration if the applicant is an EORTC member or not (whilst 
maintaining the principle of access to the wider scientific community and 
commitments owed to study participants and ethical committees).  


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♦ Protection of confidentiality must be respected.  
♦ An EORTC HQ feasibility check, including recommendations for regulatory and 
ethical matters and other restrictions on the use of the HBM, will take place. If in 
the event the HBM collections are still retained at individual clinical sites, the TR 
project leader and the involved EORTC Group are responsible for collecting and 
providing information on availability of HBM for the feasibility assessment.  
♦ Prioritized TR projects will then be reviewed by the Translational Research 
Advisory Committee (TRAC).  
♦ Once GCG and STBSG Group committees prioritization, the EORTC HQ 
feasibility assessment, and TRAC review are complete and when all applicable 
competent Ethics Committees approvals are in place and ethical principles are met, 
the TR project can be activated and HBM release and analysis can commence.  
♦ The EORTC Executive Committee will mediate any disagreements of opinion 
between TRAC, the EORTC HQ feasibility assessment, the GCG and STBSG 
Group committees and the TR project leader(s), as needed. 
 
4 Investigator authorization procedure  
 
Investigators will be authorized to register and/or randomize patients in this trial only once 
they have returned the following documents to the EORTC Headquarters:  
 
♦ The updated signed and dated Curriculum Vitae of the Principal Investigator  
♦ The (updated) list of the normal ranges, for the investigator’s institution signed and 
dated by the head of the laboratory. Please make sure normal ranges are provided 
also for those tests required by the protocol but not routinely done at the 
investigator’s institution.  
♦ A Commitment Statement and Study Agreement between EORTC and Principal 
Investigator, stating that they will fully comply with the protocol. This must include 
an estimate of yearly accrual and a statement on any conflict of interest that may 
arise due to trial participation.  
 
NB: A signed conflict of interest disclosure form will be required only if a possible 
conflict is declared on the Commitment Statement and Study Agreement.   
♦ A copy of the favorable opinion of their local or national (whichever is applicable) 
ethics committee mentioning the documents that were reviewed (including the 
version numbers and version dates of all documents). A list of all members of the 
ethics committee is also requested.  
♦ A copy of the translated and adapted (according to all national requirements) Patient 
Information / Informed Consent sheet. Version numbers and dates must be clearly 


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stated on each page.  
♦ The signature log-list of the staff members with a sample of each authorized 
signature and the indication of the level of delegations.  
♦ The full name, address, phone numbers and e-mail address of the local pharmacist 
who will be responsible for the trial medication (for any trial where the drug will be 
provided).  
♦ An accreditation, a certification, an established quality control / external quality 
assessment or another validation should be provided for the own laboratory.  
♦ The center specific applicable list of required documents will be included in the 
protocol activation package, with proper instructions as required by this protocol 
and / or the applicable national law.  
 
The new investigator will be added to the “authorization list”, and will be allowed to 
register/randomize patients in the trial as soon as  
 
♦ All the above mentioned documents are available at the EORTC Headquarters.  
♦ All applicable national legal and regulatory requirements are fulfilled.  
 
Patient registration/randomization from centers not (yet) included on the authorization list 
will not be accepted.  
 
The Coordinating Data Center will be immediately informed about each investigator included 
on the authorization list by EORTC indicating the name of the principal investigator, the 
name of the institution and the EORTC institution number.  
 
5 Treatment plan and registration/randomization procedure  
 
5.1 Patient registration & randomization procedure 
  
EORTC investigators will register and/or randomize patients through the leading group’s 
online registration system “OPEN” (cfr. leading protocol Chapter 5.1).   
After authorization of the individual site, EORTC HQ will take the necessary steps to request 
a username and password for each individual EORTC site and communicate this to the site.   
Any further requirements for this process relevant to EORTC investigators will be provided 
in a separate document with proper instructions.  
 
5.2 Treatment plan 
  
Patients randomly assigned to one of the two protocol regimens will be treated as per 
protocol (cfr. leading protocol Chapter 5.2).  
 
Patients with cardiac ejection fraction less than 50 % will not be allowed to receive 
Doxorubicin, but still can receive the rest of protocol treatment.   


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6 Reporting of Serious Adverse Events  
 
ICH GCP and the EU Directive 2001/20/EC require that both investigators and sponsors 
follow specific procedures when notifying and reporting adverse events/reactions in clinical 
trials. These procedures are described in this section of the protocol. 
   
6.1 Definitions  
 
These definitions reflect the minimal regulatory obligations; specific protocol requirements 
might apply in addition.  
 
AE: An Adverse Event is defined as “any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment”. An adverse event can 
therefore be any unfavorable and unintended signs (such as rash or enlarged liver), symptoms 
(such as nausea or chest pain), an abnormal laboratory finding (including results of blood 
tests, x-rays or scans) or a disease temporarily associated with the use of the protocol 
treatment, whether or not considered related to the investigational medicinal product.  
 
AR: An Adverse reaction of an investigational medicinal product is defined as “any 
noxious and unintended response to a medicinal product related to any dose administered”.  
All adverse events judged by either the reporting investigator or the sponsor as having a 
reasonable causal relationship to a medicinal product qualify as adverse reactions. The 
expression reasonable causal relationship means to convey in general that there is evidence or 
argument to suggest a causal relationship.  
 
UAR: An Unexpected Adverse Reaction is “any adverse reaction, the nature, or severity of 
which is not consistent with the applicable product information" (e.g. investigator's brochure 
for an unapproved investigational product or summary of product characteristics (SmPC) for 
a marketed product).  
 
When the outcome of the adverse reaction is not consistent with the applicable product 
information this adverse reaction should be considered as unexpected.  
 
Severity: The term “severe” is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate or severe, or as described in CTC grades); the event itself, 
however, may be of relative minor medical significance (such as severe headache). This is 
not the same as “serious,” which is based on patient/event outcome or action criteria usually 
associated with events that pose a threat to patient’s life or functioning. Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations.   
 
SAE: A Serious Adverse Event is defined as any untoward medical occurrence or effect in a 
patient, whether or not considered related to the protocol treatment, that at any dose:  
 
♦ results in death  
♦ is life-threatening (i.e. an event in which the subject was at risk of death at the time 
of event; it does not refer to an event which hypothetically might have caused death 
if it was more severe)  


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♦ requires inpatient hospitalization or prolongation of existing patient hospitalization  
♦ results in persistent or significant disability or incapacity  
♦ is a congenital anomaly or birth defect  
♦ is a medically important event or reaction.  
 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious such as important medical events that might not be immediately 
life-threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed in the definition above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse.  
 
! Grade 4 anaphylaxis reactions, regardless of whether a hospitalization is required also need 
to be reported as an SAE 
  
SAR: A Serious Adverse Reaction is defined as any SAE which is considered related to the 
protocol treatment.   
 
SUSAR: Suspected Unexpected Serious Adverse Reaction.   
SUSARs occurring in clinical investigations qualify for expedited reporting to the appropriate 
Regulatory Authorities within the following timeframes:  
 
♦ Fatal or life-threatening SUSARs within 7 calendar days  
♦ Non-fatal or non-life-threatening SUSARs within 15 calendar days  
 
Inpatient hospitalization: a hospital stay equal to, or greater than, 24 hours.  
Second primary malignancy is one unrelated to the treatment of a previous malignancy (and 
is NOT a metastasis from the previous malignancy).  
 
Secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the previous malignancy.  
 
 


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6.2 Exceptions  
 
The following situations do not need to be reported as SAEs:   
 
 
♦ Elective hospitalization for pre-existing conditions that have not been exacerbated 
by trial treatment.  
 
♦ A hospitalization which was planned before the patient consented for study 
participation and where admission did not take longer than anticipated.  
 
♦ A hospitalization planned for protocol related treatment or protocol related 
procedure as per institutional standard timelines.  
 
♦ Social and/or convenience admission to a hospital  
 
♦ Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an (S)AE.  
 
♦ Situations where an untoward medical occurrence did not occur (palliative care, 
rehabilitation, overdose without occurrence of an adverse event).  
 
♦ Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.  
 
By EORTC convention, clinical events related to the primary cancer being studied or to the 
primary cancer progression are not to be reported as SAEs, even if they meet any of the 
seriousness criteria from the standard SAE definition, unless the event is more severe than 
expected and therefore the investigator considers that their clinical significance deserves 
reporting. 
   
6.3 Severity assessment  
 
The severity of all AEs (serious and non-serious) in this trial should be graded using CTCAE 
v4.0 www.eortc.org\investigators-area\ctc   
 
6.4 Causality assessment  
 
The investigator is obligated to assess the relationship between protocol treatment and the 
occurrence of each SAE following the definitions in this table:  
  
Relationship to the protocol 
treatment   
Description  
Definite 
The adverse event is clearly related to the agent(s).  
Probable 
The adverse event is likely related to the agent(s). 


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Possible 
The adverse event may be related to the agent(s). 
Unlilkely 
The adverse event is doubtfully related to the 
agent(s). 
Unrelated 
The adverse event is clearly NOT related to the 
agent(s).  
 
  
The investigator will use clinical judgment to determine the relationship. Alternative causes, 
such as natural history of the underlying diseases, medical history, concurrent conditions, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
protocol treatment will be considered and investigated.  
 
The decision will be recorded on the SAE form and if necessary the reason for the decision 
will also be recorded.  
 
6.5 Expectedness assessment  
 
The expectedness assessment is the responsibility of the sponsor of the study. The 
expectedness assessment will be performed against the following reference documents:  
 
♦ For Gemcitabine: Summary of Product Characteristics (SmPC)  
♦ For Docetaxel: Summary of Product Characteristics (SmPC)  
♦ For Doxorubicin: Summary of Product Characteristics (SmPC)   
 
6.6 Reporting procedure for investigators  
 
This procedure applies to all Serious Adverse Events (SAEs) occurring from the time a 
subject is registered until   
 
For investigational arm: 30 days after last protocol treatment administration and to any SAE 
that occurs outside of the SAE detection period (after the 30-days period), if it is considered 
to have a reasonable possibility to be related to the protocol treatment or study participation.  
For the observation arm: end of week 24  
 
Registration till 30 days after last protocol treatment administration/end of 
week 24 (in Observation arm):  
All SAEs  
From day 31 after last protocol treatment administration:  
Only related 
SAEs  
 
  
Any secondary malignancy should also be reported in expedited way on a SAE form 
with the appropriate seriousness criteria! 
  
All reporting must be done by the principal investigator or authorized staff member (i.e. on 
the signature list) to confirm the accuracy of the report. 


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All SAE data must be collected on the study-specific SAE form.  
 
All SAEs must be reported immediately and no later than 24 hours from the time the 
investigator or staff became aware of the event.  
 
All SAE-related information needs to be provided in English.  
 
All additional documents in local language must be accompanied by a translation in English, 
or the relevant information must be summarized in a follow-up SAE report form.  
 
All SAE-related information must be faxed to:  
 
 EORTC Pharmacovigilance Unit:  
 Fax No. +32 2 772 8027  
 
To enable the Sponsor to comply with regulatory reporting requirements, all initial SAE 
reports should always include the following minimal information: an identifiable patient 
(SeqID), a suspect medicinal product if applicable, an identifiable reporting source, the 
description of the medical event and seriousness criteria, as well as the causality assessment 
by the investigator. Complete information requested on the SAE form of any reported serious 
adverse event must be returned within 7 calendar days of the initial report. If the completed 
form is not received within this deadline, the Pharmacovigilance Unit will make a written 
request to the investigator. 
  
Queries sent out by the EORTC Pharmacovigilance Unit need to be answered within 7 
calendar days. 
  
All forms need to be dated and signed by the principal investigator or any authorized staff 
member (i.e. on the signature list).  
 
6.7 Reporting responsibilities for EORTC  
 
The EORTC Pharmacovigilance Unit will forward all EORTC SAE reports to the appropriate 
persons within the EORTC Headquarters and enter them into AdEERs.  
 
The EORTC Pharmacovigilance Unit will take in charge the reporting of SUSARs to the 
Competent Authorities, Ethics committees, EudraVigilance Clinical Trial Module (EVCTM) 
and all EORTC participating investigators, whenever applicable.  
 
6.8 Pregnancy reporting 
  
Pregnancy occurring during a patient’s participation in this trial, although not considered an 
SAE, must be notified to the EORTC Pharmacovigilance Unit within the same timelines as 
an SAE (within 24 hours) on a Pregnancy Notification Form. The outcome of a pregnancy 
should be followed up carefully and any adverse outcome to the mother or the child should 
be reported.  
 
 
♦ Any pregnancy in a female subject diagnosed during the treatment period or within 
30 days after last protocol treatment administration must be reported to the EORTC 


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Pharmacovigilance Unit   
 
♦ This must be reported within 24 hours of first becoming aware of the event by fax, 
to the Pharmacovigilance Unit on a Pregnancy Notification Form   
 
♦ If an SAE occurs in conjunction with the pregnancy, please also complete an SAE 
form as explained in the SAE reporting chapter  
6.9 Audits 
  
The EORTC Quality Assurance and Control Unit (QA&C) regularly conducts audits of 
institutions participating in EORTC protocols. These audits are performed to provide 
assurance that the rights, safety and wellbeing of subjects are properly protected, to assess 
compliance with the protocol, processes and agreements, ICH GCP standards and applicable 
regulatory requirements, and to assess the quality of data.  
 
The investigator, by accepting to participate in this protocol, agrees that EORTC, any third 
party (e.g. a CRO) acting on behalf of the EORTC, or any domestic or foreign regulatory 
agency, may come at anytime to audit or inspect their site and all subsites, if applicable.  
  
This audit consists of interviews with the principal investigator and study team, review of 
documentation and practices, review of facilities, equipment and source data verification. 
  
The investigator will grant direct access to paper and/or electronic documentation pertaining 
to the clinical study (e.g. CRFs, source documents such as hospital patient charts and 
investigator study files) to these authorized individuals. All site facilities related to the study 
conduct could be visited during an audit (e.g. pharmacy, laboratory, archives …). The 
investigator agrees to co-operate and provide assistance at reasonable times and places with 
respect to any auditing activity.   
 
When site visits are performed for this study, the Coordinating Data Center provides all CRFs 
and related queries to the EORTC Quality Assurance and Control Unit (QA&C).  
 
A site visit will be organized in each recruiting institution within 18 months after the first 
patient has been entered and these visits will be repeated on a regular basis (approximately 
every 3 years). 
  
If a regulatory authority inspection is announced, the investigator must inform the EORTC 
Headquarters QA&C Unit immediately (contact at: 
QualityAssuranceandControlUnit@eortc.be ). In this way EORTC can provide help in 
preparing and/or facilitating the inspection. EORTC representatives/ delegates may also 
attend the inspection.  
 
6.10 External review of histology  
 
6.10.1 Local pathologist  
 
 
♦ The local pathologist shall send stained pathology slides for central review by the 
reference pathologist to confirm eligibility. At least one representative H&E 


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(haematoxylin/eosin) stained slide demonstrating the primary high grade uterine 
leiomyosarcoma with adequate mitotic rate, nuclear atypia and tumor necrosis (if 
present).  
 
For patients who consent to participate in the translational research, the local pathologist shall 
also include blocks, or if no blocks are available, at least 10 unstained slides for translational 
research (see Chapter  3).  
 
Submitted pathology material shall be labeled with the patient seqID and patient code.  
 
The local pathologist shall also send the completed Pathology Form (Form F) and a copy of 
his/her pathology report to the reference pathologist.  Personal data of the patient must be 
anonymized (black out patient name) and replaced by the seqID allocated to this patient at the 
time of randomization. 
 
Please include also the patient code and protocol number (GOG-0277) on all pages of the 
pathology report. 
 
The slides, copies of the Pathology Form and official pathology report shall be sent by mail 
to the reference pathologist, being:  
Cyril Fisher Dept of Histopathology ROYAL MARSDEN HOSPITAL - 
CHELSEA, LONDON Fulham Road 203 GB London SW3 6JJ United 
Kingdom 
Phone: +44 20 78082631 Fax: +44 20 78082578 
e-mail: cyril.fisher@rmh.nhs.uk 
 
6.10.2 Reference pathologist  
 
♦ The reference pathologist will complete the Pathology Review Form   
♦ For patients who did not take part in future research: the reference pathologist will 
return tumor material to the sites after review.  
♦ For patients consenting to future research the reference pathologist will retain the 
stained and unstained slides for future translational research, unless specifically 
required otherwise. 
 
7 Ethical considerations  
 
7.1 Patient protection  
 
The responsible investigator will ensure that this study is conducted in agreement with either 
the Declaration of Helsinki (available on the World Medical Association web site 
(http://www.wma.net )) and/or the laws and regulations of the country, whichever provides 
the greatest protection of the patient.  
 
The protocol has been written, and the study will be conducted according to the ICH 


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Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at 
http://www.ema.europa.eu/pdfs/human/ich/013595en.pdf ). 
  
The protocol must be approved by the competent ethics committee(s) as required by the 
applicable national legislation.  
 
7.2 Subject identification  
 
The name of the patient will neither be asked for nor recorded at the EORTC Headquarters. A 
sequential identification number will be automatically allocated to each patient registered in 
the trial. This number will identify the patient and will be included on all case report forms. 
In order to avoid identification errors, the patient’s code (maximum of 4 alphanumerics) and 
date of birth will also be reported on the case report forms. 
  
7.3 Informed consent  
 
All patients will be informed about  
 
♦ the aims of the study  
♦ the possible adverse events  
♦ the procedures and possible hazards to which the patient will be exposed  
♦ the mechanism of treatment allocation  
♦ strict confidentiality of any patient data  
♦ medical records possibly being reviewed for trial purposes by authorized 
individuals other than their treating physician  
 
The template of the patient’s informed consent statement is given as a separate document 
dated and version controlled to this protocol.  
 
An adapted translation of the PIS/PIC will be provided by EORTC Headquarters and it is the 
responsibility of the Coordinating investigators for this trial (sometimes called National 
Coordinators) to adapt it to national/local requirements where necessary.  
 
The bold sections of the informed consent document must be reflected in any 
translation. The content of these bold sections can either be translated literally or translated 
in any way that best captures the information given.   
 
The translated informed consent documents are to be submitted to ethics committees for 
approval. The competent ethics committee for each institution must approve the informed 
consent documents before the center can join the study. It is the responsibility of the 
competent ethics committee to ensure that the translated informed documents comply with 
ICH-GCP guidelines and all applicable national legislation.  
 
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patient is free to refuse further participation in the protocol whenever he/she wants to. This 
will not have any impact on the patient’s subsequent care. Documented informed consent 
must be obtained for all patients included in the study before they are registered and/or 
randomized at the EORTC Headquarters. The written informed consent form must be signed 
and personally dated by the patient or by the patient’s legally acceptable representative.  
 
All of the above must be done in accordance with the applicable national legislation and local 
regulatory requirements. 
 
8 Administrative responsibilities 
 
8.1 The study coordinator  
 
The EORTC Study Coordinators (in cooperation with the EORTC Headquarters) will be 
responsible for reviewing and discussing all the amendments to the protocol with the 
coordinating group.   
 
At the time of publication, the EORTC study coordinator’s responsibility is to assure, along 
with the EORTC Headquarters Team, that the results are used and analyzed following the 
EORTC policy and quality.  
 
Study coordinator (GCG):  
Petronella Beatrix Ottevanger 
Radboud University Nijmegen Medical Centre 
P.O. Box 9101 – Geert Grooteplein 10 
6500 HB Nijmegen 
The Netherlands 
Phone: +31243610353 
Fax: +31243540788 
e-mail: p.ottevanger@onco.umcn.nl  
  
Study coordinator (STBSG):  
 
Anders Krarup-Hansen   
HERLEV HOSPITAL - UNIVERSITY COPENHAGEN   
Herlev Ringvej   
2730 Herlev 2730   
Denmark   
Phone: +45 44 53 53 30   
Fax: +45 44 53 30 77   
e-mail: ankha@heh.regionh.dk   
 
 
 


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8.2 The EORTC Headquarters  
 
The EORTC Headquarters is responsible for handling investigator authorization procedure. 
All methodological questions should be addressed to the EORTC Headquarters that will 
address them to the person competent for this trial.  
 
EORTC HEADQUARTERS  
 
 Avenue E. Mounierlaan 83/11   
Brussel 1200 Bruxelles   
België - Belgique   
Fax: +32 2 7723545  
 
8.3 The EORTC group  
 
All questions concerning ongoing membership in the group should be addressed to the 
chairman and/or secretary of the group. 
  
For new membership contact Membership Committee at membership@eortc.be  
  
Gynecology EORTC group  
 
Chairman:  
 
Antonio Casado Herraez   
HOSPITAL UNIVERSITARIO SAN CARLOS    
C/ Profesor Martin Lagos, s/n   
28040 Madrid    
Spain   
Phone: +34 91 3303666   
Fax: +34 91 3303546   
e-mail: acasado.hcsc@salud.madrid.org  
   
Secretary:  
 
Petronella Beatrix Ottevanger   
RADBOUD UNIVERSITY NIJMEGEN MEDICAL CENTRE   
P.O. Box 9101 - Geert Grooteplein 10   
6500 HB Nijmegen    
The Netherlands   
Phone: +31 24 3610353   
Fax: +31 24 3540788   
e-mail: p.ottevanger@onco.umcn.nl 
    
Soft Tissue Bone Sarcoma Group 
  
Chairman:  
 
Winette Van Der Graaf   
RADBOUD UNIVERSITY NIJMEGEN MEDICAL CENTRE   


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P.O. Box 9101 - Geert Grooteplein 10   
6500 HB Nijmegen   
The Netherlands   
Phone: +31 24 3610353   
Fax: +31 24 3540788   
e-mail: w.vandergraaf@onco.umcn.nl   
 
Secretary:  
 
Alessandro Gronchi   
FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI   
Via Venezian, 1   
20133 Milano   
Italy   
Phone: +39 02 23903234   
Fax: +39 02 23902404   
e-mail: alessandro.gronchi@istitutotumori.mi.it 
 
 
9 Trial sponsorship and financing  
 
EORTC is the legal Sponsor for all EORTC and NCRN participants. 
  
The contact details of the EORTC are: 
  
 EORTC Headquarters   
Avenue E. Mounierlaan 83/11   
Brussel 1200 Bruxelles   
België - Belgique   
Phone: +32 2 7741611   
Fax: +32 2 7723545   
e-mail: eortc@eortc.be  
  
This trial is an academic trial without any financial support from the industry. 
   
10 Trial insurance 
  
A clinical trial insurance has been taken out according to the laws of the countries where the 
study will be conducted. An insurance certificate will be made available to the participating 
sites at the time of study initiation.  
  
Clinical trial insurance is only valid in centers authorized by the EORTC Headquarters. For 
details please refer to the chapter on investigator authorization. 
 
  
 
 


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APPENDIX IV (10/28/2013) 
NCRN Group-Specific Appendix to GOG Protocol GOG-0277 
 
 
A Phase III Randomized Trial of Gemcitabine  plus Docetaxel followed 
by Doxorubicin v observation for uterus-limited, high grade uterine 
leiomyosarcoma 
(GOG-0277) 
 
(EudraCT Number: 2012-002852-17) 
(NCT01533207) 
 
UK Group Specific Appendix: Version 2, 04th July 2013 
 
 
 
The study is being co-ordinated in UK by Cancer Research UK Clinical Trials Unit, 
Glasgowon behalf of the National Cancer Research Network (NCRN) and National Cancer 
Research Institute (NCRI) Sarcoma and Gynaecology Clinical Study Groups  
 
 
UK Study Co-ordinator/:  
Dr Helen Hatcher 
Chief Investigator  
 
Email: hh321@medschl.cam.ac.uk 
 
 
IMPORTANT INFORMATION 
The protocol to which this appendix refers to has been initiated and written by the 
Gynecologic Oncology Group (GOG) 
 
All technical and administrative aspects of the protocol specific to the UK (registration, 
responsibilities, safety reporting, etc.) are covered by this UK Group Specific Appendix. 
 
 
 
       
          
         
 
 
 
 


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Contact addresses for UK study co-ordinating centre 
 
UK Study Co-ordinator/: 
Dr Helen Hatcher 
Chief Investigator 
 
University of Cambridge 
 
 
 
 
Oncology Department 
 
 
 
 
Box 193 (R4) 
 
 
 
 
Addenbrooke's Hospital 
 
 
 
 
Hills Road 
 
 
 
 
Cambridge 
 
 
 
 
CB2 0QQ.  
 
 
 
 
Tel no: +44 01223 769309 
 
 
 
 
Email:  hh321@medschl.cam.ac.uk 
 
 
 
 
Project Manager: 
 
Karen Carty 
 
 
 
 
Cancer Research UK Clinical Trials Unit, Level 0 
The Beatson West of Scotland Cancer Centre 
1053 Great Western Road 
Glasgow, G12 0YN 
 
Tel no:+44 (0) 141 301 7197 
 
Fax no:++44 (0) 0141 301 7946 
 
 
 
 
Email: karen.carty@glasgow.ac.uk 
 
Clinical Trial Co-ordinator: 
Clinical Trial Co-ordinator (GOG-0277:LMS Trial) 
 
 
 
 
Cancer Research UK Clinical Trials Unit, Level 0 
The Beatson West of Scotland Cancer Centre 
1053 Great Western Road 
Glasgow, G12 0YN 
 
Tel no:++44 (0)141 301 
 
Fax no:++(0)141 301 
 
 
 
 
Clinical Trial Monitor:  
To be confirmed 
Cancer Research UK Clinical Trials Unit,  
44 Shelley Court 
Gartnavel General Hospital Complex 
Glasgow, G12 0YN 
 
 
 
 
Tel no:++ 44(0) 141 301  
Fax no:  ++ 44 (0) 141 301  
 
EORTC Pharmacovigilance 
Tel no:++32 2 774 16 76 
Unit 
 
 
 
Fax no:++32 2 772 80 27 
 
 
 
 
Email: pharmacovigilance@eortc.be 
 
Sponsor 
The European Organisation for Research and Treatment of Cancer (EORTC) is the sole 
legal Sponsor for participants in the European Union. 
 
 


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The contact details of the EORTC are: 
 
 
 
 
EORTC Headquarters 
 
 
 
 
Avenue E. Mounierlaan 83/11 
 
 
 
 
Brussel 1200 Bruxellles 
 
 
 
 
België - Belgique 
 
 
 
 
Tel no : 
+32 2 7741611 
 
 
 
 
Fax no: 
+32 2 7723545 
 
 
 
 
Email:  
55116@eortc.be 
 
UK Signatory Page 
Sponsor: 
Denis Lacombe 
 
 
 
 
 
 
 
(Date) 
Director, EORTC Headquarters 
EORTC 
European Organisation for Research and Treatment of Cancer 
AISBL-IVZW 
Avenue E.Mounierlann 83/11 
Brussel 1200 Bruxelles 
België - Belgique 
 
UK Study Coordinator/Chief Investigator: 
Dr Helen Hatcher 
 
 
 
 
 
 
 
(Date) 
University of Cambridge 
Oncology Department 
Box 193 (R4) 
Addenbrooke's Hospital 
Hills Road, Cambridge,CB2 0QQ.  
England, United Kingson 
 
 
 
 
 
 


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Table of Contents 
1. Trial Organisation 
2. Investigation Authorisation Procedure 
3. Patient Registration & Randomisation Procedure 
3.1 Central Pathological Review (Retrospective)  
3.1.1 Local Pathologist 
3.1.2 Reference Pathologist 
4. Management and Handling of Investigational Medicinal Product (IMP)  
4.1 General 
4.2 Labelling 
4.3  Storage and Accountability of IMPs 
4.4  IMP Destruction 
5. Drug Interactions/ Contraindications with Concomitant Medications 
6. Trial Management and Data Collection 
6.1 Case report forms 
6.2 Data Flow 
7. Assessment of Safety/ Reporting of Serious Adverse Events 
7.1 Definitions 
7.2 Exceptions 
7.3 Severity Assessment 
7.4 Causality Assessment 
7.5 Expectedness Assessment 
7.6 Reporting Procedure for Investigators 
7.7 Reporting Responsibilities for EORTC 
7.8 Pregnancy Reporting 
7.9 Development Safety Update Reports 
8. Study Responsibilities 
8.1  Sponsor Responsibilities (EORTC)  
8.2  CR-UK Clinical Trials Unit (CTU)  
8.3  Chief Investigator (C.I.)  
8.4  Participating Site- 94 - 
8.5  Principal Investigator (P.I.)  
9. Liability and Indemnity 
10. Regulatory Issues 
10.1 Clinical Trials Authorisation (CTA)  
10.2 Ethics and Research & Development Approval 
10.3 Informed Consent 
10.4  Confidentiality 
10.5  Quality Assurance/Quality Control 
10.6  Monitoring 
10.7 Audits and Inspections 
11. Patient Information Sheets and Consent Forms 
12. GP Letter 
13. Translational Research 
 
 
 


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1. Trial Organisation 
 
 This trial is an Intergroup Trial jointly conducted by Gynecologic Oncology Group 
(GOG) from USA, the EORTC Gynaecology Group, EORTC Soft Tissue Bone 
Sarcoma Group and National Cancer Research Network [NCRN] United Kingdom. 
 
 GOG is the lead coordinating group in this Intergroup Trial and is therefore 
responsible for overall trial conduct (including trial design, protocol finalisation, trial 
activation, data management[including the quality control of data], statistical analysis 
and publication.) 
 
 In the UK the trial is being run under the auspices of the NCRN/NCRI Sarcoma and 
Gynaecology Clinical Study Groups with funding from Cancer Research UK. The 
Cancer Research UK Clinical Trials Unit, Glasgow (CTU) is co-ordinating the UK 
participation in the trial on behalf of NCRI/NCRN and NHS Greater Glasgow & 
Clyde (NHS GG&C). 
 
 The Cancer Research UK Clinical Trials Unit, Glasgow will be main point contact for 
UK sites. All questions in relation to the trial should be addressed to the Cancer 
Research UK Clinical Trials Unit. 
 
 The EORTC is the sole legal Sponsor for participants in the European Union. 
 
 NHS GG&C (Legal name Greater Glasgow Health Board [GGHB]) is the Sponsor’s 
contact (EORTC) for correspondence in the UK. GGHB and the EORTC have entered 
into an agreement for the study which outlines the roles and responsibilities of each 
party in relation to UK participation in the trial. 
 The content of this appendix is applicable only for UK participating investigators; this 
appendix complements or supercedes the corresponding sections in the protocol. 
 
 This trial is an academic trial without any financial support from industry. 
 
2. Investigation Authorisation Procedure 
 
Investigators will be authorised to register and/or randomise patients to the trial when they 
have returned the following documents to the Cancer Research UK Clinical Trial Unit, 
Glasgow and completed the site initiation process for the trial:  
 
 Board/Trust R&D approval letter 
 Fully signed Clinical Study Site Agreement. 
 Completed Staff Contact and Responsibilities Sheets for all members of staff. 
 Up to date, signed and dated CV’s for the Principal Investigator, Co-Investigators and 
study team must be provided. The CV should detail the qualifications, experience and 
training (including GCP training) of site personnel relevant to their role in the study, 
and should be updated every 2 years. 
 Copy of GCP certificate for Principal Investigator, Co Investigators and study team (if 
no formal certificate is available, some evidence should be present [i.e. register log 
email].If PI has had no GCP training, this should be arranged as soon as possible, and 
some evidence of this provided). 


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 Local versions of Patient Information Sheets, Consent Forms and GP Letters on 
hospital headed paper. 
 Full contact details for all site personnel. 
 Biochemistry and Haematology normal ranges and laboratory accreditation 
certificates 
 
Once all of the above documentation has been received and the site initiation process for the 
site is complete the Cancer Research UK Clinical Trials Unit will inform the NCI Cancer 
Trials Support Unit (CTSU) to enable the institution to be registered on the authorisation list. 
 
The site will be notified by email or fax when they are activated and are able to recruit 
patients to the trial. 
 
3. Patient Registration & Randomisation Procedure 
 
UK Investigators will register and/or randomise patients through the NCI Cancer Trials 
Support Unit (CTSU) online registration system “OPEN” (Refer to Study Protocol Chapter 
5.1) 
 
After authorisation of each site, the Cancer Research UK Clinical Trials Unit, Glasgow will 
take the necessary steps to request a username and password for each sites and communicate 
this to the site. 
 
Any further details relevant to UK Investigators will be provided at a later time in a separate 
document.  
 
3.1 Central Pathological Review (Retrospective) 
 
3.1.1 Local Pathologist 
 
Central pathology review will be performed retrospectively for all patients entered to the 
study to confirm eligibility for the study. This is mandatory for the study. 
 
Following entry to the study the local pathologist will require to send stained pathology slides 
for central review by the reference pathologist to confirm eligibility. At least one 
representative H&E (haematoxylin/eosin) H&E stained slide demonstrating the primary high 
grade uterine leiomyosarcoma with adequate mitotic rate, nuclear atypia and tumour necrosis 
(if present).  
 
For patients who have consented to take part in future translational research the local 
pathologist shall also include blocks or if no blocks available at least 10 unstained slides for 
translational research (see chapter 13) 
 
Submitted pathology material shall be labelled with the patients sequentialID, patient initials, 
surgical/pathology number and block identifier. 
 
The local pathologist shall also send the completed Pathology Form (Form F) and a copy of 
his/her pathology report to the reference pathologist. Personal data of the patient must be 
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number allocated to the patient at time of randomisation. Please also include the patient 
initials and protocol number (GOG-0277) on all pages of the pathology report 
 
The slides, copies of the Pathology Form (Form F) and official pathology report shall be sent 
by post to the reference pathologist for the study (Professor Cyril Fisher) at the below 
address: 
 
Professor Cyril Fisher 
Royal Marsden Hospital - Chelsea 
Department of Histopathology 
Fulham Road,  
LONDON, SW3 6JJ 
United Kingdom 
Tel no:   
++ (0) 20 78082631 
Fax no:    
++ (0) 20 78082578 
Email:  
cyril.fisher@rmh.nhs.uk 
 
UK Sites will be provided with a supply of Royal Mail Safeboxes which should be used to 
send pathology slides and associated paperwork to the Reference Pathologist for the study 
(Professor Cyril Fisher) 
 
3.1.2 Reference Pathologist 
 
The reference pathologist will complete the pathology review form. 
 
For patients who have not consented to take part in future translational research , the 
reference pathologist will return tumour material to the sites after pathology review.  
 
For patients who have consented to take part in the future translational research, the reference 
pathologist will retain the stained and unstained slides for future translational research, unless 
specifically required otherwise. 
 
4. Management and Handling of Investigational Medicinal Product (IMP) 
 
4.1 General 
 
All the IMPs for use in the trial should be taken from usual pharmacy shelf stock, there is no 
provision for funding, reimbursement or discounted stock. 
 
All IMPs should be stored prepared and administered in line with study protocol, normal 
hospital procedures and information contained within the current summary of product 
characteristics for each product. 
 
Dose banding of IMPs is permitted where it is local policy to do so. The Cancer Research UK 
Clinical Trials Unit, Glasgow should be informed of this during the set-up phase of the study. 
 


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4.2 Labelling  
 
Labelling for dispensed IMPs (Gemcitabine, Docetaxel,and Doxorubicin) 
Pharmacy sites do not have to follow the template below, but should ensure that all supplies 
have at a minimum the following additional labelling text in addition to normal dispensing 
labels.  (XXXX – to be completed according to local information) 
 
 
 
 
4.3  
Storage and Accountability of IMPs 
 
The Investigator or a delegated individual (e.g. pharmacist) must ensure that study drugs are 
stored and dispensed in accordance with local standard operation procedures and applicable 
regulatory requirements. 
 
Each patient taking part in the study should have a log maintained of the IMP administered, 
the date of administration, the cycle number, the dose administered and the brand, batch 
number and expiry date of the product administered. Logs can be supplied by the Cancer 
Research UK Clinical Trials Unit, Glasgow for use for the study but local documentation can 
also be used after approval by the Cancer Research UK Clinical Trials Unit, Glasgow. 
 
4.4  
IMP Destruction 
 
IMP destruction, if necessary, should be undertaken in line with local policies and procedures 
and a destruction log completed.  
 
 
5. Drug Interactions/ Contraindications with Concomitant Medications 
 
Please refer to the current Summary of Product Characteristics for the product for details on 
drug interactions and contraindications with concomitant medications. 
 
6. Trial Management and Data Collection 
 
6.1 Case report forms  
 
6.2 Data Flow 
 
 
 All queries will be sent from GOG Statistical and Data Centre (SDC) to the 
participating sites via SDC Electronic Data Entry System (SEDES) online application. 
  
LMS study (GOG-0277) EudraCT number: 2012-002852-17 
Principal  investigator: XXXX 
Sponsor: European Organisation of Research and Treatment of Cancer 
(EORTC) 
For clinical trial use only  
 
Cycle No: XXXX          Patient Trial  No: XXXX 


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 Investigators/ Authorised personnel will submit CRFs via SDC Electronic Data Entry 
System (SEDES) online application. 
 
 The GOG SDC is responsible for raising validation checks and for overall quality 
control of trial data. 
 
7. Assessment of Safety/ Reporting of Serious Adverse Events 
 
ICH GCP and the EU Directive 2001/20/EC require that both investigators and sponsors 
follow specific procedures when notifying and reporting adverse events/ reactions in clinical 
trials. These procedures are described in this section. 
 
7.1 
Definitions 
 
These definitions reflect the minimal regulatory obligations; specific protocol requirements 
might apply in addition. 
 
AE: An Adverse Event is defined as “any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment”. An adverse event can 
therefore be any unfavourable and unintended signs (such as rash or enlarged liver), 
symptoms (such as nausea or chest pain), an abnormal laboratory finding (including results of 
blood tests, x-rays or scans) or a disease temporarily associated with the use of the protocol 
treatment, whether or not considered related to the investigational medicinal product. 
 
AR: An Adverse reaction of an investigational medicinal product is defined as “any 
noxious and unintended response to a medicinal product related to any dose administered”. 
All adverse events judged by either the reporting investigator or the sponsor as having a 
reasonable causal relationship to a medicinal product qualify as adverse reactions. The 
expression reasonable causal relationship means to convey in general that there is evidence or 
argument to suggest a causal relationship. 
 
UAR: An Unexpected Adverse Reaction is “any adverse reaction, the nature, or severity of 
which is not consistent with the applicable product information" (e.g. investigator's brochure 
for an unapproved investigational product or summary of product characteristics (SmPC) for 
a marketed product). 
When the outcome of the adverse reaction is not consistent with the applicable product 
information this adverse reaction should be considered as unexpected. 
 
Severity: The term “severe” is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate or severe, or as described in CTC grades); the event itself, 
however, may be of relative minor medical significance (such as severe headache). This is 
not the same as “serious,” which is based on patient/event outcome or action criteria usually 
associated with events that pose a threat to patient’s life or functioning. Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations.  
 
SAE: A Serious Adverse Event is defined as any untoward medical occurrence or effect in a 
patient, whether or not considered related to the protocol treatment, that at any dose: 
results in death 
 


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♦ is life-threatening (i.e. an event in which the subject was at risk of death at the time of 
event; it does not refer to an event which hypothetically might have caused death if it was 
more severe) 
♦ requires inpatient hospitalization or prolongation of existing patient hospitalization 
♦ results in persistent or significant disability or incapacity 
♦ is a congenital anomaly or birth defect 
♦ is a medically important event or reaction. 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious such as important medical events that might not be 
immediately life-threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result 
in hospitalization, or development of drug dependency or drug abuse. 
! Grade 4 anaphylaxis reactions, regardless of whether a hospitalization is required also 
need to be reported as an SAE 
SAR: A Serious Adverse Reaction is defined as any SAE which is considered related to the 
protocol treatment.  
 
SUSAR: Suspected Unexpected Serious Adverse Reaction.  
SUSARs occurring in clinical investigations qualify for expedited reporting to the appropriate 
Regulatory Authorities within the following timeframes: 
 
♦ Fatal or life-threatening SUSARs within 7 calendar days 
♦ Non-fatal or non-life-threatening SUSARs within 15 calendar days 
Inpatient hospitalization: a hospital stay equal to, or greater than, 24 hours. 
 
Second primary malignancy is one unrelated to the treatment of a previous malignancy (and 
is NOT a metastasis from the previous malignancy). 
 
Secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the previous malignancy. 
 
7.2 
Exceptions 
 
The following situations do not need to be reported as SAEs:  
 
♦ Elective hospitalization for pre-existing conditions that have not been exacerbated by trial 
treatment. 
♦ A hospitalization which was planned before the patient consented for study participation 
and where admission did not take longer than anticipated. 
♦ A hospitalization planned for protocol related treatment or protocol related procedure as 
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♦ Social and/or convenience admission to a hospital 
♦ Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that leads 
to the procedure is an (S)AE. 
♦ Situations where an untoward medical occurrence did not occur (palliative care, 
rehabilitation, overdose without occurrence of an adverse event). 
♦ Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
By EORTC convention, clinical events related to the primary cancer being studied or to the 
primary cancer progression are not to be reported as SAEs, even if they meet any of the 
seriousness criteria from the standard SAE definition, unless the event is more severe than 
expected and therefore the investigator considers that their clinical significance deserves 
reporting.  
 
7.3 
Severity Assessment 
 
The severity of all AEs (serious and non-serious) in this trial should be graded using CTCAE 
v4.0.  A copy of this can be downloaded from the following website: 
 
www.eortc.org\investigators-area\ctc 
 
7.4 
Causality Assessment 
 
The investigator is obligated to assess the relationship between protocol treatment and the 
occurrence of each SAE following the definitions in this table: 
 
Relationship 
to 
the 
protocol treatment  
Description 
Definite 
The adverse event is clearly related to the agent(s).  
Probable 
The adverse event is likely related to the agent(s). 
Possible 
The adverse event may be related to the agent(s). 
Unlikely 
The adverse event is doubtfully related to the agent(s). 
Unrelated 
The adverse event is clearly NOT related to the agent(s). 
 
The investigator will use clinical judgment to determine the relationship. Alternative causes, 
such as natural history of the underlying diseases, medical history, concurrent conditions, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
protocol treatment will be considered and investigated. 
The decision will be recorded on the SAE form and if necessary the reason for the decision 
will also be recorded. 
 
7.5 
Expectedness Assessment 
 
The expectedness assessment is the responsibility of the sponsor of the study. The 
expectedness assessment will be performed against the following reference documents: 
 
♦ For Gemcitabine: Summary of Product Characteristics (SmPC) 
♦ For Docetaxel: Summary of Product Characteristics (SmPC) 


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♦ For Doxorubicin: Summary of Product Characteristics (SmPC) 
 
7.6 
Reporting Procedure for Investigators 
 
This procedure applies to all Serious Adverse Events (SAEs) occurring from the time a 
subject is registered until  
 
For investigational arm: 30 days after last protocol treatment administration and to any SAE 
that occurs outside of the SAE detection period (after the 30-days period), if it is considered 
to have a reasonable possibility to be related to the protocol treatment or study participation. 
 
For the observation arm: end of week 24 
 
Registration till 30 days after last protocol treatment 
administration/ end of week 24 (in Observation arm): 
All SAEs 
From day 31 after last protocol treatment 
administration: 
Only related SAEs 
 
 
Any secondary malignancy should also be reported in expedited way on a SAE form 
with the appropriate seriousness criteria! 
 
All reporting must be done by the principal investigator or authorized staff member (i.e. on 
the signature list) to confirm the accuracy of the report. 
 
All SAE data must be collected on the study-specific SAE form. 
 
All SAEs must be reported immediately and no later than 24 hours from the time the 
investigator or staff became aware of the event. 
 
All SAE-related information needs to be provided in English. 
 
All additional documents in local language must be accompanied by a translation in English, 
or the relevant information must be summarized in a follow-up SAE report form. 
 
All SAE-related information must be faxed to: 
 
EORTC Pharmacovigilance Unit: 
 
Fax No. +32 2 772 8027 
 
To enable the Sponsor to comply with regulatory reporting requirements, all initial SAE 
reports should always include the following minimal information: an identifiable patient 
(SeqID), a suspect medicinal product if applicable, an identifiable reporting source, the 
description of the medical event and seriousness criteria, as well as the causality assessment 
by the investigator. Complete information requested on the SAE form of any reported serious 
adverse event must be returned within 7 calendar days of the initial report. If the completed 
form is not received within this deadline, the Pharmacovigilance Unit will make a written 
request to the investigator. 
 
Queries sent out by the EORTC Pharmacovigilance Unit need to be answered within 7 
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All forms need to be dated and signed by the principal investigator or any authorized staff 
member (i.e. on the signature list). 
 
7.7 
Reporting Responsibilities for EORTC 
 
The EORTC Pharmacovigilance Unit will forward all EORTC/NCRN SAE reports to the 
appropriate persons within the EORTC Headquarters and enter them into AdEERs. 
The EORTC Pharmacovigilance Unit will take in charge the reporting of SUSARs to the 
Competent Authorities, Ethics committees, EudraVigilance Clinical Trial Module (EVCTM) 
and all participating investigators, whenever applicable, or as specified in the intergroup 
agreement. 
 
7.8 
Pregnancy Reporting 
 
Pregnancy occurring during a patient’s participation in this trial, although not considered an 
SAE, must be notified to the EORTC Pharmacovigilance Unit within the same timelines as 
an SAE (within 24 hours) on a Pregnancy Notification Form. The outcome of a pregnancy 
should be followed up carefully and any adverse outcome to the mother or the child should 
be reported. This also applies to pregnancies in female partners of a male patient participating 
in this trial. 
♦ Any pregnancy in a female subject or in a female partner of a male subject diagnosed 
during the treatment period or within 30 days after last protocol treatment administration 
must be reported to the EORTC Pharmacovigilance Unit  
♦ This must be reported within 24 hours of first becoming aware of the event by fax, to the 
Pharmacovigilance Unit on a Pregnancy Notification Form  
♦ If an SAE occurs in conjunction with the pregnancy, please also complete an SAE form 
as explained in the SAE reporting chapter 
 
7.9 Development Safety Update Reports 
 
Development Safety Update Reports (DSURs) will be prepared by GOG in the ICH E2F 
format. The DSUR is to present a comprehensive, thoughtful annual review and evaluation 
of pertinent safety information collected during the reporting period related to a drug under 
investigation, whether or not it is marketed, by: (1) examining whether the information 
obtained by the sponsor during the reporting period is in accord with previous knowledge of 
the investigational drug safety;(2) describing new safety issues that could have an impact on 
the protection of clinical trial subjects;(3) summarising the current understanding and 
management of identified and potential risks; and (4) providing an update on the status of the 
clinical investigation/development programme and study results. 
 
8. Study Responsibilities 
 
The European Organisation for Research and Treatment of Cancer (EORTC) is the sole legal 
Sponsor for participants in the European Union. 
 
NHS Greater Glasgow and Clyde [NHS GG&C] (Legal name Greater Glasgow Health Board 
[GGHB]) is the Sponsor’s contact (EORTC) for correspondence in the UK.  
 


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Prior to study initiation, an intergroup agreement will be put in place between the EORTC 
and [NHS GG&C] (Legal Name Greater Glasgow Health Board). The roles and 
responsibilities of each party in relation to UK participation in the trial are laid out in this 
agreement signed by both organisations. 
 
A Clinical Study Agreement will be put in place between NHS Greater Glasgow and Clyde 
and each of the participating sites. This agreement outlines the responsibilities of each party’s 
responsibilities in the running of the trial; the sponsor, the Chief Investigator (C.I.), the 
Cancer Research UK Clinical Trials Unit, Glasgow (CTU), the Principal Investigator (P.I.) at 
the Participating Site and the Participating Site. In summary, they are as follows: 
 
8.1  
Sponsor Responsibilities (EORTC) 
The  Sponsor’s responsibilities will be for Authorisation and Ethics Committee opinion, GCP 
and Conduct and Pharmacovigilance. In the UK, the majority of the Sponsor’s 
responsibilities have been delegated to NHS GG&C which has, in turn, delegated these to the 
Chief Investigator (CI) who performs these via the CTU as the co-ordinating centre for the 
study in the UK. As such, the main role of the Sponsor is to ensure that NHS GG&C, the CI 
and CTU fulfil their responsibilities as outlined in the Clinical Study Agreement and to 
ensure that any identified “risks” either have controls or action points put in place. 
 
8.2  
CR-UK Clinical Trials Unit (CTU) 
NHS GG&C via the CTU is responsible for the co-ordination of the clinical trial in the UK. 
This includes all regulatory submissions (ethics, R&D and CTA), all administration relating 
to the submissions and any amendments, circulation of all correspondence to participating 
sites, ongoing communication with participating sites, and where applicable the management 
of any financial arrangements (e.g. payment for pathology samples etc). 
 
8.3 
 Chief Investigator (C.I.) 
The Chief Investigator has delegated the majority of his/her responsibilities to the CTU. The 
C.I. is directly responsible for ensuring the protocol and any amendments are in place, for 
review of SAE forms and determination of whether they meet the criteria for a SUSAR, and 
to provide advice and recommendations on medical issues that arise involving the 
management of the patients on the study. As the Chief Investigator is external to NHS GG&C 
an agreement will be put in place between the Chief Investigator’s employer and NHS 
GG&C for this study to outline the responsibilities of each party. 
 
8.4 
 Participating Site 
The Participating Site is responsible for the management of the trial within their site. This 
includes ensuring local management approval has been given, ensuring the study is 
conducted according to ICH GCP requirements, and ensuring the appropriate insurance or 
indemnity is in place. The Participating Site is also responsible for arranging access for on-
site monitoring and auditing as identified in the study protocol and also for regulatory 
inspections. 
 
8.5 
 Principal Investigator (P.I.) 
The P.I. is responsible for the delegation of study activities within their unit and ensuring all 
personnel are adequately trained and qualified to carry out their responsibilities. The P.I will 
be required to provide evidence of GCP training (usually a certificate) or  undergo the 
required GCP training. Regarding the management of patients within their site, the P.I. is 
responsible for the safety and well being of trial patients, reporting any deviations from the 


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protocol to the CTU as well as any SAEs or safety issues. Full details of the responsibilities 
of the P.I. are outlined in the Clinical Study Agreement. Two original copies of this will be 
held – one with NHS GG&C and the other at the Participating Site. A photocopy of the 
signed agreement will also be held within the CTU and EORTC. 
 
9. Liability and Indemnity 
 
The Health Board/NHS Trust at each participating site is responsible for the following: 
 
1. 
Acts and omissions of its own staff and others engaged by it, including the Clinical 
Trials Unit and PI; 
2. 
Ensuring the appropriate insurance administered by the National Health Service 
Litigation Authority is in place; 
3. 
Ensuring any non-NHS employee involved in the clinical trial has an Honorary 
Contract with the Trust to cover access to patients and liability arrangements. 
 
These responsibilities are outlined and agreed within the Clinical Study Agreement.  
 
Clinical trial insurance has been taken out according to the laws of the countries where the 
study will be conducted by the EORTC. An insurance certificate will be made available to 
participating sites at the time of study initiation.  
 
Clinical trial insurance is only valid in centres in the UK which have been authorised.  Please 
refer to the section 2 of this appendix for details of the investigator authorisation procedure 
for the study. 
 
10. 
Regulatory Issues 
 
10.1 Clinical Trials Authorisation (CTA) 
 
The Cancer Research UK Clinical Trials Unit, Glasgow will apply to the MHRA for a 
clinical trials authorisation (CTA) to conduct the trial in the UK and will also be responsible 
for the maintenance of the CTA. 
 
10.2 Ethics and Research & Development Approval 
 
Ethics favourable opinion will be sought for the study from a Main REC prior to 
commencement of this trial.  Further to that approval each participating site will be 
responsible for obtaining their own local approval by submitting an SSI to their appropriate 
R&D department for management approval. 
 
10.3 Informed Consent 
 
Consent to enter the study must be sought from each participant only after full explanation 
has been given, the participant has been given an information sheet and a minimum of 24 
hours to consider trial participation.  Signed participant consent must be obtained, the consent 
forms should also be signed by the person undertaking the consent procedure at site, who 
must be detailed on the Staff Contact and Responsibility Log as having this authorisation. 
The Principal Investigator is responsible for ensuring if taking consent is delegated to a 


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designee, the designee is suitably qualified by training or experience to take informed 
consent. 
 
 The right of the participant to refuse to participate without giving reasons must be respected.  
After the participant has entered the trial the clinician remains free to give alternative 
treatment to that specified in the protocol at any stage if he/she feels it is in the best interests 
of the participant, but the reasons for doing so must be recorded.  In these cases the 
participants remain within the study for the purposes of follow-up and data analysis.  All 
participants are free to withdraw at any time from the protocol treatment without giving 
reasons and without prejudicing further treatment. 
 
An original completed consent form must be retained at each site in the appropriate section of 
the Investigator Site File, and a copy placed in the patient’s medical records. All patients 
must be given an original of the signed patient information sheet and consent form for their 
records. Consent forms must be retained on site and not submitted to the Trials Office. 
 
10.4  Confidentiality 
 
National Health Service Guidelines for storage, transmittal and disclosure of patient 
information will be followed at all times. 
 
This study will be carried out in accordance with ICH GCP Guidelines. Following formal 
admission to the study, patient data will be recorded in the hospital case record in the usual 
way including the circumstances of their entry to the study. Additionally data will be held in  
study case report forms (CRF). These files will be identified by a trial number and patient 
initials only. 
 
Representatives from the Study Sponsors and from the regulatory authorities will be given 
access to the records that relate to the study. They will have full access to the anonymous 
CRF for the purposes of data validation. 
 
Results of the study may be communicated at scientific meetings and will contribute to the 
scientific literature. At no time will this be done in such a way that an individual patient may 
be identified. 
 
 
10.5  Quality Assurance/Quality Control 
 
Quality Assurance/Quality Control will be maintained by the following requirements and 
activities: 
 
• All study sites taking part in the trial will be required to participate in site initiation to 
ensure compliance with the protocol and allow training on study procedures and data 
collection methods. 
 
• Trial Investigators and site staff must ensure that the trial is conducted in compliance 
with the protocol, GCP and applicable regulatory requirements. 
 
• The CR-UK CTU, Glasgow will the assist the Trial Investigators and check they are 
complying with protocol, GCP and regulatory requirements by monitoring trial 


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documentation. Trial data and documentation will be checked for completeness, 
accuracy and reliability at monitoring visits.  
 
 
10.6  Monitoring 
 
Central Monitoring 
Study sites will be centrally monitored by checking CRFs and other study documents for 
protocol compliance, data accuracy and completeness. 
 
On-Site Monitoring 
All UK participating study sites will be visited by a member of the CR-UK Clinical Trials 
Unit monitoring team. The PI will allow the study staff access to source documents as 
requested. In addition, the pharmacy department responsible for the trial will be visited to 
allow monitoring of the pharmacy site file and review of security, storage and accountability 
of trial drug. Investigators and site staff will be notified in advance about forthcoming 
monitoring visits. On occasion, members of the CR-UK CTU monitoring team may be 
accompanied by other trial staff from the unit for training purposes. 
 
 
10.7 Audits and Inspections 
 
Trial Investigators must permit trial related monitoring, audits, REC review and regulatory 
inspections as required, by providing direct access to source data, CRFs and other documents 
(patients medical records, trial site file, and other pertinent data). 
 
The study may be subject to inspection and audit by EORTC under their remit as Sponsor the 
CR-UK CTU and other regulatory bodies, i.e. the MHRA, to ensure adherence to GCP, the 
Gynaecologic Oncology Group (GOG) as the lead co-ordinating group for the trial. 
 
If an inspection is scheduled at any participating site, the site must notify the CR-UK CTU at 
the earliest opportunity. 
 
11. 
Patient Information Sheets and Consent Forms 
 
The UK Main Patient Information Sheet and Consent Form and Translational Patient 
Information Sheet will be provided separately for this study. Please check local approval 
letters to ensure the most current approved Patient Information Sheets and Consent Forms are 
being used. 
 
12. 
GP Letter 
 
The UK GP letter will be provided separately for this study. Please check local approval 
letters to ensure the most current GP letter is being used. 
 
13. 
Translational Research 
 
In this trial, tissue specimens will be collected for future translational research. However, 
specimen submission for translational research is not mandatory for participation in the 


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clinical study. Specimens will be collected from enrolled patients who are willing and who 
have consented to the future translational research. 
 
 **Please note submission of a stained pathology slide for confirming eligibility to the study 
is mandatory for all patients as detailed in section 3.1 for central pathological review is 
mandatory for all patients.** The samples provided for central pathology review will be 
returned to sites after pathology review has taken place for patients who have not consented 
to participate in the future translational research . 
 
For patients who have consented to take part in the future translational research, the reference 
pathologist will retain the unstained slides for future translational research, unless specifically 
required otherwise.