Clinical trial NCT01519869
Conditions: Primary Peritoneal Carcinoma Ovarian Carcinoma Fallopian Tube Carcinoma
Keywords: peritoneal carcinoma ovarian fallopian tube neoadjuvant chemotherapy surgical debulking
Sponsor: Rachel Miller
Start date: 2012-03-01; Completion date: 2019-10-11
Enrollment: 28 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a prospective study to evaluate the hypothesis that platinum-based neoadjuvant chemotherapy followed by interval surgical debulking with platinum-based adjuvant chemotherapy is associated with improved maximal surgical cytoreduction rates, comparable survival, decreased morbidity, and increased quality of life in patients with International Federation of Gynecologic Oncology stages IIIC and IV ovarian, primary peritoneal, or fallopian tube cancer when compared to historical controls and to evaluate the hypothesis that cancer induced inflammation is a predictor of poor prognosis and response to therapy in this group of ovarian cancer patients.

Detailed description:

Arms: arm 1: platinum-based neoadjuvant chemotherapy followed by interval surgical debulking with platinum-based adjuvant chemotherapy
Interventions: intervention 1: neoadjuvant chemotherapy
Intervention descriptions: intervention 1: platinum-based neoadjuvant chemotherapy followed by interval surgical debulking with platinum-based adjuvant chemotherapy

Protocol documents:
Prot_SAP_000.pdf: 
PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 Study Title: Trial of Chemotherapy in Ovarian, Fallopian Tube and Peritoneal Carcinoma 
Institution/Site:  
University of Kentucky 
Document (Approval/Update) Date: 
11/11/2014 
NCT Number: 
NCT01519869 
IRB Number 
11-0903 
Coversheet created: 
11/10/20 
 
 


11-GYN-098-MCC 
 
 
Neoadjuvant Platinum-based Chemotherapy in Advanced Ovarian, Fallopian Tube, 
and Primary Peritoneal Carcinoma Trial Protocol 
 
A non-randomized phase II study of neoadjuvant chemotherapy with interval 
surgical debulking in patients with advanced ovarian, fallopian tube, primary 
peritoneal carcinoma 
 
PI:   
Rachel Ware Miller, MD 
 
Co-investigators:   
J.R. van Nagell, MD 
Frederick R. Ueland, MD 
Christopher P. DeSimone, MD 
Paul DePriest, MD 
 
Biologics: 
 
Daret St. Clair, PhD 
 
 
 
D. Allan Butterfield, PhD 
 
Statistician: 
 
Emily Van Meter, PhD 
 
Pathologist: 
 
Michael Cibull, MD and Rouzan Karabakhtsian, MD 
 
Participating Institutions:  
University of Kentucky 
 
 
 
 
 
 
 
Protocol Version 9.2 dated 11/11/2014 


 
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SCHEMA 
 
Patients with FIGO Stage IIIC/IV ovarian, fallopian tube, primary peritoneal carcinoma 
↓ 
 
3 Cycles Neoadjuvant Chemotherapy* 
 
↓ 
 
Interval Surgical Debulking** 
 
↓ 
 
3-5 Cycles Adjuvant Chemotherapy+ 
 
 
*Paclitaxel 175mg/m2 IV over 3 hours followed by Carboplatin AUC 6 IV over 30 minutes 
every 21 days  
 
**Approximately 3-4 weeks after 3rd cycle of chemotherapy 
 
+Preferably starts  within 2 weeks of surgery (exceptions may be made by the 
Principal Investigator) with same dose parameters as neoadjuvant chemotherapy; 
adjuvant chemotherapy consists of 3-5 cycles based on discretion of treating 
physician with the goal that patients are treated with one cycle beyond 
normalization of CA 125/no radiographic or clinical evidence of disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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OUTCOME MEASURES 
PRIMARY ENDPOINT 
 
Rate of maximal surgical cytoreduction (ie, no gross residual disease) 
 
SECONDARY ENDPOINTS 
 
Progression-free survival (PFS) 
 
Overall survival (OS) 
 
Response rate (RR) 
 
Toxicity related to treatment 
 
Surgical outcomes 
 
Quality of life 
 
Correlative studies (blood, tumor tissue) 
 
 


 
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TABLE OF CONTENTS 
 
 
 
 
 
 
 
PAGE 
 
1.0 
OBJECTIVES  
 
 
 
 
 
 
 
  5           
 
2.0 
BACKGROUND AND RATIONALE  
 
 
 
 
  6          
 
3.0  
PATIENT ELIGIBILITY AND EXCLUSIONS  
 
 
 
15 
 
4.0 
STUDY MODALITIES 
 
 
 
 
 
 
17 
 
5.0 
TREATMENT PLAN  
 
 
 
 
 
 
21 
 
6.0 
TREATMENT MODIFICATIONS 
 
 
 
 
 
25 
 
7.0 
STUDY PARAMETERS 
 
 
 
 
 
 
31 
 
8.0 
EVALUATION CRITERIA 
 
 
 
 
 
 
32 
 
9.0 
DURATION OF STUDY 
 
 
 
 
 
 
40 
 
10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
 
41 
 
11.0  BIOLOGIC STUDIES  
 
 
 
 
 
 
42 
 
 
12.0 
STATISTICAL CONSIDERATIONS  
 
 
 
 
43 
 
13.0 
BIBLIOGRAPHY 
 
 
 
 
 
 
 
45 
 
 
APPENDIX I  
FIGO Staging System for Primary Carcinoma of the Ovary (1985) 
APPENDIX II  
FACT-O TOI 
APPENDIX III  
Anaphylaxis Precautions  
APPENDIX IV  
Carboplatin Dose Calcification 
APPENDIX V  
Standards for Operative Note Details 
APPENDIX VI  
Chemotherapy Standard Order Set 
APPENDIX VII 
Biological Correlative Processing Instructions 
 


 
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1.0 
OBJECTIVES 
 
 
This is a prospective study to evaluate the hypothesis that:    
 
 
a) platinum-based neoadjuvant chemotherapy followed by interval surgical 
debulking with platinum-based adjuvant chemotherapy is associated with 
improved maximal surgical cytoreduction rates, comparable survival, 
decreased morbidity, and increased quality of life in patients with 
International Federation of Gynecologic Oncology (FIGO, Appendix I) 
stages IIIC and IV ovarian, primary peritoneal, or fallopian tube cancer 
when compared to historical controls 20,45, and  
 
b) cancer induced inflammation is a predictor of poor prognosis and 
response to therapy in this group of ovarian cancer patients. 
 
 
1.1 
Primary Objectives 
 
 
 
 
1.11 
To determine maximal surgical cytoreduction debulking rate (see 
Appendix V), i.e. no gross residual disease, in a group of patients with 
FIGO stages  IIIC and IV ovarian, primary peritoneal, or fallopian tube 
cancer who received 3 cycles of platinum-based neoadjuvant 
chemotherapy. 
 
 
1.2 
Secondary Objectives 
 
 
 
 
1.21 
To determine progression-free survival in a group of patients with 
FIGO stages IIIC and IV ovarian, primary peritoneal, or fallopian 
tube cancer treated by neoadjuvant chemotherapy followed by 
interval debulking and adjuvant chemotherapy. 
 
 
 
 
1.22 
To determine overall survival in a group of patients with 
FIGO stages IIIC and IV ovarian, primary peritoneal, or fallopian 
tube cancer treated by neoadjuvant chemotherapy followed by 
interval debulking and adjuvant chemotherapy. 
 
 
 
1.23 
To determine response rate to chemotherapy in patients who  
 
 
 
undergo neoadjuvant chemotherapy followed by interval debulking 
 
 
 
and adjuvant chemotherapy. 
 
 
 
1.24 
To evaluate the toxicity from chemotherapy, as measured by the  
Common Toxicity Criteria for Adverse Events v4.0.  
 
 
 
 
 
1.25 
To evaluate operative outcomes including length of surgery,  
 
 
length of hospital stay, ICU admissions, transfusions, and   
 
 
intraoperative  complications (blood loss >1500mL, unintentional  
 
 
damage to organs requiring repair). 
 
 
 
1.26  To evaluate Quality of Life (QOL, as measured by the FACT-O  
 
 
 
TOI) following treatment with this regimen. (Appendix II) 
 


 
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1.27 
To assess, in an exploratory manner, the correlation between 
biologic indicators of inflammation and oxidative stress, including 
TNF-a, TNF receptor II, protein oxidation, CRP, Il-6 and Il-8 and 
tumor tissue oxidation before and after neo-adjuvant therapy, and 
clinical outcomes, including overall survival, tumor response, and 
quality of life variables. 
 
 
 
 
2.0 
BACKGROUND AND RATIONALE 
 
 
2.1 
Standard Management of Advanced Ovarian, Primary Peritoneal, and  
 
 
Fallopian Tube Carcinoma 
 
With over 200,000 new cases of ovarian cancer diagnosed worldwide 
each year, ovarian cancer is the 2nd most common gynecologic cancer 
and the most common cause of gynecologic cancer death.  It is estimated 
that there will be an estimated 21,880 new cases of ovarian cancer and 
13,850 deaths from the disease in 2010 in the United States1.  The 
standard management of advanced epithelial ovarian, primary peritoneal, 
and fallopian tube cancer is primary debulking surgery followed by 
systemic chemotherapy with carboplatin and paclitaxel2-7.  The extent of 
surgical cytoreduction or debulking at the time of primary surgery 
improves patient survival8.   While rates of optimal tumor debulking, 
defined as less than 1cm residual disease, at centers with experienced 
gynecologic oncologists have been reported to be as high as 70% in 
selected institutions, most centers will achieve optimal surgical debulking 
in only 30-60% of patients with Stage IIIC/IV ovarian, primary peritoneal, 
or fallopian tube cancer9,10.   
 
 
2.2 
New Strategies to Improve Outcomes 
 
Five-year overall survival for ovarian cancer is around 50% for all 
patients.  Unfortunately, over 2/3 of patients have stage III or stage IV 
disease at the time of diagnosis.  The 5-year survival for these patients is 
30%, as opposed to 90% for patients with disease confined to the ovary.  
Despite advancements in surgical techniques and chemotherapy, trends 
in survival have changed little over the past 30 years. 
 
Initial surgical debulking has been the standard of care for patients with 
ovarian cancer since the 1930’s.  The landmark study by Griffiths in 1975 
showed an inverse relationship between the extent of residual disease 
after primary surgery and survival11.  The concept of surgical debulking to 
improve survival is based on several principles including:  1) elimination 
of pharmacologic sanctuaries by removal of poorly vascularized masses, 
2) increased sensitivity to chemotherapy secondary to higher growth 
fraction of small residual tumors, and 3) less resistance to chemotherapy 
as a result of fewer chemotherapy cycles.  Bristow published a meta-
analysis in 2002 showing that optimal cytoreductive surgery was the most 
significant determinant of patient survival in those patients with stage III or 
IV ovarian cancer treated with platinum-based chemotherapy8.  The 
definition of “optimal” with respect to surgical debulking for ovarian cancer 


 
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has evolved over time.  Initially, ≤ 2 cm residual disease was considered 
optimal, which was subsequently reduced to ≤ 1 cm.  More recently, the 
concept of optimal surgical debulking to less than or equal to 1 cm of 
residual disease has shifted to maximal surgical debulking, which is 
defined as no gross residual disease.  Frequently patients with advanced 
ovarian cancer have disease involving the rectosigmoid and the upper 
abdomen including the liver, porta hepatis, spleen, distal pancreas, and 
diaphragm.  In order to achieve maximal surgical cytoreduction resulting 
in no gross residual disease, surgeons must perform aggressive surgical 
procedures including en bloc resection of the uterus, ovaries, and sigmoid 
colon, liver resection, diaphragm stripping, splenectomy, and distal 
pancreatectomy.  Several reports have indicated acceptable complication 
rates and feasibility of performing these procedures for the purpose of 
cytoreductive surgery in ovarian cancer12-19.  However, maximal and 
optimal surgical cytoreductive rates vary widely among institutions, 
ranging from less than 25% to 75% in more experienced centers8.   
Patients with extensive liver disease, pulmonary metastases, or extensive 
disease throughout the small bowel mesentery generally cannot be 
maximally debulked to no gross residual disease status prior to initiating 
adjuvant chemotherapy. 
 
Neoadjuvant chemotherapy, followed by interval surgical cytoreduction 
and adjuvant chemotherapy, has been proposed as an alternative to 
initial surgical cytoreduction in patients with advanced ovarian cancer.      
 
 
2.3 
Rationale for Neoadjuvant Chemotherapy and Interval Debulking 
 
There is no evidence to support initial surgical debulking in patients with 
advanced ovarian cancer that is unlikely to be surgically resectable.  
There is evidence to suggest that there is survival benefit when surgical 
debulking to less than 1 cm residual disease is possible.  However, the 
greatest benefit is seen in patients with no gross residual disease after 
initial cytoreductive surgery.  It is also clear that there is no benefit of 
initial cytoreductive surgery in patients with ovarian cancer when more 
than 1 cm residual disease remains after attempted debulking. 
 
 
2.4 
Role of Neoadjuvant Platinum-based Chemotherapy and Interval   
 
 
Debulking in Ovarian, Primary Peritoneal, and Fallopian Tube Carcinoma 
 
Vergote et al. conducted a randomized phase III trial comparing upfront 
debulking surgery with neoadjuvant chemotherapy in patients with Stage 
IIIC or IV epithelial ovarian carcinoma (EORTC 55971)20.  Patients were 
randomized to either primary debulking surgery followed by at least 6 
courses of platinum-based chemotherapy (Arm A) or 3 courses of 
platinum-based neoadjuvant chemotherapy, interval debulking surgery (in 
patients with a response or stable disease) and at least 3 more courses of 
platinum-based chemotherapy (Arm B).  Seven-hundred eighteen 
patients were enrolled and 670 were randomized.  Less than half of the 
patients (41.6%) undergoing primary surgery had ≤1cm residual disease 
at the completion of cytoreductive surgery, as opposed to 80.6% of 
patients who had ≤1cm residual disease after interval debulking.  Only 


 
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19.4% of the patients undergoing primary surgery had no residual tumor 
(maximal surgical debulking) after cytoreductive surgery, compared to 
51.2% of patients in the neoadjuvant chemotherapy group.  Overall 
survival and progression-free survival were similar in the two groups.  In 
the primary surgery group, the median overall survival was 29 months, 
versus 30 months in the neoadjuvant chemotherapy group.  The median 
progression-free survival was 12 months in both groups.  In multivariate 
analyses, absence of residual tumor after surgery was the strongest 
independent predictor of survival (P<0.001), followed by stage IIIC 
disease (P=0.001), small tumor size before randomization (P=0.001), 
endometrioid histologic type (P=0.005), and younger age (P=0.005).  
They concluded that “neoadjuvant chemotherapy is not inferior to primary 
cytoreductive surgery for patients with stage IIIC or IV ovarian 
carcinoma,” and that there were “no significant advantages” observed in 
either arm of the trial “with respect to survival, adverse effects, quality of 
life, or postoperative morbidity or mortality”.   
 
Kumar et al. presented findings from a similar randomized trial at the 
2007 Annual ASCO meeting21.  The trial included 128 patients with 
epithelial ovarian cancer, who were randomized to either upfront 
debulking surgery followed by 6 cycles of paclitaxel and carboplatin (Arm 
A) or neoadjuvant chemotherapy with 3 cycles of paclitaxel and 
carboplatin followed by interval debulking surgery then 3 more cycles of 
the same chemotherapy (Arm B).  Patients in the neoadjuvant 
chemotherapy arm had a higher optimal debulking rate (p < 0.0001), 
decreased blood loss during surgery (mean loss 520 ml vs. 373 ml, p < 
0.003), and reduced postoperative infections (14.8% vs. 2.5%, <0.04).  
Mean operative time and hospital stay were similar in both arms.  The 
median overall survival and disease free survival were 42 vs. 29 months 
(p=0.07) and 20 vs. 25 months (p = 0.11) for arms A and B, respectively, 
which is not significantly different at a median follow up of 41 months.  
Quality of life scores were significantly better in the neoadjuvant 
chemotherapy arm (93 vs. 114, p < 0.001).  They concluded, 
“neoadjuvant chemotherapy in advanced epithelial ovarian cancer is 
associated with a higher optimal debulking rate with reduced 
postoperative morbidity and improved quality of life”. 
 
In 2009, Onda et al. published “Feasibility study of neoadjuvant 
chemotherapy followed by interval debulking surgery for stage IIIC/IV 
ovarian, tubal, and peritoneal cancers:  Japan Clinical Oncology Group 
Study JCOG0206” in Gynecologic Oncology22.  The study included 56 
patients with clinically diagnosed staged III/IV müllerian carcinomas 
based on imaging studies, cytology, and tumor markers.  All patients 
underwent diagnostic laparoscopy to confirm the clinical diagnosis.  The 
patient subsequently underwent 4 cycles of paclitaxel and carboplatin 
followed by interval debulking then 4 more cycles of the same 
chemotherapy.  The primary endpoint was complete clinical remission 
and the secondary endpoint was the positive predictive value of clinical 
diagnosis.  The authors found that the positive predictive value of clinical 
diagnosis was 95% for tumor origin, histology, and stage of disease.  
Complete clinical response was seen in 42% of patients, which was 


 
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confirmed with diagnostic laparoscopy at the end of treatment.  The 
median overall survival was 45 months and the median progression-free 
survival was 14 months. 
 
 
2.5   
Rationale for Clinical Trial Design 
 
2.51 
Study Population 
 
 
A study population limited to patients with probable Stage IIIC or 
 
Stage IV ovarian, fallopian tube, or primary peritoneal carcinomas 
 
was selected because of the relatively high frequency of these 
 
cases and the limited probability that optimal cytoreduction (no 
 
visible disease) could be achieved by primary surgery alone.  
 
Furthermore, the results of this trial would be better generalized to 
 
the population at large with epithelial ovarian and primary 
 
peritoneal cancers by including the largest subset of these 
 
patients.  Patients with early stage epithelial ovarian cancers were 
 
not included because > 95 percent of these cases can be 
 
optimally debulked by primary surgery, and selective 
 
chemotherapy can be given postoperatively. 
 
2.52 
Sample Size Considerations 
 
Using previous results from a European study of neoadjuvant 
chemotherapy, 51.2% of patients in the neoadjuvant arm achieved 
maximal surgical debulking as compared to 19.4% of patients in 
the primary debulking control arm.20 Therefore, based on a 
hypothesis test of a single proportion with 90% power and a two-
sided type I error rate equal to 0.05, the first-stage sample size 
necessary for this single arm study to detect the same 
improvement in the percentage of neoadjuvant chemotherapy 
patients achieving optimal surgical debulking as compared to the 
European controls is 9 patients. The trial will be terminated if no 
more than 2 patients achieve maximal surgical debulking, as 
defined by no gross residual disease.  If the 9th patient is enrolled 
and only two prior patients meet requirements for maximal 
surgical debulking, then enrollment will be on hold until after 
surgery for the 9th patient.  If maximal surgical debulking is 
achieved in 3 or more of the 9 patients enrolled, the trial will 
continue to a second stage, which will involve enrollment of an 
additional 14 patients for a total of 23. Conservatively allowing 
20% drop out or loss to follow up, we plan to enroll 28 total 
patients. 
 
 
 
2.53 
Diagnostic Criteria 
 
 
 
In the aforementioned publication (see 2.4) by Onda et al. 
concerning the feasibility of neoadjuvant chemotherapy followed 
by interval debulking for stage III/IV ovarian, tubal, and peritoneal 
cancers, the authors reported that the positive predictive value of 
a combination of imaging studies, cytology, and tumor markers 


 
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was 100% for tumor origin and histology, and 95% for stage of 
disease.22  Furthermore, they concluded that it would be 
acceptable to omit diagnostic laparoscopy as a staging test in the 
future.  Based on this data, the diagnostic criteria needed for entry 
into this trial include evidence of metastatic disease on imaging 
studies (CT, CT/PET, MRI), cytologic examination of ascites 
and/or pleural fluid, or fine-needle aspirate of a tumor mass. 
- 
 
 
2.54 
Choice of Cytotoxic Chemotherapy and Optimum Number Cycles 
 
Since the mid 1980’s, platinum-based chemotherapy has been the 
standard of care in the treatment of ovarian cancer.  In GOG 47, 
227 patients were randomized to either doxorubicin-
cyclophosphamide versus cyclophosphamide-doxorubicin-
cisplatin.  Patients in the cisplatin arm had statistically significant 
improved progression-free and overall survival23.  In a search for 
better tolerated platinum agents, carboplatin was found to be as 
effective, and with fewer side effects than cisplatin, including 
emesis, nephrotoxicity, and neurotoxicity24-27.  In GOG 111, over 
400 patients were randomized to receive cisplatin-cyclophos-
phamide versus cisplatin-paclitaxel.  The paclitaxel arm resulted in 
significantly prolonged progression-free and overall survival28.  
Because of the convenience of avoiding pre- and post- 
chemotherapy hydration, and improved side effect profile, 
carboplatin was evaluated as a possible combination with 
paclitaxel in two randomized trials.  This combination was 
equivalent in efficacy to cisplatin-paclitaxel, but much better 
tolerated29,30. In 2004, carboplatin-paclitaxel was identified as the 
standard first-line therapy for ovarian cancer by the Ovarian 
Cancer Consensus. 
 
There is no prospective data on the recommended number of 
cytotoxic chemotherapy cycles for advanced epithelial ovarian, 
fallopian tube, or primary peritoneal carcinoma.  However, 6-8 
cycles are generally recommended based on historical phase III 
clinical trials.  There is no prospective data indicating that 
cumulative dose intensity, or number of cycles impacting overall 
survival. 
 
 
 
2.55 
Selected Substitution of Docetaxel for Paclitaxel 
 
Publication of results from GOG Protocol 011128 and a confirmatory 
European trial31 led to adoption of paclitaxel and carboplatin as 
the standard primary therapy for patients with advanced epithelial 
and peritoneal primary cancer. However, it is estimated that on 
the order of 5% of patients in the population eligible for 
participation in the current trial will develop peripheral neuropathy 
or refractory acute hypersensitivity infusion reactions which would 
necessitate discontinuation of paclitaxel. Docetaxel is a novel 
taxane with reduced potential for neurotoxicity compared with 
paclitaxel. In addition, docetaxel has been safely substituted for 


 
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paclitaxel in patients experiencing severe acute hypersensitivity to 
paclitaxel refractory where re-challenge is either unsuccessful or 
deemed unsafe.  
 
With regard to efficacy, there is evidence that docetaxel is an 
alternative treatment option to paclitaxel for patients with epithelial 
ovarian and peritoneal primary cancer. Docetaxel has been 
combined with cisplatin or carboplatin extensively in phase II and 
III clinical trials.  Docetaxel has substantial activity against platinum-
refractory ovarian carcinoma32 and is also active as primary therapy 
in ovarian cancer.33,34,34,36 A phase III randomized trial (SCOTROC) of 
docetaxel and carboplatin versus paclitaxel and carboplatin in 
patients with advanced epithelial ovarian cancer has recently 
been published.37 In this trial, patients received carboplatin at an 
AUC of 5 with either docetaxel at 75 mg/m2 1-hour IV infusion or 
paclitaxel at 175 mg/m2 3-hour IV infusion. Results of this trial 
demonstrated no significant difference in median progression-free 
survival (15.0 months versus 14.8 months), two year overall survival 
(64.2% versus 68.9%) or objective tumor response (58.7% 
versus 59.5%) for the combination of docetaxel and carboplatin 
versus the combination of paclitaxel and carboplatin, 
respectively. While docetaxel and carboplatin produced more 
neutropenia (Grade 3-4 neutropenia 94% for docetaxel and 
carboplatin versus 84% for paclitaxel and carboplatin, p < .001) 
and neutropenic complications than treatment with paclitaxel-
carboplatin, the docetaxel and carboplatin regimen was 
significantly less neurotoxic (Grade 2 neurosensory toxicity in 
11% for docetaxel and carboplatin versus 30% for paclitaxel and 
carboplatin, p < .001).  
 
The results of the SCOTROC trial have led many oncologists to 
select substitution of docetaxel for paclitaxel in first line therapy for 
patients with advanced epithelial and peritoneal primary cancer. 
Thus, in order to optimize cytotoxic therapy in all arms of the 
current trial, reduce the likelihood of protocol violations and avoid 
imbalances in the type of taxane utilized in each treatment arm, in 
the current trial docetaxel will be selectively substituted for paclitaxel 
in circumstances in which peripheral neuropathy or hypersensitivity 
warrants discontinuation of paclitaxel.  
 
 
 
2.56 
Post-Remission Therapy 
 
It is expected that all of the chemotherapy regimens employed in 
this trial will achieve an overall response rate of greater than 75%. 
However, as many as 90% of patients with stage III and stage IV  
epithelial ovarian, peritoneal primary and fallopian tube cancer in 
clinical complete remission will ultimately recur and die of 
disease. Therefore, a number of strategies are under active 
consideration to delay or prevent recurrence. Among these 
strategies include “consolidation” treatment with cytotoxic, 


 
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hormonal, or biologic targeted agents.   For example, recent data 
have revealed that continuation of single-agent paclitaxel on a 
monthly schedule for 12 cycles significantly extended 
progression-free survival.38 Certainly consolidation therapy has 
been implemented variably in clinical practice outside clinical trials 
with the decision based on physician and patient preference, with 
no evidence that overall survival is influenced by either treatment 
of patients in complete clinical remission or for that matter, at the 
time of clinical disease progression.  Due to the lack of evidence 
that any current consolidation approach is associated with an 
improvement in overall survival, and our desire to preserve the 
integrity of the progression-free interval, consolidation therapies 
will not be used. 
 
 
 
 
 
 
 
 
 
 
 
 
2.57 
CA-125 as a Biological Marker of Progressive Disease 
 
Serum levels of CA-125, a tumor-associated glycoprotein 
antigen, are elevated in 80% of patients with epithelial ovarian 
cancer.39 CA-125 has been monitored, often on a frequent basis, 
to verify response to therapy, presence of residual disease, and 
as early evidence of recurrence. However, CA-125 is not entirely 
tumor specific, and can be elevated in a variety of benign 
conditions, such as endometriosis, uterine fibroids, and pelvic 
inflammation; this is particularly true in pre-menopausal women. In 
addition, levels of CA-125 can be discordant with tumor response, 
both as false-positive and false-negative trends.  Nonetheless, 
because imaging modalities such as contrast computed 
tomography appear to be relatively insensitive in detecting 
disease progression, it has been standard practice for patients 
and physicians to interpret a progressive rise in CA-125 post-
therapy as evidence of recurrent or progressive disease, and will 
make therapeutic decisions based solely on the CA-125. This 
has complicated the assessment of PFS in prior randomized 
trials, as patients will receive new therapy prior to clinical 
documentation of progressive disease on the basis of physical 
examination or radiographic findings. The current trial will employ 
a conservative formula to define progressive disease based on 
serial elevation of CA-125 40 (in addition to other standard 
definitions in the management of solid tumors), but only following 
completion of initial chemotherapy. Although imperfect, it is 
preferable to apply uniform criteria that include CA-125 rather 
than absorb uncharacterized events that would compromise the 
secondary endpoint of PFS.  Progression during the period of 
cytotoxic chemotherapy will require radiographic or physical 
confirmation.  
 
 
2.6 
Quality of Life (QoL) 
  
 
 
 
 
Most women with stage III and stage IV epithelial ovarian, primary  
 
 
peritoneal, and fallopian tube cancer will succumb to their malignancy  
 
 
therefore, QoL is an important consideration in determining optimal  


 
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13
 
 
treatment regimen.  The primary objective of measuring QoL in this  
 
 
trial is to determine if the use of neoadjuvant chemotherapy, followed  
 
 
by interval debulking reduces disease related symptoms (improves  
 
 
QoL).   In the current trial, QoL will be assessed using the Trial   
 
 
Outcome Index of the Functional Assessment of Cancer Therapy- 
 
 
Ovary (FACT-O TOI).41,42  This 26-item summary score captures the  
 
 
FACT-G QOL dimensions of Physical Well-Being (7 items), Functional 
 
 
Well-Being (7 items), and the Ovarian Cancer Subscale (12 item).  By  
 
 
combining these three subscales, one is assured of capturing the full  
 
 
range of physical aspects of QOL in advanced ovarian cancer,   
 
 
including pain, fatigue, abdominal symptoms and functional status.  By 
 
 
combining questions GP4, O1, and O3, which assess abdominal pain, 
 
 
swelling, and cramps respectively, a comprehensive patient reported  
 
 
assessment of disease related abdominal symptoms including ascites  
 
 
can be evaluated.  
 
 
 
The timing of the QoL assessments is critical to capture data useful  
 
 
for this regimen.  This is complicated by the fact that the acute affects  
 
 
of cytotoxic therapy may cause a decrease in QoL.  In order to avoid  
 
 
the confounding affects of acute chemotherapy related toxicity,  
 
 
questionnaires will be completed just before (21 days after the last  
 
 
dose) the next cycle of chemotherapy and focus on QoL within the last 
 
 
seven days.  Thus assessments will be made:  
 
 
 
 
 
 
1. 
Prior to cycle 1 (t=0 weeks) 
 
 
 
 
2. 
Prior to surgery (after 3 doses of chemotherapy, t=9  
 
 
 
 
 
weeks) 
 
 
 
 
3. 
Prior to cycle 4 (after 3 doses of chemotherapy and at  
 
 
 
 
 
least 1 after surgery, t=10 weeks) 
 
 
 
 
4. 
3 weeks after completion of chemotherapy (t=19 weeks) 
 
 
 
 
5. 
3 months after completion of chemotherapy (t=28  
 
 
 
 
 
weeks) 
 
2.7 
Biologic Correlates 
 
Human and experimental epithelial cell cancers induce a vigorous innate 
immune response at both primary and metastatic sites. On cellular level 
this innate immune response is mediated by tumor associated 
macrophages (TAMs) and to a lesser extent platelets, mast cells, 
granulocytes, NK-cells, and fibroblasts. Despite the failure of this innate 
immune response to induce an adaptive response to the cancer and 
failure to eliminate the cancer, this innate response intensifies with cancer 
progression.  Macrophages and other immune cells secrete cytokines 
which induce and maintain this process. At tumor sites these cytokines 
such as interleukin (IL-) 1,6,8, and 10, tumor necrosis factor (TNF-), α and 
β, TNF receptor II and tumor growth factor (TGF), and vascular 
endothelial growth factor (VEGF) play  important roles in suppression of 
the adaptive immune response, induction of a pathologic tumor 
vasculature and interstitial fluid space, tumor neo-vascularization, 
progression, metastasis, and resistance to chemo-  and radio-therapy. 
Once in the systemic circulation these cytokines contribute to 


 
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14
development of cachexia, weight loss, protein wasting, decreased 
performance status and an increase in chemotherapy toxicity. It is now 
clear that reactive oxygen species (ROS) and reactive nitrogen species 
(RNS) generated by this process are critical in the regulation and 
induction of the toxic effects of cytokines. By measuring ROS and RNS of 
tumor tissue obtained after neoadjuvant chemotherapy, we will be able to 
determine how measures of tumor protein damage relate to response. 
 
In patients, the intensity of the innate response to cancers may predict for 
survival and poor response to therapy. Serum levels of certain cytokines 
such as TNF, IL-6 and the combination of CRP and serum albumin 
predict negatively for overall survival in some cancers (e.g. lung, 
colorectal), although this has not been explored in ovarian cancer.  
 
We hypothesize that in patients with ovarian cancer, systemic biologic 
markers of the innate immune response (i.e cytokines and surrogates for 
levels of oxidative stress) will correlate with overall survival and allow for 
the identification of patient subsets that may benefit from anti-
inflammatory interventions. Specifically we will capture TNF-a, TNF 
receptor II, protein oxidation, CRP, Il-6 and Il-8 at three time points and 
tumor tissue oxidation in operative specimens.  This study will provide an 
exploratory evaluation of this hypothesis and determine the feasibility of 
assessing the hypothesis in a randomized clinical trial.  
 
2.8 
Inclusion of Women and Minorities 
 
 
This trial 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 epithelial ovarian, fallopian tube, and 
 
peritoneal primary cancer population treated by participating institutions. 
 
 


 
11-GYN-098-MCC 
15
 
 
3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS 
 
3.1   
Eligible Patients 
 
 
3.11  Patients with biopsy proven stage IIIC/IV epithelial ovarian cancer, 
primary peritoneal, fallopian tube carcinoma.  If a core biopsy is 
not possible, fine-needle aspirate showing adenocarcinoma is 
acceptable in the setting of a pelvic mass and presence of 
metastasis outside the pelvis measuring at least 2 cm, regional 
lymph-node metastasis or proof of stage IV disease, and ratio of 
CA 125 to CEA greater than 25.  If CA 125 to CEA ratio is 25 or 
lower, barium enema, gastroscopy, and mammography must be 
negative.20 
 
3.12 
Patients must have adequate: 
 
 
Bone marrow function:  Absolute neutrophil count (ANC) greater 
than or equal to 1,500/µl, equivalent to Common Toxicity Criteria 
for Adverse Events v4.0(CTCAE) Grade 1.  This ANC cannot have 
been induced or supported by granulocyte colony stimulating 
factors. 
 
Platelets greater than or equal to 100,000/µl, CTCAE Grade 0-1. 
 
Renal function:  Creatinine ≤1.5 x institutional upper limit of normal 
(ULN), CTCAE Grade 1. 
 
Hepatic function:  Bilirubin ≤ 1.5 x ULN, CTCAE Grade 1.  SGOT 
and alkaline phosphatase ≤ 2.5 x ULN, CTCAE Grade 1. 
 
Neurologic function:  Neuropathy (sensory and motor) less than or 
equal to CTCAE Grade 1. 
 
Blood coagulation parameters:  PT such that international 
normalized ratio (INR) is ≤ 1.5 (or an in-range INR, usually 
between 2 and 3, if a patient is on a stable dose of therapeutic 
warfarin for management of venous thrombosis) and a PTT <1.2 x 
ULN. 
 
3.13  Patients must have a World Health Organization Performance 
 
Status ≤2.  
 
3.14 
Patients must be a candidate for surgery. 
 
3.15  An approved informed consent must be signed by the patient. 
 
3.2 
Ineligible Patients 
 


 
11-GYN-098-MCC 
16
 
3.21 
Patients who have received prior radiotherapy to any portion of  
 
 
the abdominal cavity or pelvis are excluded.  Prior radiation for  
 
 
localized cancer of the breast, head and neck, or skin is permitted, 
 
 
provided that it was completed more than three years prior to  
 
 
registration, and the patient remains free of recurrent or metastatic 
 
 
disease.  
 
3.22 
Patients who have received prior chemotherapy for any abdominal 
or pelvic tumor are excluded.  Patients may have received prior 
adjuvant chemotherapy for localized breast cancer, provided that 
it was completed more than three years prior to registration, and 
that the patient remains free of recurrent or metastatic disease.  
 
3.23 
Patients with a known synchronous primary endometrial cancer, 
or a past history of primary endometrial cancer, are excluded, 
unless all of the following conditions are met:  Stage not greater 
than IA, no more than superficial myometrial invasion, without 
vascular or lymphatic invasion, no poorly differentiated subtypes 
(including papillary serous, clear cell or other FIGO Grade 3 
lesions).  
 
3.24 
With the exception of non-melanoma skin cancer and other 
specific malignancies noted above, patients with other invasive 
malignancies who had (or have) any evidence of the other cancer 
present within the last five years or whose previous cancer 
treatment contraindicates this therapy are excluded.  
 
3.25 
Patients with acute hepatitis or active infection that requires 
 
parenteral antibiotics are excluded. 
 
3.26 
Patients with World Health Organization Performance Status of 3 
 
or 4. 
 
3.27 
Patients who are pregnant or nursing.  
 
3.28 
Patients under the age of 18. 
 
3.29 
Patients with a pelvic mass of any size that is causing pain, or 
 
other subjective symptoms that are intolerable to the patient. 
 
3.30 
Patients who are not candidates for interval surgical debulking 
secondary to significant medical comorbidities. 


 
11-GYN-098-MCC 
17
4.0 
STUDY MODALITIES 
4.1 
Paclitaxel (NSC #673089) 
4.11 
Formulation: Paclitaxel is supplied as a 6mg/mL non-aqueous 
solution in multi dose vials containing 30mg/5mL, 
100mg/16.7mL, or 300mg/50mL of paclitaxel. In addition to 6mg 
of paclitaxel, each mL of sterile non-pyrogenic solution contains 
527mg of purified Cremophor® EL (polyoxyethylated castor oil) 
and 49.7% (v/v) dehydrated alcohol, USP. 
4.12 
Storage: Unopened vials of paclitaxel are stable to the date 
indicated on the package when stored between 20 to 25°C 
(68 to 77°F). Protect from light. 
4.13 
Preparation: Paclitaxel must be diluted prior to infusion. 
Paclitaxel should be diluted in 0.9% Sodium Chloride for 
Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 
0.9% Sodium Chloride Injection, USP; or 5% Dextrose in 
Ringer’s Injection to a final concentration of 0.3 to 1.2mg/mL. 
The solutions are physically and chemically stable for up to 27 
hours at ambient temperature (approximately 25°C / 77°F) and 
room lighting conditions. 
NOTE: In order to minimize patient exposure to the plasticizer 
DEHP, which may be leached from PVC infusion bags or 
sets, diluted paclitaxel solutions should be stored in bottles 
(glass, polypropylene) or plastic (polypropylene, polyolefin) 
bags and administered through polyethylene-lined 
administration sets. 
Paclitaxel should be administered through an inline filter with a 
microporous membrane not greater than 0.22 microns. Use of 
filter devices such as IVEX2® or IVEX-HP®, which incorporate 
short inlet and outlet PVC-coated tubing, has not resulted in 
significant leaching of DEHP. 
All patients should be premedicated with corticosteroids, 
diphenhydramine, and H2 antagonists prior to paclitaxel 
administration in order to prevent severe hypersensitivity 
reactions. 
 
 
 
 
 
4.14 
Adverse Effects: Consult the package insert for the most current  
 
 
and complete information. 
 
4.15 
Supplier: Commercially available both from Bristol-Myers Squibb 
Oncology as well as generic manufacturers. Consult the 
American Hospital Formulary Service Drug Information guide, 
Facts and Comparisons, or the package insert for additional 
information. 


 
11-GYN-098-MCC 
18
 
 
4.2 Carboplatin (Paraplatin® - NSC #241240) 
 
 
 
 
4.21  Formulation: Carboplatin is supplied as a sterile, pyrogen-free,  
 
 
 
10mg/mL aqueous solution in multi-dose vials containing  
 
 
 
50mg/5mL, 150mg/15mL, 450mg/45mL, or 600mg/60mL of  
 
 
 
carboplatin. 
 
 
 
 
4.22  Storage: Unopened vials of carboplatin are stable to the date  
 
 
 
indicated on the package when stored at 25°C (77°F).   
 
 
 
Excursions from 15 to 30°C (59 to 86°F) are permitted. Protect  
 
 
 
from light. Carboplatin multi dose vials maintain microbial,  
 
 
 
chemical, and physical stability for up to 14 days at 25°C  
 
 
 
following multiple needle entries.  
 
 
 
 
 
 
 
4.23 
Preparation: Carboplatin aqueous solution can be further  
 
 
 
diluted to concentrations as low as 0.5mg/mL with 5%   
 
 
 
Dextrose in Water or 0.9% Sodium Chloride for Injection, USP.  
 
 
 
When prepared as directed, carboplatin aqueous solutions are  
 
 
 
stable for 8 hours at room temperature (25°C / 77°F). Since no  
 
 
 
antibacterial preservative is contained in the formulation, it is  
 
 
 
recommended that carboplatin solutions be discarded 8 hours  
 
 
 
after dilution.  
 
 
NOTE: Aluminum reacts with carboplatin causing precipitate 
 
formation and loss of potency; therefore, needles or  
 
intravenous sets containing aluminum parts  that may come in 
 
contact with the drug must NOT be used for the preparation or 
 
administration of carboplatin. 
 
4.24 
Adverse Effects: Consult the package insert for the most 
 
current and complete information.  
 
4.25  Supplier: Commercially available both from Bristol-Myers 
 
Squibb Oncology as well as generic manufacturers. 
 
Consult the American Hospital Formulary Service Drug 
 
Information guide, Facts and Comparisons, or the package 
 
insert for additional information.  
 
4.26  Dose Calculations 
 
 
See Appendix IV 
4.3  
Docetaxel (Taxotere® RP-56976, NSC #628503) 
4.31 
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.  


 
11-GYN-098-MCC 
19
  
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.  
4.32  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.  
4.33  Preparation: Docetaxel must be combined with its 
supplied diluent (final concentration = 10mg/mL) and then 
further diluted prior to infusion. Docetaxel should be diluted 
in 0.9% Sodium Chloride for Injection, USP or 5% Dextrose 
Injection, USP to produce a final concentration of 0.3 to 
0.74mg/mL. The fully prepared docetaxel infusion solution 
should be used within 4 hours (including the infusion 
duration).  
 
NOTE: In order to minimize patient exposure to the 
plasticizer DEHP, which may be leached from PVC 
infusion bags or sets, the final docetaxel dilution for infusion 
should be stored in bottles (glass, polypropylene) or 
plastic (polypropylene, polyolefin) bags and administered 
through polyethylene-lined administration sets.  
 
All patients should be premedicated with oral 
corticosteroids for 3 days starting 1 day prior to docetaxel 
administration in order to reduce the incidence and 
severity of fluid retention as well as the severity of 
hypersensitivity reactions.  
 
4.34  Adverse Effects: Consult the package insert for the most current 
 
and complete information. 
 
4.35  Supplier: Commercially available from Aventis. 
Consult the American Hospital Formulary Service Drug 
Information guide, Facts and Comparisons, or the 
package insert for additional information. 
  
4.4 
Quality of Life Measures 
 
The FACT-O TOI has been selected as the multidimensional, combined 
 
generic and disease-specific QOL questionnaire for use with ovarian 
 
cancer patients. The questionnaire is a 26-item self-report measure 
 
developed specifically for cancer patients and designed to be used in a 
 
variety of settings, including clinical trials.  
 
 
FACT-O TOI displays the QOL measures in the following order, 
 
recognizing the need for ease of administration and scoring: (1) FACT-G, 
 
(2) Additional Concerns: Ovarian component, (3) Additional items: stomach 
 
pain.  (See Appendix II) 


 
11-GYN-098-MCC 
20
 
 
5.0 
TREATMENT PLAN  
 
 
5.1 
Treatment Plan 
 
 
 
 
 
 
 
 
SCHEMA 
 
Patients with FIGO Stage IIIC/IV ovarian, fallopian tube, primary peritoneal carcinoma 
↓ 
 
3 Cycles Neoadjuvant Chemotherapy* 
 
↓ 
 
Interval Surgical Debulking** 
 
↓ 
 
3-5 Cycles Adjuvant Chemotherapy+ 
 
 
*Paclitaxel 175mg/m2 IV over 3 hours followed by Carboplatin AUC 6 IV over 30 minutes 
every 21 days  
 
**Approximately 3-4 weeks after 3rd cycle of chemotherapy 
 
+Preferably start within 2 weeks of surgery (exceptions may be made by the Principal 
Investigator) with the same dosing parameters as neoadjuvant chemotherapy; adjuvant 
chemotherapy consists of 3-5 cycles based on discretion of treating physician with the 
goal that patients are treated with one cycle beyond normalization of CA 125/no 
radiographic or clinical evidence of disease 
 
 
 
 
 


 
11-GYN-098-MCC 
21
 
 
5.12 
Methods of Chemotherapy 
 
 5.121 All drugs are dosed to a maximum body surface area 
(BSA) of 2.0 m2 as per GOG Chemotherapy Procedure Manual, 
and BSA is only recalculated if there is a +/- 10% weight change 
(either up or down). 
  
 
 
5.122 Sequence and timing of drug administration:  
 
Paclitaxel will be infused over 3 hours. Due to the risk of 
immediate hypersensitivity reaction, paclitaxel should 
always be the first drug to be infused during any 
combination. (Note, for circumstances in which 
docetaxel should be substituted for paclitaxel: Docetaxel 
will be administered as a 1 hour IV infusion at a starting 
dose of 75 mg/m2).  
 
Carboplatin will be administered as a 30 minute infusion, 
following paclitaxel (or docetaxel) administration.  
 
 
 
 
5.123 Pre-Medication:  
 
 
 
 
 
5.1231 Paclitaxel  
 
 
 
 
 
 
For all courses where paclitaxel is to be  
 
 
 
 
 
 
administered, it is recommended that a preparative  
 
 
 
 
 
regimen be employed  one hour prior to the   
 
 
 
 
 
treatment regimen on that day, to reduce the risk  
 
 
 
 
 
associated with hypersensitivity reactions to these  
 
 
 
 
 
drugs. This regimen should include a standard  
 
 
 
 
 
dose of dexamethasone (12mg IV or PO), an  
 
 
 
 
 
anti-histamine H1 (diphenhydramine 25-50 mg IVP 
 
 
 
 
 
or PO, or an equivalent dose of an alternate H1  
 
 
 
 
 
blocker such as loratadine 10mg PO), and a  
 
 
 
 
 
standard dose of antihistamine H2 (famotidine     
   
 
 
 
 
20mg IV or PO). 
 
 
 
 
 
5.1232  Docetaxel  
 
 
 
 
 
 
For all courses in which docetaxel should be  
 
 
 
 
 
substituted for paclitaxel: Docetaxel will be   
 
 
 
 
 
administered as a 1 hour IV infusion at a starting  
 
 
 
 
 
dose of 75 mg/m2, it is recommended that patients  
 
 
 
 
 
be premedicated with dexamethasone 8 mg orally  
 
 
 
 
 
taken the night before, morning of, and evening  
 
 
 
 
 
after each treatment (total dose, 24 mg/wk), and  
 
 
 
 
 
an anti-histamine H1 (diphenhydramine 25-50 mg  
 
 
 
 
 
IVP or orally, or an equivalent dose of an alternate  
 
 
 
 
 
H1 blocker such as loratadine 10mg PO) one  
 
 
 
 
 
hour prior to docetaxel. 
 


 
11-GYN-098-MCC 
22
 
 
 
 
 
 
5.124 Antiemetic Regimens 
  
 
 
It is anticipated that nausea and vomiting may be a 
  
 
 
significant side effect of each regimen. The following 
  
 
 
representative antiemetic regimens are suggested:  
  
 
 
• Ondansetron 16 mg IV 30 minutes prior to  
  
 
 
administration of chemotherapy and dexamethasone 10
  
 
 
mg IV 30 minutes prior to drug administration  
  
 
 
OR 
 
 
 
 
• Granisetron 2 mg PO, 30   
 
 
 
 
 
minutes prior to chemotherapy, with or without  
 
 
 
lorazepam 0.5 mg IV 30 minutes prior to  
 
 
 
 
chemotherapy. 
 
 
5.125 Dosing of Carboplatin 
 
 
 
(See Appendix IV) 
 
 
 
 
5.126 Prohibited Concomitant Therapeutic Modalities 
 
 
 
Prior to documented disease progression, the following  
 
 
 
therapeutic modalities are prohibited:  
 
 
Reassessment or cytoreductive surgery 
 
 
Anti-neoplastic therapy not otherwise specified in 
the current protocol, including cytotoxic, biologic, 
hormonal, or radiation therapy, regardless of 
indication (treatment of measurable disease or 
consolidation therapy). 
 
 
 
 
5.2 
Quality of Life Assessment Intervals 
 
 
 
When determining the specific assessment times, the investigator  
 
 
must balance treatment toxicities, the natural history of the disease,  
 
 
and time since initiating therapy along with an acute awareness of the  
 
 
study objectives. The investigators for the proposed study recommend 
 
 
five assessment points to include (time references are estimates and 
are acceptable plus or minus one week): 
 
 
 
5.21 
Baseline, defined as prior to cycle 1 (t = 0 weeks). This   
 
 
 
assessment allows a pretreatment baseline against which to  
 
 
 
compare later results. 
 
 
 
5.22  Prior to interval surgical debulking, 3 weeks after 3rd cycle of  
 
 
 
platinum-based chemotherapy (t = 9 weeks) 
 


 
11-GYN-098-MCC 
23
5.23  Prior to the 4th cycle of platinum-based chemotherapy (after 
patient has received 3 doses of chemotherapy and is post 
surgery, t = 10 weeks)  
 
 
 
5.24  3 weeks after completion of platinum-based chemotherapy (t =  
 
 
 
19 weeks)  
 
 
 
5.25  3 months after completion of platinum-based chemotherapy (t  
 
 
 
= 28 weeks)   
 
 
5.3 
Biologic correlate sample procurement 
 
 
 
5.3.1 One serum sample (10 cc red top) and one plasma sample (5 cc 
 
 
purple top) will be obtained at three time points: 1) Before the first  
 
 
cycle of chemotherapy is administered; 2) Immediately prior to surgery 
 
 
after neoadjuvant therapy is completed; and 3) within 24-72 hours after  
surgery. 
 
5.3.2 Tumor tissue (approximately 2 grams) will be saved at the time 
of surgery and snap frozen in liquid nitrogen. 
 
5.3.3 Samples will be collected and stored by the Markey Cancer 
Center Biospecimen Shared Resource Facility.  (See Appendix VII,  
Biologic Correlates Processing Instructions)


 
11-GYN-098-MCC 
24
 
 
 
6.0 
TREATMENT MODIFICATIONS 
 
 
In order to maintain dose-intensity and cumulative dose-delivery on this 
 
study, reasonable efforts will be made to minimize dose reduction and 
 
treatment delays as specified. Any patient whose treatment is delayed must 
 
be evaluated on a weekly basis until adequate hematologic and non-
 
hematologic parameters have been met. No dose escalation is planned for 
 
this study. 
 
 
6.1 
Individual Dose Modification Levels 
 
All modifications are relative to the actual starting doses for the specific 
regimen. For application of individual dose modifications, see specific 
guidelines below. Allowable drug dose levels and instructions are 
summarized in Tables A, B, C, and D. 
 
 
 
 
General Guidelines for Hematologic Toxicity (Section 6.2) 
 
Hematologic Nadirs, Table A (Section 6.3) 
 
Dose Levels for Docetaxel, Table B (Section 6.3) 
 
Delayed Hematologic Recovery, Table C (Section 6.4) 
 
Non-Hematologic Toxicity Table D (Section 6.5) 
 
 
6.2 
General Guidelines for Hematologic Toxicity 
 
 
 
 
6.21 
Initial treatment modifications will consist of cycle delay and/or  
 
 
 
dose reduction as directed. 
 
 
 
 
6.22  Treatment decisions will be based on the absolute neutrophil  
 
 
 
count (ANC) rather than the total white cell count (WBC). 
 
6.23 
Lower Limits for ANC and Platelet Count 
 
6.231 Cytotoxic Chemotherapy -   
 
 
Courses of treatment with cytotoxic chemotherapy 
(carboplatin, paclitaxel, docetaxel) will not begin until 
the ANC is ≥ 1000 cells/mm3 (CTCAE Grade 1) and the 
platelet count is ≥ 75,000/mm3. All treatment will be 
delayed for a maximum of three weeks until these 
values are achieved. Patients who fail to recover 
adequate counts within a three-week delay will no 
longer receive protocol-directed cytotoxic therapy. 
 
 
6.24  Use of Hematopoietic Cytokines and Protective Agents 
 
The use of hematopoietic cytokines and protective reagents 
are restricted as noted:  


 
11-GYN-098-MCC 
25
6.241 In general, patients will NOT receive prophylactic 
filgrastim (G-CSF), PEG-filgrastim (Neulasta), or 
sargramostim (GM-CSF) unless they experience 
treatment delays or recurrent neutropenic 
complications after treatment modifications as 
specified. In particular, hematopoietic growth factors 
should not be used to avoid initial chemotherapy dose 
modifications as stipulated in the protocol. However, 
patients may also receive growth factors for 
management of neutropenic complications in 
accordance with the NCCN clinical treatment 
guidelines and facility standard of care treatment 
practices (note: Neulasta may be administered on the 
same day as the chemotherapy if prescribed by the 
attending physician).  
6.242 Patients will NOT receive prophylactic thrombopoietic 
agents unless they experience recurrent Grade 4 
thrombocytopenia after treatment modifications as 
specified below.  
6.243 Patients should not receive erythropoietin (EPO).  
Patients may receive iron supplements, and/or 
transfusions as clinically indicated for management of 
anemia.  
6.244 Patients may NOT receive amifostine or other 
protective reagents.  
6.25  Dose Modifications for Paclitaxel and Docetaxel  
 
There will be no dose modifications for paclitaxel based on 
 
hematologic toxicity. Dose modifications for docetaxel (if 
 
substituted for paclitaxel according to protocol guidelines) 
 
for hematologic toxicity should be made according to 
 
parameters below in Table A, Table B and Table C. 
6.3 
Modifications for Hematologic Toxicity (Nadirs)  
6.31 
Initial occurrence of dose-limiting neutropenia (defined in 
 
6.32) or dose limiting thrombocytopenia (defined in 6.33) will 
 
be handled according to Table A, using the regimen 
 
modifications in Table B.   
6.32 
Dose-Limiting Neutropenia (DLT-ANC) is defined by the 
occurrence of febrile neutropenia or prolonged Grade 4 
neutropenia persisting ≥ 7 days, delay of treatment for more 
than 7 days because of neutropenia, ANC of 1000-1499 
cells/mcl on day 1. There will be no modifications for 
uncomplicated Grade 4 neutropenia lasting less than 7 


 
11-GYN-098-MCC 
26
days. Febrile neutropenia is defined within the CTCAE as 
fever with or without clinically or microbiologically 
documented infection with ANC less than 1,000 /mm3 and 
fever greater than or equal to 38.5°C. 
 
6.33 
Dose-limiting thrombocytopenia (DLT-PLT) is defined by any 
occurrence of Grade 4 thrombocytopenia (<25,000/mm3) or 
bleeding associated with Grade 3 thrombocytopenia (25,000 
to <50,000/mm3), delay of treatment on day 1 of a cycle by 
more than 7 days because of thrombocytopenia. There will 
be no modifications for uncomplicated Grade 3 
thrombocytopenia.  
 
Table A: Modification Instructions for Dose-Limiting Hematologic Toxicity  
(In conjunction with Table B when docetaxel substituted for paclitaxel) 
DLT 
ANC 
DLT 
PLT 
First Occurrence 
Second Occurrence 
Third Occurrence 
Yes 
No 
Reduce carboplatin 
one AUC unit (and 
docetaxel one dose 
level*) 
Add G-CSF and 
Discontinue 
Protocol-Directed 
Cytotoxic 
Therapy 
current drug doses 
Yes 
Yes 
Reduce carboplatin 
one AUC unit (and 
docetaxel one dose 
level*) 
Add G-CSF and 
Discontinue 
Protocol-Directed 
Cytotoxic 
Therapy 
carboplatin one AUC 
unit (and docetaxel 
one dose level*) 
No 
Yes 
Reduce carboplatin 
one AUC unit (and 
docetaxel one dose 
level*) 
Decrease carboplatin 
one AUC unit (and 
docetaxel one dose 
level*) 
Discontinue 
Protocol-Directed 
Cytotoxic 
Therapy 
 
* See Table B below, for patients in whom docetaxel has been substituted for paclitaxel 
according to guidelines in Section 6.51. 
 
Table B: 
Dose Levels for Docetaxel* 
Starting Dose Level 
Dose Level -1 
Dose Level -2 
75 mg/m2 
65 mg/m2 
55 mg/m2 
 
* For patients in whom docetaxel has been substituted for paclitaxel according to 
guidelines in Section 6.51. 
 


 
11-GYN-098-MCC 
27
 
6.4 
Modifications for Delayed Hematologic Recovery:  
6.41  Delay on the basis of neutropenia (Delay-ANC) is defined if 
 
the ANC is less than 1,000 cells/mm3 (CTCAE Grade 2 or 
 
worse) within 24 hours prior to scheduled therapy, or less than 
 
1,000 cells/ mm3, if the patient received G-CSF during the 
 
previous cycle.  
6.42  Delay on the basis of thrombocytopenia (Delay-PLT) is 
 
defined if the platelet count is less than 75,000/mm3 within 24 
 
hours prior to scheduled therapy.  
6.43  Modifications noted below are only required for management 
 
of delays in the absence of dose reductions stipulated by nadir 
 
DLT-ANC and/or DLT-PLT (as noted above).  In other words, if 
 
the patient experiences DLT-ANC and Delay-ANC, make the 
 
modifications as indicated for the nadir counts without 
 
additional modifications based on delayed recovery.  
 
Table C. 
Modifications for Delayed Hematologic Recovery 
Category 
Delay 
(days) 
Modification 
Delay-ANC 
1-7 
No Change 
8-21 
Add G-CSF with Next Cycle 
>21 
Discontinue Protocol-Directed 
Delay-PLT 
1-7 
No Change 
8-21 
Decrease carboplatin one 
AUC unit (and docetaxel one 
dose level*)
>21 
Discontinue Protocol-Directed 
Cytotoxic Therapy** 
 
 
* For patients in whom docetaxel has been substituted for paclitaxel according to 
guidelines in Section 6.51. 
**Applies to platinum/taxane therapy. 
 


 
11-GYN-098-MCC 
28
 
6.5 
Adjustments for Non-Hematologic Toxicity 
 
 
Table D: 
Modifications for Non-Hematologic Toxicity 
Drug 
Regime
n -2 
Regime
n -1 
Regimen 
Starting Dose 
Paclitaxel 
110 mg/m2 
135 mg/m2 
175 mg/m2 
Carboplatin 
4.0 
5.0 
6.0 
Docetaxel 
55 mg/m2 
65 mg/m2 
75 mg/m2 
 
 
Table D should be used for dose level modifications for non-hematologic 
 
toxicity only as indicated specifically in the sections below.   
 
 
 
6.51 
Grade 2 (or greater) peripheral neuropathy requires reduction  
 
 
 
of one  dose level in paclitaxel and delay in all subsequent  
 
 
 
protocol-directed therapy for a maximum of three weeks until  
 
 
 
recovered to Grade 1. If peripheral neuropathy fails to recover  
 
 
 
to Grade 1 by a maximum delay of three weeks from time  
 
 
 
therapy is due, then paclitaxel should be withheld from all  
 
 
 
subsequent chemotherapy cycles and docetaxel at the starting  
 
 
 
dose level of 75 mg/m2 substituted for paclitaxel unless   
 
 
 
medically contraindicated. 
 
In such cases where docetaxel has been substituted for 
 
paclitaxel, if CTCAE Grade 3 or 4 peripheral neuropathy 
 
occurs during or after the first cycle of docetaxel substitution 
 
then subsequent doses of docetaxel will be delayed for a 
 
maximum of three weeks until recovered to CTCAE Grade  
 
2. If peripheral neuropathy fails to recover to Grade  2 by a 
 
maximum delay of three weeks from time therapy is due, 
 
then all docetaxel should be withheld from all subsequent 
 
chemotherapy cycles.  
There will be no dose modifications in Carboplatin for 
neurotoxicity. 
 
 
 
6.52 
Renal toxicity (associated with reduction in GFR) is not   
 
 
 
expected as a direct complication of chemotherapy in this  
 
 
 
untreated patient population using the prescribed dose and  
 
 
 
schedule of each regimen. As such, there are no specific dose  
 
 
 
modifications for renal toxicity. However, the target AUC dose  
 
 
 
of carboplatin must be recalculated each cycle in any patient  
 
 
 
who develops renal insufficiency, defined by serum creatinine  
 
 
 
greater than 1.5 x institutional upper limit normal (ULN). 
 
 
 
6.53 
Hepatic toxicity is not expected as a direct complication of  
 
 
 
chemotherapy in this untreated patient population using the  
 
 
 
prescribed dose and schedule for each regimen. However, the  
 
 
 
development of Grade 3 (or greater) elevations in SGOT  


 
11-GYN-098-MCC 
29
 
 
 
(AST), SGPT  (ALT), alkaline phosphatase or bilirubin requires  
 
 
 
reduction of one dose level in paclitaxel and delay in  
 
 
 
 
subsequent therapy for a maximum of three weeks until  
 
 
 
recovered to Grade 1.  
 
 
 
6.54 
There will be no dose modifications for alopecia, nausea,  
 
 
 
constipation, or diarrhea. It is recommended that routine  
 
 
 
medical measures be employed to manage nausea,  
 
 
 
 
constipation, and diarrhea.  
 
 
 
6.55 
In general, the occurrence of a hypersensitivity reaction to  
 
 
 
paclitaxel, carboplatin, or docetaxel is not considered a dose- 
 
 
 
limiting toxicity. Patients may be retreated at full doses after  
 
 
 
administration of medication to prevent hypersensitivity   
 
 
 
reactions, and adjustments in infusion rates should be made. 
 
 
 
However, if despite these safety measures repeat  
 
 
 
 
attempt at infusion of the inciting drug results in a recurrent  
 
 
 
hypersensitivity reaction, the inciting drug should be  
 
 
 
 
discontinued for the remainder of the study. In the event of  
 
 
 
recurrent grade 4 hypersensitivity reaction to paclitaxel,  
docetaxel should be substituted for paclitaxel.  
 
 
 
6.56 
Potential modifications for other non-hematologic toxicities with 
 
 
 
an impact on organ function of Grade 2 (or greater) require  
 
 
 
discussion with one of the study co-chairs.  
 
 


 
11-GYN-098-MCC 
30
7.0 
STUDY PARAMETERS 
 
 
Pre-
treatment_ 
Prior to initial 
chemo-
therapy 
During platinum-based 
neoadjuvant chemotherapy 
 
Cycle 
    1     
Cycle 
    2     
Cycle 
    3 
 
 
 
Interval  
Debulking 
 
During platinum-based Adjuvant chemotherapy 
 
Cycle 
    4 
Cycle 
    5 
Cycle 
    6 
Cycle 
    7 
Cycle 
    8 
 
Post-treatment 
Every 3 months 
for 2 yrs, every  
6 months for 3  
yrs, then  
annually  
History and 
physical 
X 
Prior to each cycle 
 
Prior to each cycle 
X 
Toxicity 
Assessment 
X 
Prior to each cycle 
 
Prior to each cycle 
X 
Urine or 
serum 
pregnancy 
test (if 
applicable) 
X 
 
 
 
 
CBC/ 
Differential/ 
Platelets 
 
X 
 
Weekly* 
 
 
Weekly* 
As clinically 
indicated 
Complete 
metabolic 
panel 
(including 
Creatinine 
and liver 
function 
tests), 
Ca/PO4/Mg 
 
 
 
X 
 
 
 
Prior to each cycle* 
 
 
 
 
Prior to each cycle* 
 
 
As clinically  
indicated 
PT/INR, PTT 
X 
 
 
 
As clinically 
indicated 
EKG 
X 
 
 
 
 
CEA 
X 
 
 
 
 
CT or MRI 
X 
3 weeks after cycle 3, prior to 
interval debulking 
 
3 weeks after final cycle of chemotherapy 
X 
Chest X-Ray 
X 
(unless 
CT/MRI 
already 
performed) 
 
 
 
 
Serum CA-
125 Level 
X 
Prior to each cycle 
 
Prior to each cycle 
X 
Blood for 
biologic 
study*** 
X 
 
X** 
 
 
Tumor tissue 
for biologic 
study 
 
 
X 
 
 
QoL Survey 
X 
3 weeks after cycle 3, prior to 
interval debulking surgery 
 
Prior to cycle 4 and 3 weeks after final cycle of 
chemotherapy 
At first  
3 month visit 
 
*Laboratory studies may be obtained up to three days prior to each specified time point. 
**Prior to surgery and within 24 to 72 hours after surgery 
***5 ml Purple top (protein bound HNE, RNS, and protein oxidation) and 10 ml red top (IL-6, IL-8, TNFα, 
TNF receptor II, CRP) 


 
11-GYN-098-MCC 
31
8.0 
EVALUATION CRITERIA 
 
 
Response and progression will be evaluated in this study using the
 
international criteria proposed by the Response Evaluation Criteria in Solid 
 
Tumors (RECIST v1.0) Committee.43 Changes in only the largest diameter 
 
(unidimensional measurement) of the tumor lesions are used in the RECIST 
 
criteria. Note: Lesions are either measurable or non-measurable using the 
 
criteria provided below. The term “evaluable” in reference to measurability 
 
will not be used because it does not provide additional meaning or accuracy. 
 
 
8.1 
Definitions 
 
 
 
8.11 
Measurable Disease 
 
Measurable lesions are defined as those that can be accurately 
 
measured in at least one dimension (longest diameter to be 
 
recorded) as ≥ 20 mm with conventional techniques (CT, MRI, 
 
x-ray) or as ≥ 10 mm with spiral CT scan. All tumor 
 
measurements must be recorded in millimeters (or decimal 
 
fractions of centimeters). 
 
 
 
8.12 
Non-Measurable Disease 
 
 
 
 
 
All other lesions (or sites of disease), including small lesions  
 
 
 
(longest diameter <20 mm with conventional techniques or <10 
 
 
 
mm using spiral CT scan), are considered non-measurable  
 
 
 
disease. Bone lesions, leptomeningeal disease, ascites,  
 
 
 
pleural/pericardial effusions, lymphangitis cutis/pulmonis,  
 
 
 
inflammatory breast disease, abdominal masses (not followed  
 
 
 
by CT or MRI), and cystic lesions are all non-measurable. 
 
 
 
8.13 
Target Lesions 
 
All measurable lesions, up to a maximum of five lesions per 
organ, and 10 lesions in total, representative of all involved 
organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on 
the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). A sum of the longest diameter 
(LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as 
reference by which to characterize the objective tumor 
response. 
 
 
 
8.14 Non-target lesions 
 
 
 
 
All other lesions (or sites of disease) should be identified as  
 
 
 
non-target lesions and should also be recorded at baseline.  
 
 
 
Non-target lesions include measurable lesions that exceed the  
 
 
 
maximum numbers per organ or total of all involved organs as  
 
 
 
well as non-measurable lesions. Measurements of these  


 
11-GYN-098-MCC 
32
 
 
 
lesions are not required but the presence or absence of each  
 
 
 
should be noted throughout follow-up. 
 
 
8.2 
Guidelines for Evaluation of Measurable Disease 
 
 
 
8.21 
Method of Measurement 
 
 
 
 
8.211 General Aspects of Tumor Measurement 
 
 
 
 
 
All measurements should be taken and recorded in  
 
 
 
 
metric notation using a ruler or calipers. All baseline  
 
 
 
 
evaluations should be performed as closely as possible  
 
 
 
 
to the beginning of treatment and never more than 4  
 
 
 
 
weeks before the beginning of the treatment. 
 
 
 
 
Note: Tumor lesions that are situated in a previously  
 
 
 
 
irradiated area might or might not be considered   
 
 
 
 
measurable. 
 
 
 
 
 
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 when both methods  
 
 
 
 
have been used to assess the anti-tumor effect of a  
 
 
 
 
treatment. 
 
 
 
 
8.212 Specific Methods of Tumor Measurement 
 
 
 
 
 
 
8.2121 Clinical lesions. Clinical lesions will only be  
 
 
 
 
 
considered measurable when they are superficial 
 
 
 
 
 
(e.g., skin nodules and palpable lymph nodes). In 
 
 
 
 
 
the case of skin lesions, documentation by color  
 
 
 
 
 
photography, including a ruler to estimate the  
 
 
 
 
 
size of the lesion, is recommended. 
 
 
 
 
 
 
8.2122 Chest x-ray. Lesions on chest x-ray are   
 
 
 
 
 
acceptable as measurable lesions when they are 
 
 
 
 
 
clearly defined and surrounded by aerated lung.  
 
 
 
 
 
However, CT is preferable. 
 
 
 
 
 
 
8.2123 Conventional CT and MRI. These techniques  
 
 
 
 
 
should be performed with cuts of 10 mm or less  
 
 
 
 
 
in slice thickness contiguously. Spiral CT should  
 
 
 
 
 
be performed using a 5 mm contiguous  
 
 
 
 
 
 
reconstruction algorithm. This applies to tumors  
 
 
 
 
 
of the chest, abdomen, and pelvis. Head and  
 
 
 
 
 
neck tumors and those of extremities usually  
 
 
 
 
 
require specific protocols. 
 
 
 
 
 
 
PET scanning information will not be evidence of 
 
 
 
 
 
disease progression or measurable disease.  


 
11-GYN-098-MCC 
33
 
 
 
 
 
PET CT Fusion studies may not meet technical  
 
 
 
 
 
requirements. Any CT used must use criteria for  
 
 
 
 
 
assessing according to RECIST. 
 
 
 
 
 
 
8.2124 Ultrasound (US). When the primary endpoint of  
 
 
 
 
 
the study is objective response evaluation, US  
 
 
 
 
 
should not be used to measure tumor lesions. It  
 
 
 
 
 
is, however, a possible alternative to clinical  
 
 
 
 
 
measurements of superficial palpable lymph  
 
 
 
 
 
nodes, subcutaneous lesions, and thyroid  
 
 
 
 
 
nodules. US might also be useful to confirm the  
 
 
 
 
 
complete disappearance of superficial lesions  
 
 
 
 
 
usually assessed by clinical examination. 
 
8.2125 Endoscopy, Laparoscopy. The utilization of 
 
these techniques for objective tumor evaluation 
 
has not yet been fully and widely validated.  
However, such techniques can be useful to 
confirm complete pathological response when 
biopsies are obtained. 
 
 
 
 
 
 
8.2126 Tumor markers. Tumor markers alone cannot be 
 
 
 
 
 
used to assess response. If markers are initially  
 
 
 
 
 
above the upper normal limit, they must   
 
 
 
 
 
normalize for a patient to be considered in  
 
 
 
 
 
complete clinical response. 
 
 
 
 
 
 
8.2127 Cytology, Histology. These techniques can be  
 
 
 
 
 
used to differentiate between partial responses  
 
 
 
 
 
(PR) and complete responses (CR) in rare  
 
 
 
 
 
cases. 
 
 
 
 
 
 
The cytological confirmation of the neoplastic  
 
 
 
 
 
origin of any effusion that appears or worsens  
 
 
 
 
 
during treatment when the measurable tumor  
 
 
 
 
 
has met criteria for response or stable disease is  
 
 
 
 
 
mandatory to differentiate between response or  
 
 
 
 
 
stable disease (an effusion may be a side effect  
 
 
 
 
 
of the treatment) and progressive disease. 
 


 
11-GYN-098-MCC 
34
 
8.3 
Response Criteria  
 
 
 
8.31  Evaluation of Target Lesions 
 
 
 
 
8.311 Complete Response (CR): Disappearance of all   
 
 
 
 
target lesions 
 
 
 
 
 
8.312  Progressive Disease (PD): At least a 20% increase in  
 
 
 
 
the sum of the LD of target lesions, taking as reference  
 
 
 
 
the smallest sum LD  recorded since the treatment  
 
 
 
 
started or the appearance of one or more  new lesions 
 
 
 
 
 
8.313  Stable Disease (SD): Neither sufficient shrinkage to  
 
 
 
 
qualify for PR nor sufficient increase to qualify for PD,  
 
 
 
 
taking as reference the smallest sum LD since the  
 
 
 
 
treatment started 
 
 
 
8.32 Evaluation of non-target lesions 
 
 
 
 
 
8.321  Complete Response (CR): Disappearance of all non- 
 
 
 
 
target lesions and normalization of tumor marker level 
 
 
 
 
Note: If serum CA-125 levels are initially above the  
 
 
 
 
upper normal limit, they must normalize for a patient to  
 
 
 
 
be considered in complete clinical response. 
 
 
 
 
8.322 Incomplete Response: 
 
 
 
 
 
 
 
8.3221 Stable Disease (SD): Persistence of one or more 
 
 
 
 
 
non-target lesion(s) and/or maintenance of tumor 
 
 
 
 
 
marker level above the normal limits 
 
 
 
 
 
 
 
 
 
 
8.3222 Progressive Disease (PD): Appearance of one  
 
 
 
 
 
or more new lesions and/or unequivocal   
 
 
 
 
 
progression of existing non-target lesions 
 
 
 
 
 
 
Although a clear progression of “non-target”  
 
 
 
 
 
lesions only is exceptional, in such  
 
 
 
 
 
 
circumstances the opinion of the treating   
 
 
 
 
 
physician should prevail. 
 
 
 
 
 
 
8.32221 
Progression Based On Serum CA- 
 
 
 
 
 
 
 
125 
 
 
 
 
 
 
 
Progression can be based upon  
 
 
 
 
 
 
 
serum CA-125, only during the  
 
 
 
 
 
 
 
period following completion of  
 
 
 
 
 
 
 
cytotoxic chemotherapy, if one of  
 
 
 
 
 
 
 
the three conditions are met: 
 


 
11-GYN-098-MCC 
35
 
 
 
1.  Patients with elevated CA- 
 
 
 
125 pretreatment and  
 
 
 
 
normalization of CA-125 must  
 
 
 
show evidence of CA-125 greater  
 
 
 
than or equal to two times the  
 
 
 
upper normal limit on two   
 
 
 
occasions at least one week apart 
 
 
 
 
 
 
 
 
or 
 
 
 
 
2.  Patients with elevated CA-125  
 
 
 
pretreatment, which never   
 
 
 
normalizes must show evidence of  
 
 
 
CA-125 greater than or equal to  
 
 
 
two times the nadir value on two  
 
 
 
occasions at least one week apart 
 
 
 
 
 
 
 
 
 
 
or 
 
 
 
 
3.  Patients with CA-125 in the  
 
 
 
normal range pretreatment must  
 
 
 
show evidence of CA-125 greater  
 
 
 
than or equal to two times the  
 
 
 
upper normal limit on two   
 
 
 
occasions at least one week apart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
When disease progression is  
 
 
 
 
 
 
 
defined by CA-125 criteria alone,  
 
 
 
 
 
 
 
imaging using the same modality  
 
 
 
 
 
 
 
and encompassing the same field  
 
 
 
 
 
 
 
as in the initial pretreatment  
 
 
 
 
 
 
 
evaluation should be obtained  
 
 
 
 
 
 
 
within 2 weeks that such  
 
 
 
 
 
 
 
 
progression is documented  
 
 
 
 
 
 
 
8.32222 
Progression Based on  
 
 
 
 
 
 
 
 
Development or Worsening of  
 
 
 
 
 
 
 
Ascites or Pleural Effusions  
 
 
 
 
 
 
 
Suspected progression based  
 
 
 
 
 
 
 
solely on developing or worsening  
 
 
 
 
 
 
 
ascites or pleural effusions must  
 
 
 
 
 
 
 
be verified cytologically 
 
 
 
8.33  Evaluation of Best Overall Response 
 
 
 
 
The best overall response is the best response recorded from  
 
 
 
the start of the treatment until disease progression/recurrence  
 
 
 
(taking as reference for progressive disease the smallest  
 
 
 
measurements recorded since the treatment started). The  
 
 
 
patient's best response assignment will depend on the   
 
 
 
achievement of both measurement and confirmation criteria. 
 


 
11-GYN-098-MCC 
36
 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Note:  
X Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made 
to document the objective progression, even after 
discontinuation of treatment. 
X In some circumstances, it may be difficult to distinguish residual 
disease from normal tissue. When the evaluation of complete 
response depends on this determination, it is recommended that 
the residual lesion be investigated (e.g., fine needle 
aspirate/biopsy) before confirming the complete response status. 
X In rare cases when there is evidence of disease on CT, MRI or 
physical examination, a discrepancy may exist between trends 
in CA125 levels and data from either imaging or physical 
examination. If there is evidence of disease on CT, MRI or 
physical examination, such disease is shrinking, and there is no 
evidence of new disease, then rising CA125 levels according to 
Section 8.32221 would be insufficient to determine disease 
progression.  
X Patients who are not evaluated for response will be classified as 
either: having no target lesions at the time of enrollment onto the 
study, not reassessed due to early death, or unknown (not 
assessable, or insufficient data), 
 
 
8.4 
Confirmatory Measurement/Duration of Response 


 
11-GYN-098-MCC 
37
 
8.41 
Confirmation 
 
In order for a patient to be assigned a status of PR or CR,  
  
changes in tumor measurements must be confirmed by  
  
repeat assessments that should be performed no less than 
  
4 weeks after the criteria for response are first met 
 
8.42  Duration of Overall Response 
 
The duration of overall response is measured from the time 
 
measurement criteria are met for CR or PR (whichever is first 
 
recorded) until the first date that recurrent or progressive 
 
disease is objectively documented (taking as reference for 
 
progressive disease the smallest measurements recorded since the 
 
treatment started). 
 
The duration of overall CR is measured from the time 
 
measurement criteria are first met for CR until the first date that 
 
recurrent disease is objectively documented. 
 
 
8.5 
Definitions Related to Evaluation Unrelated to Objective Response 
 
  
8.51 
Overall Survival is the observed length of life from entry into the 
  
 
study to death, regardless of cause or the date of last  
  
 
contact. 
 
  
8.52  Progression-Free Survival is the period from study  
  
 
entry until disease progression, death or date of last 
  
 
contact. 
The time to progression will be determined by the clinical 
investigator. 
  
 
The defined date of disease progression will depend on 
  
 
the method of determination as follows: 
 
  
8.521 For disease progression defined by imaging or  
  
 
palpation of at least a 20% increase in the sum of the 
  
 
LD of target lesions, the appearance of one or more 
  
 
new lesions, or unequivocal progression of existing  
  
 
non-target lesions, the date of progression will be  
  
 
defined as the date such lesions were first found to be 
  
 
progressed by imaging or palpation. 
 
  
8.522 For disease progression defined by development or 
  
 
worsening of ascites or pleural effusions, the date of 
  
 
progression will be defined as the date of cytologic  
  
 
verification. 


 
11-GYN-098-MCC 
38
 
  
8.523  For disease progression defined by CA125 criteria 
  
 
alone, the date of progression will be defined as the 
  
 
first date of the initial CA125 of greater than or equal 
  
 
to two times the nadir value or upper limit of normal, 
  
 
whichever of these is applicable. Given that imaging 
  
 
using the same modality and encompassing the same 
  
 
field as in the initial pretreatment evaluation is required 
  
 
within 2 weeks of the confirmatory (second) CA125 
  
 
value, if imaging criteria are met for progression, then 
  
 
the date of progression would be defined as the date of 
  
 
the imaging study. 
 
  
8.53  Recurrence-Free Survival (patients with no measurable  
  
 
disease) is the period from study entry until disease recurrence, 
  
 
death or date of last contact. 
 
 
8.54 
Subjective Parameters including performance status,  
 
 
specific symptoms, and side effects are graded according to 
 
 
the CTCAE v4.0. 
 
 
 
Response and progression will be evaluated in this study using  
 
 
the Response Evaluation Criteria in Solid Tumors (RECIST), v1.0. 


 
11-GYN-098-MCC 
39
 
 
 
9.0 
DURATION OF STUDY 
 
 
9.1 
Patients will receive treatment until disease progression, the  
 
 
 
development of adverse events requiring discontinuation of protocol  
 
 
treatment, or completion of 8 cycles of carboplatin/paclitaxel  
 
 
 
chemotherapy, whichever comes first. The patient may voluntarily  
 
 
withdraw from the study at any time.   
 
 
9.2 
All patients will be followed for disease status and toxicity until death  
 
 
or voluntary withdrawal from study to a maximum of five years. In  
addition, following study therapy, patients will be monitored for  
delayed toxicity every three months for the first two years, every six  
months for the next three years, and then annually (or at disease 
progression or death) to a maximum of five years.  
 
 
9.3 
Adequate Duration of Study to Evaluate Toxicity. The minimal length  
 
 
of trial to evaluate toxicity is defined as receiving one course of  
 
 
therapy and receiving any follow-up information for evaluation of  
 
 
toxicity. 
 


 
11-GYN-098-MCC 
40
10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
 
Informed consent must be obtained and an IRB approved consent form must be 
signed by the patient prior to initiating any study procedures. 
 
All data will be reported using the University of Kentucky’s Markey Cancer Center 
OnCore data system. Range checks on variables will be in place to reduce the 
amount of data entry errors. 
 
The Lucille P. Markey Cancer Center Data Safety Monitoring Committee (DSMC) 
will serve as the data safety monitoring board for this study. The PI is responsible 
for ensuring that study data is supplied to the DSMC as requested. The PI, in 
accordance with cancer center policies, is responsible for data management and 
quality.  


 
11-GYN-098-MCC 
41
11.0  BIOLOGIC STUDIES 
 
 
11.1   Collection and handling of specimens 
 
One serum sample (10 cc red top SST tube) and one plasma (5 ml EDTA 
containing tube) sample will be obtained at three time points:  1) Before 
the first cycle of chemotherapy is administered; 2) Immediately prior to 
surgery after neoadjuvant therapy is completed; and 3) within 24-72 hours 
after surgery.  Serum levels of cytokine (TNF, TNF receptor II, IL-6 and 
IL-8) and CRP will be determined and plasma levels of oxidative modified 
proteins will be measured and the resulting adducted proteins will be 
identified. Samples will be collected and stored by the Markey Cancer 
Center Biospecimen Shared Resource Facility. 
 
 
11.2   Collection and handling of tumor specimens 
 
 
 
Tumor tissue (approximately 2 gms) will be saved at the time of surgery 
and snap frozen in liquid nitrogen.   
 
 
11.3  Site performing biologic studies 
All laboratory testing will be performed in the laboratories of Dr. Daret St. 
Claire, 306 Health Sciences Research Building, and Dr. Allan Butterfield, 
249 Chemistry-Physics Building, University of Kentucky. 
11.4 
Residual specimen will be stored long-term in the Biospecimen Shared 
Resource Facility. 
 


 
11-GYN-098-MCC 
42
12.0 
STATISTICAL CONSIDERATIONS 
 
 
12.1 
Study Design 
 
 
This study is a single arm feasibility study of neoadjuvant chemotherapy 
with interval surgical debulking in patients with advanced ovarian, 
fallopian tube, and primary peritoneal carcinoma to determine the 
percentage of patients that achieve maximal surgical debulking as 
defined by no gross residual disease following a Simon’s 2-stage 
design.44 Other endpoints include overall survival, progression-free 
survival, surgical and toxicity outcomes, quality of life measures and 
exploratory biologic correlative studies.  
 
 
12.2 
Sample Size 
 
The primary objective of this study is to determine the percentage of 
patients that achieve maximal surgical debulking with the use of 
neoadjuvant chemotherapy in advanced ovarian, fallopian tube, and 
primary peritoneal carcinomas. The selection of this primary endpoint 
was due to previous research that suggests complete resection of all 
macroscopic disease has been shown to be the most important 
prognostic factor in advanced ovarian carcinoma.5,20,41,42,43 Using 
previous results from the larger European study of neoadjuvant 
chemotherapy, 51.2% of patients in the neoadjuvant arm achieved 
maximal surgical debulking as compared to 19.4% of patients in the 
primary debulking control arm.20 Therefore, based on a hypothesis 
test of a single proportion with 90% power and a two-sided type I error 
rate equal to 0.05 the first-stage sample size necessary for this single 
arm study to detect the same improvement in the percentage of 
neoadjuvant chemotherapy patients achieving maximal surgical 
debulking as compared to the European controls is 9 patients. The 
trial will be terminated if 2 or fewer patients achieve maximal surgical 
debulking as defined by no gross residual disease. If the trial 
continues to the second stage, an additional 14 patients will be 
enrolled for a total of 23. Conservatively allowing 20% drop out or loss 
to follow up, we plan to enroll 28 total patients. 
 
 
12.3 
Statistical Analysis 
 
Following study completion, the percentage of subjects achieving 
maximal surgical debulking will be estimated along with exact 95% 
binomial confidence interval.  A chi-square test for one proportion will be 
employed to test the null hypothesis that the percentage of subjects 
achieving maximal surgical debulking is equal to 19.4%. Various partial 
response rates (i.e. proportion of patients with various sizes of residual 
tumor after debulking) will also be estimated along with exact 95% 
binomial confidence intervals. We plan to explore options to adjust results 
for the two-stage design. Analyses of secondary outcomes will include 
Kaplan-Meier mean estimates of overall and progression-free survival 
rates. This will be primarily descriptive in nature due to the small patient 


 
11-GYN-098-MCC 
43
numbers; however, these results will be compared against historical US 
controls as well as the larger European study45,20. 
 
There will also be information collected on any adverse events, surgical 
outcomes, biomarkers, and quality of life (QOL) surveys. Toxicities will be 
graded according to Common Toxicity Criteria (CTCAE) v4.0.  Incidence 
tables will be generated to summarize incidence of patients reporting at 
least one episode of each specific adverse event, incidence of adverse 
events causing withdrawal, and incidence of serious adverse events. 
Descriptive statistics (means, standard deviations, medians, and ranges) 
will be calculated for quality of life survey outcomes collected throughout 
the study at baseline, 9, 10, 19, and 28 weeks. Percent change in scores 
from baseline to each of the weeks collected will be calculated for each 
patient and plots will be constructed to show trends over time for mean 
scores. 
 
The requested biospecimens from 28 patients will be used for the following purposes 
and analysis: i) correlation between several inflammation and oxidative stress markers 
(measured up/down regulated) using the Kappa statistic ; ii) comparisons of biomarker 
status (measured up/down regulated) using McNemar’s test for paired pre vs. post-
treatment samples; and iii) estimating association of each marker (up versus down-
regulated) with survival time using Kaplan-Meier survival curves, estimating tumor 
response using proportions and chi-square or Fisher’s exact test for comparison of 
proportions between up vs. down-regulated and two-group comparisons of QOL 
variables measured quantitatively using either two-sample t-tests or nonparametric 
analogs between each level (up/down regulated) of each marker.  The patient numbers 
will be adequate for detecting moderate/large correlations for the (i) analysis while 
analyses (ii) and (iii) will be primarily exploratory.         
 
 
 


 
11-GYN-098-MCC 
44
13.0  BIBLIOGRAPHY 
 
1. National Cancer Institute.  Estimated new cancer cases and deaths for 2010. 
 
SEER Cancer Statistics Review 1975-2007. 
 
2. McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY et al. 
 
Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in 
 
patients with stage III and stage IV ovarian cancer. N Eng J Med 334:1-6, 1996. 
 
3. Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E et al. 
 
Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-
 
cyclophosphamide in women with advanced epithelial ovarian cancer: three-year 
 
results. J Natl Cancer Inst 92:699-708, 2000. 
 
4. Alberts DS, Green S, Hannigan EV, O'Toole R, Stock-Novack D, Anderson P et 
 
al. Improved therapeutic index of carboplatin plus cyclophosphamide versus 
 
cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group 
 
of a phase III randomized trial in stages III and IV ovarian cancer. J Clin Oncol 
 
10:706-17, 1992. 
 
5. du Bois A, Luck HJ, Meier W, Adams HP, Mobus V, Costa S et al. A randomized  
 
clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line 
 
treatment of ovarian cancer. J Natl Cancer Inst Sep.3;95.(17):1320.-9. 95:1320, 
 
2003. 
 
6. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA et al. 
 
Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel 
 
in patients with optimally resected stage III ovarian cancer: a Gynecologic 
 
Oncology Group study. J Clin Oncol 21:3194-200, 2003. 
 
7. Swenerton K, Jeffrey J, Stuart G, Roy M, Krepart G, Carmichael J et al. 
 
Cisplatincyclophosphamide versus carboplatin-cyclophosphamide in advanced 
 
ovarian cancer: a randomized phase III study of the National Cancer Institute of 
 
Canada Clinical Trials Group.  J Clin Oncol 10:718-26, 1992. 
 
8. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ.  Survival effect 
 
of maximal cytoreductive surgery for advanced ovarian carcinoma during the 
 
platinum era:  a meta-analysis.  J Clin Oncol 20:1248-59, 2002. 
 
9. Covens AL.  A critique of surgical cytoreduction in advanced ovarian cancer.  
 
Gynecol Oncol 78:269-74, 2000. 
 
10. Dauplat J, Le ABouedec G, Pomel C, Scherer C.  Cytoreductive surgery for 
 
advanced stages of ovarian cancer.  Semin Surg Oncol 19:42-8, 2000.  
 
11. Griffiths CT.  Surgical resection of tumor bulk in the primary treatment of 
 
ovarian carcinoma.  Natl Cancer Inst Mongr 42:101-4, 1975. 
 
12. Bridges JE, Leung Y, Hammond IG, McCartney AJ.  En bloc resection of 
 
epithelial ovarian tumors with concomitant rectosigmoid colectomy:  the KEMH 
 
experience.  Int J Gynecol Cancer 3:199-202, 1993. 


 
11-GYN-098-MCC 
45
 
13. Gilette-Cloven N, Burger RA, Monk BJ, McMeekin DS, Vasilev S, DiSaia PJ, et 
 
al.  Bowel resection at the time of primary cytoreduction for epithelial ovarian 
 
cancer.  J Am Coll Surg 193:626-32, 2001. 
 
14. Mourton Sm, Temple LK, Abu-Rustum NR, Gemignani ML, Sonoda Y, Bochner 
 
BH, et al.  Morbidity of rectosigmoid resection and primary anastomosis in 
 
patients undergoing primary cytoreductive surgery for advanced epithelial 
 
ovarian cancer.  Gynecol Oncol 99:608-14, 2005. 
 
15. Aletti GD, Podratz KC, Jones MB, Cliby WA. Role of rectosigmoidectomy and 
 
stripping of pelvic peritoneum in outcomes of patients with advanced ovarian 
 
cancer.  J Am Coll Surg 203:521-6, 2006. 
 
16. Chi DS, Franklin CC, Levine DA, Akselrod F, Sabbatini P, Jarnagin WR, et al.  
 
Improved optimal cytoreduction rates for stages IIIC and IV eptithelial ovarian, 
 
fallopian tube, and primary peritoneal cancer:  a change in surgical approach.  
 
Gynecol Oncol 94:650-4, 2004. 
 
17. Eisenhauer EL, Abu-Rustum NR, Sonoda Y, Levine DA, Poynor EA, Aghajanian 
 
C, et al.  The addition of extensive upper abdominal surgery to achieve optimal 
 
cytoreduction improves survival in patients with stages IIIC-IV epithelial ovarian 
 
cancer.  Gynecol Oncol 103:1083-90, 2006. 
 
18. Chi DS, Eisenhauer EL, Zivanovic O, Sonoda Y, Abu-Rustum NR, Levine DA, et 
 
al.  Improved progression-free and overall survival in advanced ovarian cancer 
 
as a result of a change in surgical paradigm.  Gynecol Oncol 114:26-31, 2009.. 
 
19. Zivanovic O, Sima CS, Iasonos A, Hoskins WJ, Pingle PR, Leitao MM Jr, et al.  
 
The effect of primary cytoreduction on outcomes of patients with FIGO stage IIIC 
 
ovarian cancer stratified by the initial tumor burden in the upper abdomen 
 
cephalad to the greater omentum.  Gynecol Oncol 116:351-7, 2010. 
 
20. Vergote I, Trope CG, Amant F, Kristensen GB, Ehlen T, Johnson N, Verheijen 
 
RH, van der Burg M, et al.  Neoadjuvant Chemotherapy or Primary Surgery in 
 
Stage IIIC or IV Ovarian Cancer.  N Engl J Med 363:943-953, 2010. 
 
21. Kumar L, Hariprasad R, Kumar S, Bhatla N, Thulkar S, Vijayaraghavan M, Deo 
 
S, et al.  Neoadjuvant chemotherapy (NACT) followed by interval debulking 
 
surgery versus uprofront surgery followed by chemotherapy (CT) in advanced 
 
epithelial ovarian carcinoma (EOC):  A prospective randomized study—Interim 
 
results.  Presented at 2007 ASCO Annual Meeting.   
 
22. Onda T, Kobayashi H, Nakanishi T, Hatae M, Iwasaka T, Konishi I, et al.  
 
Feasibility study of neoadjuvant chemotherapy followed by interval debulking 
 
surgery for stage III/IV ovarian, tubal, and peritoneal cancers:  Japan Clinical 
 
Oncology Group Study JCOG0206.  Gynecol Oncol 113:57-62, 2009. 
 
23. Omura G, Blessing JA, Ehrlich CE, Miller A, Yordan E, Creasman WT, et al.  A 
 
randomized trial of cyclophosphamicde and doxorubicin with or without cisplatin 


 
11-GYN-098-MCC 
46
 
in advanced ovarian carcinoma.  A Gynecologic Oncology Group Study.  Cancer 
 
57:1725-30, 1986. 
 
24. Alberts DS, Green S, Hannigan EV, O’Toole R, Stock-Novack D, Anderson P, et 
 
al.  Improved therapeutic index of carboplatin plus cyclophosphamide versus 
 
cisplatin plus cyclophosphamide:  final report by the Southwest Oncology Group 
 
of a phase III study randomized trial in stages III and IV ovarian cancer.  J Clin 
 
Oncol 10:706-17, 1992. 
 
25. Swenerton K, Jeffrey J, Stuart G, Roy M, Krepart G, Carmichael J, et al.  
 
Cisplatin-cyclophosphamide versus carboplatin=cyclophosphamide in advanced 
 
ovarian cancer:  a randomized phase III study of the National Cancer Institute of 
 
Canada Clinical Trials Group.  J Clin Oncol 10:718-26, 1992. 
 
26. Gurney H, Crowther D, Andersen H, Murphy D, Prendiville J, Ranson M, et al.  
 
Five year follow-up and dose delivery analysis of cisplatin, iproplatin or 
 
carboplatin in combination with cyclophosphamide in advanced ovarian 
 
carcinoma. Ann Oncol 1:427-33, 1990. 
 
27. Conte PF, Bruzzone M, Carnino F, Chiara S, Donadio M, Facchini V, et al.  
 
Carboplatin, doxorubicin and cyclophosphamide versus cisplatin, doxorubicin 
 
and cyclophosphamide:  a randomized trial in stage III-IV epithelial ovarian 
 
carcinoma.  J Clin Oncol 9:658-63, 1991. 
 
28. McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al.  
 
Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in 
 
patients with stage III and stage IV ovarian cancer.  N Engl J Med 334:1-6, 1996. 
 
29 Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al.  
 
Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel 
 
in patients with optimally resected stage III ovarian cancer:  a Gynecologic 
 
Oncology Group Study.  J Clin Oncol 21:3194-200, 2003. 
 
30. Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E et al. 
 
Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-
 
cyclophosphamide in women with advanced epithelial ovarian cancer: three-year 
 
results. J Natl Cancer Inst 92:699-708, 2000. 
 
31. Rose PG, Blessing JA, Ball HG, Hoffman J, Warshal D, DeGeest K et al. A 
 
phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal 
 
carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 88:130-5, 
 
2003. 
 
32. Dieras V, Guastalla JP, Ferrero JM, Cure H, Weber B, Winckel P et al. A 
 
multicenter phase II study of cisplatin and docetaxel (Taxotere) in the first-line 
 
treatment of advanced ovarian cancer: a GINECO study. Cancer Chemother 
 
Pharmacol 53:489-95, 2004. 
 
33. Pfisterer J, du BA, Wagner U, Quaas J, Blohmer JU, Wallwiener D et al. 
 
Docetaxel and carboplatin as first-line chemotherapy in patients with advanced 
 
gynecological tumors. A phase I/II trial of the Arbeitsgemeinschaft 


 
11-GYN-098-MCC 
47
 
Gynakologische Onkologie (AGO-OVAR) Ovarian Cancer Study Group. 
 
Gynecol.Oncol 92:949-56, 2004. 
 
34. Vasey PA, Atkinson R, Coleman R, Crawford M, Cruickshank M, Eggleton P et 
 
al. Docetaxelcarboplatin as first line chemotherapy for epithelial ovarian cancer. 
 
Br J Cancer 84:170-8, 2001. 
 
35. Vorobiof DA, Rapoport BL, Chasen MR, Cohen GL, Mahomed R, Karime M. 
 
Phase II clinical trial of carboplatin and docetaxel in patients with metastatic 
 
ovarian cancer: active combination with low incidence of peripheral neuropathy. 
 
Int J Gynecol Cancer 13:287-91, 2003. 
 
36. Vasey PA, Jayson GC, Gordon A, Gabra H, Coleman R, Atkinson R et al. Phase 
 
III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-
 
line chemotherapy for ovarian carcinoma. J Natl Cancer Inst 96:1682-91, 2004. 
 
37. Markman M, Liu PY, Wilczynski S, Monk B, Copeland LJ, Alvarez RD et al. 
 
Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in 
 
patients with advanced ovarian cancer after complete response to platinum and 
 
paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic 
 
Oncology Group trial. J Clin Oncol 21:2460-5, 2003. 
 
38. Bast RC, Jr., Klug TL, St John E, Jenison E, Niloff JM, Lazarus H et al. A 
 
radioimmunoassay using a monoclonal antibody to monitor the course of 
 
epithelial ovarian cancer. N Engl J Med 309:883-7, 1983. 
 
39. Rustin GJ, Marples M, Nelstrop AE, Mahmoudi M, Meyer T. Use of CA-125 to 
 
define progression of ovarian cancer in patients with persistently elevated levels. 
 
J Clin Oncol 19:4054-7, 2001. 
 
40. Basen-Engquist K, Bodurka-Bevers D, Fitzgerald MA, Webster K, Cella D, Hu S 
 
et al. Reliability and validity of the functional assessment of cancer therapy-
 
ovarian. J Clin Oncol 19:1809-17, 2001. 
 
41. Cain JM, Wenzel LB, Monk BJ, Cella D. Palliative care and quality of life 
 
considerations in the management of ovarian cancer. In: Gershenson DM, 
 
McGuire WP. Ovarian Cancer:  Controversies in Management. New York: 
 
Churchill Livingstone 281-307, 1998. 
 
40. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et 
 
al. New guidelines to evaluate the response to treatment in solid tumors. 
 
European Organization for Research and Treatment of Cancer, National Cancer 
 
Institute of the United States, National Cancer Institute of Canada. J Natl Cancer 
 
Inst 92:205-216, 2000. 
 
41. Vergote I, Amant F, Leunen K. Neoadjuvant chemotherapy in advanced ovarian 
 
cancer: what kind of evidence is needed to convince US gynecological 
 
Oncologists? Gynecol Oncol 119: 1-2, 2010.  
 
42. Dewdney SB, Rimel BJ, Reinhart AJ, et al. The role of neoadjuvant 
 
chemotherapy in the management of patients with advanced stage ovarian 


 
11-GYN-098-MCC 
48
 
cancer: survey results from members of the society of gynecologic oncologists. 
 
Gynecol Oncol 119:18-21, 2010. 
 
43. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ.  Survival effect 
 
of maximal cytoreductive surgery for advanced ovarian carcinoma during the 
 
platinum era:  a meta-analysis.  J Clin Oncol 20:1248-59, 2002. 
 
44. Simon R.  Optimal two-stage designs for phase II clinical trials.  Controlled 
 
Clinical Trials 10:1-10, 1989. 
 
45. Bookman MA, Brady MF, McGuire WP, Harper PG, Alberts DS, Friedlander M, et  
 
al.  Evaluation of New Platinum-Based Treatment Regimens in Advanced-Stage  
 
Ovarian Cancer:  A Phase III Trial of the Gynecologic Oncology Group.  J Clin  
 
Oncol 27(9):  1419-1425, 2009. 
 
 
 


 
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APPENDIX I 
 
FIGO STAGE GROUPING FOR PRIMARY CARCINOMA OF THE OVARY  
 
(2009) 
 
These categories are based on findings at clinical examination and/or surgical 
exploration. The histologic characteristics are to be considered in the staging, as are 
results of cytologic testing as far as effusions are concerned.  It is desirable that a biopsy 
be performed on suspicious areas outside the pelvis. 
 
Stage I  
Growth limited to the ovaries. 
 
 
 
Stage IA  
Growth limited to one ovary; no ascites. 
 
 
 
 
No tumor on the external surface; capsule intact. 
 
 
Stage IB  
Growth limited to both ovaries; no ascites. 
 
 
 
 
No tumor on the external surfaces; capsules intact. 
 
 
Stage IC*  
Tumor either Stage IA or IB but with tumor on the   
 
 
 
 
surface of one or both ovaries; or with capsule  
 
 
 
 
 
ruptured; or with ascites present containing   
 
 
 
 
 
malignant cells or with positive peritoneal  
 
 
 
 
 
 
washings. 
 
Stage II  
Growth involving one or both ovaries with pelvic extension. 
 
 
 
Stage IIA  
Extension and/or metastases to the uterus and/or tubes. 
 
 
 
Stage IIB  
Extension to other pelvic tissues. 
 
 
 
Stage IIC*  
Tumor either Stage IIA or IIB but with tumor on the surface  
 
 
 
 
of one or both ovaries; or with capsule(s) ruptured; or with  
 
 
 
 
ascites present containing malignant cells or with positive  
 
 
 
 
peritoneal washings. 
 
Stage III  
Tumor involving one or both ovaries with peritoneal implants outside the  
 
 
pelvis and/or positive retroperitoneal or inguinal nodes. Superficial liver  
 
 
metastasis equals Stage III.  Tumor is limited to the true pelvis but with  
 
 
histologically verified malignant extensions to small bowel or omentum. 
 
Stage IIIA  
Tumor grossly limited to the true pelvis with negative nodes but with 
 
 
histologically confirmed microscopic seeding of abdominal peritoneal  
 
 
surfaces.  
 
Stage IIIB  
Tumor of one or both ovaries with histologically confirmed implants of 
 
 
abdominal peritoneal surfaces, none exceeding 2 cm in diameter. Nodes 
 
 
negative. 
 
Stage IIIC  
Abdominal implants >2 cm in diameter and/or positive retroperitoneal  
 
 
or inguinal nodes. 
 


 
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Stage IV  
Growth involving one or both ovaries with distant metastasis. If pleural  
 
 
effusion is present there must be positive cytologic test results to allot a  
 
 
case to Stage IV. Parenchymal liver metastasis equals Stage IV. 
 
* In order to evaluate the impact on prognosis of the different criteria for allotting cases 
to Stage IC or IIC, it would be of value to know if rupture of the capsule was (1) 
spontaneous or (2) caused by the surgeon and if the source of malignant cells detected 
was (1) peritoneal washings or (2) ascites. 
 
  


 
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APPENDIX II 
 
See attached FACT-O TOI 


 
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APPENDIX III 
 
Anaphylaxis Precautions 
 
 
Equipment Needed 
__ Tourniquet 
__ Oxygen 
__ Oral and endotracheal airways and intubation equipment 
__ Epinephrine 1:1000 solution for IV or endotracheal injection 
__ Antihistamines 
__ Corticosteroids 
__ IV infusion solutions, tubing, catheters, and tape 
 


 
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APPENDIX IV 
 
CARBOPLATIN DOSE CALCULATION INSTRUCTION 
 
1) 
The Cockcroft-Gault formula will be used in GOG trials (not the Jelliffe formula). 
 
2) 
Conversion of IDMS creatinine levels to “non-IDMS” values will not be permitted. 
 
3) 
The carboplatin calculation tool on the GOG website has been updated. A legacy 
 
carboplatin calculator (using the Jelliffe formula and IDMS to “non-IDMS” 
 
conversion) is also available, if needed for dose modifications (see below). 
 
Dosing of Carboplatin: 
 
1) 
The carboplatin dose will be calculated to reach a target area under the curve 
 
(AUC) according to the Calvert formula using an estimated glomerular filtration rate 
 
(GFR) from the Cockcroft-Gault formula. 
 
2) 
The initial dose of carboplatin must be calculated using GFR. In the absence of 
 
renal toxicity greater than or equal to CTCAE Grade 2 (serum creatinine >1.5 x 
 
ULN) or toxicity requiring dose modification, the dose of carboplatin will not need 
 
to be recalculated for subsequent cycles, but will be subject to dose modification 
 
for toxicity as noted in the protocol. 
 
3) 
Carboplatin doses will be based on the subject’s weight at baseline and will remain 
 
the same throughout the study. However, the doses will be recalculated if the 
 
patient has a weight change of greater than or equal to 10% from baseline. 
 
4) 
In patients with an abnormally low serum creatinine (less than 0.7 mg/dl), the 
 
creatinine clearance should be estimated using a minimum value of 0.7 mg/dl. If 
 
a patient is currently being dosed using a creatinine value less than 0.7 mg/dl, 
 
adjust dose with next planned treatment. 
 
5) 
For trials where patients enter and are treated within less than or equal to 12 
 
weeks of surgery: If a more appropriate (higher) baseline creatinine value is 
 
available from the pre-operative period (within 4 weeks of surgery date), that value 
 
may also be used for the initial estimation of GFR. 
 
 
CALVERT FORMULA:  
 
 
Carboplatin dose (mg) = target AUC x (GFR + 25)  
 
 
NOTE: the GFR used in the Calvert formula should not exceed 125 ml/min.  
 
 
Maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 ml/min.  
 
 
The maximum allowed doses of carboplatin are:  
 
 
AUC6=900mg  
 
AUC5=750mg 
 
AUC4=600mg 


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


 
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APPENDIX V 
 
Standards for Operative Note Details 
 
Surgeon is responsible for indicating the extent of surgical cytoreduction in operative 
findings in dictated operative report.  Detail must include one of the following statements 
regarding the extent of surgical cytoreduction: 
 
 
“Maximal surgical cytoreduction” 
 
No evidence of gross residual  
 
 
 
 
 
 
 
disease 
 
 
“Optimal surgical cytoreduction” 
 
≤ 1cm gross residual disease* 
 
 
“Suboptimal surgical cytoreduction”  
> 1cm gross residual disease* 
 
*For any evidence of gross residual disease, surgeons must specify the location of 
residual disease and approximate amount or size of residual disease, preferably with 
measurements (i.e., “5 cm tumor plaque in left upper quadrant”), but alternatively with 
anatomical description (ie, “coating entire right hemidiaphragm” or “confluent disease 
throughout majority of small bowel mesentery”). 


 
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APPENDIX VI 
 
See attached Standard Chemotherapy Order Sets 


 
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APPENDIX VII 
BIOLOGICAL CORRELATIVE PROCESSING INSTRUCTIONS 
 
 
 
A.  Pertinent Study Objective:   
Secondary Objective 1.27:  To assess the correlation between biologic indicators of 
inflammation and oxidative stress, including TNF-α, TNF receptor II, protein 
oxidation, CRP, IL-6 and IL-8 and tumor tissue oxidation before and after neo-
adjuvant therapy, and clinical outcomes, including overall survival, tumor response, 
and quality of life variables.   
 
B. Samples required:   
5.3.1 – One serum sample (10 cc SST tube) and one plasma sample (5 cc purple 
top) will be obtained at three time points: 
1. Before the first cycle of chemotherapy. 
2. Immediately prior to surgery after Neoadjuvant therapy is completed. 
3. 24 TO 72 hours after surgery. 
5.3.2 –Tumor tissue (2 gms) will be obtained at the time of surgery and snap frozen 
in liquid nitrogen.   
 
C. Sample Processing Instructions:   
Serum Sample 
 
Samples will be collected in a 10 mL red top tube (serum separator tube) at the 
patient’s bedside.  This collection will allow for an adequate volume of serum to 
perform the listed laboratory correlative studies. Samples should be allowed to clot 
for 30 minutes before centrifugation and processing into aliquots.  Samples will be 
centrifuged at 1000 g for 15 minutes at 4˚ C.  Samples will then be aliquoted into 5 
cryovials containing a minimum of 0.3 ml (300 µL) and stored in a -80 Celsius freezer 
to be batched and run at a later date.  
 
Plasma 
Samples will be collected in a 5 mL purple top tube at the patient’s bedside and 
placed on ice immediately and until time of processing.  This collection will allow for 
an adequate volume of plasma to perform the listed laboratory correlative studies. 
After collection at the bedside, the samples should be transported to the lab within 15 
minutes for processing and separation into aliquots.  Samples will be centrifuged at 
3000 rpm for 10 minutes at 4˚ C.  Samples will then be aliquoted into 3 cryovials 
containing a minimum of 0.5 ml (500 µL) and stored in a -80 Celsius freezer to be 
batched and run at a later date. 
 
Tumor Tissue  
 
A 2 gram sample of tumor tissue will be obtained at the time of surgery and snap frozen 
in liquid nitrogen. 

ICF_001.pdf: