Clinical trial NCT01367002
Conditions: Endometrial Cancer
Keywords: Uterine serous papillary carcinoma Type II endometrial cancer HER2/neu Paclitaxel, Carboplatin, Trastuzumab
Sponsor: Yale University
Start date: 2011-06-01; Completion date: 2022-06-30
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to estimate whether the addition of trastuzumab to paclitaxel and carboplatin chemotherapy improves progression free survival when compared to paclitaxel and carboplatin alone in Uterine Serous Papillary Carcinoma (USPC) patients overexpressing Her2/neu at 3+ level by immunohistochemistry (IHC)or positive by fluorescence in situ hybridization (FISH).

Detailed description:
The purpose of this study is to perform a randomized Phase II evaluation of Carboplatin/Paclitaxel with or without Trastuzumab (Herceptin) in patients with HER2/neu+ advanced stage/recurrent disease with an emphasis on determining the progression free survival in USPC patients and assessing immunologic markers predictive of trastuzumab response.

Arms: arm 1: Chemotherapy arm 2: Monoclonal antibody
Interventions: intervention 1: Carboplatin/Paclitaxel intervention 2: Trastuzumab
Intervention descriptions: intervention 1: Paclitaxel 175 mg/m2 will administered intravenously every 21 days for 6 cycles. Carboplatin AUC 5 will be administered intravenously every 21 days for 6 cycles. 100% of patients will receive Carboplatin/Paclitaxel. intervention 2: Paclitaxel 175 mg/m2 will be administered intravenously every 21 days for 6 cycles. Carboplatin AUC 5 will be administered intravenously every 21 days for 6 cycles. On day 1, an 8 mg/kg loading dose of trastuzumab will be administered over a 90 minute period. Beginning on day 21, patients will receive 6mg/kg of trastuzumab, administered intravenously every 21 days and continued indefinitely every 21 days after 6 cycles of cytotoxic therapy are completed and until progression of the disease or prohibitive toxicities occur. 50% of patients will receive Carboplatin/Paclitaxel with the addition of Trastuzumab.

Protocol documents:
Prot_SAP_000.pdf: 
ClinicalTrials.gov ID: NCT01367002 
Title: RANDOMIZED PHASE II EVALUATION OF CARBOPLATIN/PACLITAXEL WITH 
AND WITHOUT TRASTUZUMAB (HERCEPTIN®) IN HER2/neu+ PATIENTS WITH 
ADVANCED/RECURRENT UTERINE SEROUS PAPILLARY CARCINOMA 
Document: Protocol and SAP 
Date: 5/6/2020 


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RANDOMIZED PHASE II EVALUATION OF CARBOPLATIN/PACLITAXEL WITH AND 
WITHOUT 
TRASTUZUMAB 
(HERCEPTIN®) 
IN 
HER2/neu+ 
PATIENTS 
WITH 
ADVANCED/RECURRENT UTERINE SEROUS PAPILLARY CARCINOMA
STUDY CONTACTS
STUDY PI:
Alessandro D Santin MD 
Yale University School of Medicine
Department of Obstetrics, Gynecology & Reproductive Sciences, 
Division of Gynecologic Oncology
333 Cedar Street, LSOG Bld. Room 305, PO Box 208063, 
New Haven, CT, 06520-8063 
Phone: 203-737-4450
Fax: 203-737-4339
E-mail: alessandro.santin@yale.edu
Co-PI:
Amanda Nickles Fader MD
Johns Hopkins Medical Institution
600 N. Wolfe Street, Phipps 287
Baltimore, MD 21287
Phone: 410-955-8240
E-mail: amandanfader@gmail.com
Gynecologic Pathologist:
Pei Hui MD 
Yale University
Department of Pathology 
310 Cedar St.  LH 222
New Haven, CT 06510
Phone:  203-785-5439
Fax:  203-737-2470
E-mail: pei.hui@yale.edu
STATISTICIAN 
Eric R Siegel MS
Department of Biostatistics 
University of Arkansas for Medical Sciences, 
4301 W. Markham, Little Rock, 
Little Rock, AR, 72205-7199.
Phone: 501-526-6717
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Fax: 501-526-6717
E-mail: SiegelEricR@uams.edu
MULTI-SITE /REMOTE MONITORING COORDINATOR:
Lisa D Baker RN, BSN, OCN
Clinical Research Coordinator
Gyn-Oncology
Yale University School of Medicine
Phone: 203-785-6398
Fax 203-785-7480
E-mail: lisa.baker@yale.edu
CLINICAL RESEARCH COORDINATOR:
Marthanne Luther RN, MPH
Gyn-Oncology
Yale University School of Medicine
203-737-2781
Fax 203-785-7480
E-mail: martha.luther@yale.edu
REGULATORY COORDINATOR:
Kay Debski
Gyn-Oncology
Yale University School of Medicine
203-737-5653
Fax: 203-785-7480
E-mail: kay.debski@yale.edu
SPECIMEN PROCUREMENT COORDINATOR:
Michele Montagna, MS                                                                  
FMB 340, New Haven, CT 06520                                              
Telephone (203)737-7660 Fax (203) 785-7480                         
E-mail: michele.montagna@yale.edu
MULTI SITE DATA MANAGER
Kerry DeBenedictis, MA
Gyn-Oncology
Yale University School of Medicine
Phone: (203) 737-8085
Fax: (203) 785-7480
Email: kerry.debenedictis@yale.edu
                                       
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RANDOMIZED II SCHEMA
Surgically Staged III-IV (TAH/BSO/Washings/PPALND)
or Recurrent Uterine Serous Papillary Carcinoma Patients
with Measurable Disease
Patients must be HER2/neu+ as performed by immunohistochemistry (IHC) for HER2/neu+ 
expression and/or fluorescence in situ hybridization (FISH) to detect amplified HER2 gene 
expression on primary or recurrent tumor specimens.
                              
                                                                      Randomize
 
*Additional cycles may be administered if the investigator feels that the subject would receive clinical 
benefit from continued chemotherapy treatment            
 **first dose of Trastuzumab will be at 8mg/kg, in subsequent cycles the dose will be decreased to 6 
mg/kg as described in section 6.124.6.
                
Paclitaxel (175 mg/m2 IV over 3 
hours) and carboplatin IV (AUC 
5) x 6 cycles every 21 days*; 
Trastuzumab **6 mg/kg IV every 
21 days until disease progression 
or prohibitive toxicities occur 
Paclitaxel (175 mg/m2 IV over 3 
hours) and carboplatin IV (AUC 
5) x 6 cycles every 21 days
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TABLE OF CONTENTS
PAGE
 1.0
OBJECTIVES
1
 2.0
BACKGROUND AND RATIONALE
2
 3.0
PATIENT ELIGIBILITY AND EXCLUSIONS; INCLUSION OF MINORITIES   
5
 4.0
STUDY MODALITIES
8
 5.0
CORRELATIVE STUDIES                                                                                                  13
 6.0     TREATMENT PLAN AND ENTRY/REGISTRATION PROCEDURE
            14
 7.0
TREATMENT MODIFICATIONS
17
 8.0
STUDY PARAMETERS
            20
 9.0
EVALUATION CRITERIA
23
10.0
DURATION OF STUDY
24
11.0
STUDY MONITORING AND REPORTING PROCEDURES
                                    25
12.0     PROCEDURES FOR REPORTING UPIRSO’S (SAE’s)                    
33
13.0    MULTI-SITE MANAGEMENT AND COORDINATION                                                   37
14.0
STATISTICAL CONSIDERATIONS                                                                                   40
     
15.0
BIBLIOGRAPHY 
                                                           43
SUGGESTED PATIENT INFORMATION/INFORMED CONSENT
APPENDIX A
FIGO Staging Criteria
           APPENDIX B
Performance Status Criteria
APPENDIX C
Adverse Events to Study Agents
APPENDIX D
Specimen Shipping Instructions
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1.0
OBJECTIVES
1.1
Primary objective
1.1.1
To estimate whether the addition of trastuzumab to paclitaxel and carboplatin 
chemotherapy improves progression free survival (PFS) when compared to 
paclitaxel and carboplatin alone in USPC patients overexpressing HER2/neu 
at 3+ level by IHC or positive by FISH 
 
1.2
Secondary objectives
1.2.1
To assess objective response rate (ORR)
1.2.2
To assess overall survival (OS)
1.2.3
To assess the safety profile of trastuzumab in USPC patients
1.3
Exploratory/correlative objectives
1.3.1
To determine peripheral blood natural killer (NK) cell numbers and activity in 
HER2/neu+ USPC patients to provide a basis for assessing the possible 
therapeutic contributions of immune mechanisms of action of trastuzumab
1.3.2
To study HER2/neu extracellular domain (ECD) circulating levels in the 
plasma of USPC patients overexpressing HER2/neu before, during and after 
treatment to elucidate whether changes in HER2/neu ECD would predict 
response to  trastuzumab
1.3.3
To determine whether CA-125 levels correlate with disease activity in 
advanced and/or recurrent disease.
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2.0 
BACKGROUND AND RATIONALE
Cancer of the uterine corpus is the most prevalent gynecologic tumor in women, with an estimated 
43,470 cases and 7,950 deaths in the United States in 2010 (1). Uterine serous papillary carcinoma 
(USPC) is an aggressive variant of endometrial cancer (2). Although it accounts for less than 10% 
of all endometrial tumors, it accounts for a disproportionate number of relapses and endometrial 
cancer-related deaths (2).  USPC, referred to as a Type II endometrial cancer, is characterized by a 
high-grade, complex histology and is biologically more aggressive than its type I counterpart, 
endometrioid adenocarcinoma (2).  Type I and II endometrial cancers appear to have a different 
pattern of molecular alterations that underlie pathogenesis and progression. While endometrioid 
carcinomas tend to have alterations in the tumor suppressor gene, PTEN, these are uncommon in 
USPC, with p53 mutations and HER2/neu expression occurring more commonly in this tumor 
subtype (3). Both early-stage (Stage I/II with disease confined to the uterus) and advanced disease 
states (Stage III/IV with metastases present outside of the uterus) behave aggressively. USPC has a 
tendency to invade the lymphatic and vascular spaces and lymph nodes and to microscopically or 
macroscopically involve other intraperitoneal structures, despite minimal or no invasion present 
within the uterus. These tumor characteristics lead to high recurrence rates and a poor prognosis for 
patients (2-5).
Because of poor results with surgery alone, both radiation therapy and chemotherapy have been 
added postoperatively in an effort to improve outcomes (5).  However, the benefit of these 
modalities as well as the optimal treatment for each disease stage remains unclear. Our research 
group recently reported on the largest series of Stage I/II USPC patients in the literature and 
demonstrated a significant improvement in recurrence rates, progression free and overall survival 
in 
patients 
treated 
with 
carboplatin/paclitaxel-based 
regimens 
(6). 
Specifically, 
all 
carboplatin/paclitaxel +/-RT-treated patients had a lower risk of recurrence (9.2%) compared to 
radiation-only-treated (24.2%, p=0.04) and observed patients after surgery (30.2%, p=0.004). On 
multiple logistic regression analyses, adjuvant treatment strategy (p=0.036) and sub-stage 
(p=0.003) were significantly associated with recurrence. Five-year progression-free (p=0.009) and 
overall survival (p=0.012) were again highest in chemotherapy treated patients when compared to 
RT-treated and OBS patients. 
Recurrence rates in women diagnosed with advanced stage disease are much higher than for early-
stage disease, with rates of 50-90% reported in published studies (7-11). These recurrences are often 
extra-pelvic and largely unsalvageable and highlight the need for effective systemic therapy in the 
treatment of this disease. Goff and colleagues reported that 72% of surgically staged USPC patients 
will have advanced-stage disease (extra-uterine, Stage III-IV) at the time of initial laparotomy (10). 
GOG #33 demonstrated that para-aortic nodal disease was more common in patients with USPC 
tumors, and GOG #94 demonstrated that in Stage III/IV UPSC patients treated with whole abdominal 
radiation, the majority of failures were multisite and extrapelvic (with distant failures not being 
uncommon) (9). These findings indicate that radiation therapy alone has a limited role in the 
management of USPC.  It has been suggested that USPC tumors more closely resemble ovarian 
cancers than endometrial cancers. The high rates of intra-abdominal disease spread and intra-
abdominal failures reported support this concept, and have led to the use of ovarian cancer-based 
chemotherapy regimens as treatment.  As more effective chemotherapeutic agents have been 
identified in endometrial cancer, combination regimens have demonstrated improved responses, and 
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at least in populations with advanced disease, chemotherapy (doxorubicin and cisplatin) has shown 
superiority to radiation alone (GOG #122) (11).
Chemotherapy, either alone or in combination with radiotherapy, has been evaluated in the 
management of advanced-staged endometrial cancer. As USPC is a rare tumor subtype, it is often 
grouped with more common endometrial tumor subtypes (ie, endometrioid adenocarcinoma) in 
prospective treatment studies. However, studies suggest that USPC patients tend to fare worse and 
may exhibit more heterogeneity of response to chemotherapy than their counterparts with less 
aggressive subtypes (2-5). Therefore, there is potential benefit in studying UPSC as its own clinical 
entity. 
In terms of the relevant studies on advanced-stage endometrial cancer—many of which included 
USPC patients—there are several reports that help guide management. Burke reported on 62 patients 
with high-risk endometrial cancer (21% with USPC or CC histologies) treated with cisplatin, 
adriamycin, and cyclophosphamide following surgical staging (12). Three-year survival was 82% in 
patients without extra-uterine disease. Levenback described 20 patients with all stages of USPC 
treated with the same regimen and reported a 5-year survival of 23% (13). Paclitaxel has demonstrated 
significant activity in endometrial cancer patients with advanced or recurrent disease in two GOG 
phase II studies (GOG 86-O, 129-C) (14-15). The combination of cisplatin and adriamycin versus 
cisplatin, adriamycin and paclitaxel (TAP) was then studied in GOG #177, a Phase III trial of primary, 
advanced-stage endometrial cancer patients with superior progression-free and overall survival 
outcomes noted in the TAP cohort (16).  TAP is currently being evaluated sequentially with radiation 
in GOG-184, and is also being compared to paclitaxel/carboplatin in GOG-209, a Phase III 
equivalence study, in the same cohort of patients. 
Paclitaxel has also demonstrated activity specifically in USPC tumors as reported by Ramondetta and 
colleagues from M.D. Anderson Cancer Center (17). They reported a 77% objective response rate in 
a small series of patients with advanced disease. Hoskins reported experience using paclitaxel and 
carboplatin with and without radiation in 63 patients with advanced and recurrent endometrial cancer. 
In a subgroup of 15 patients with advanced USPC tumors, the response rate was 60%, and 2 out of 4 
patients with recurrent disease responded to the regimen (18). Carboplatin has demonstrated 
comparable activity to cisplatin in most gynecologic malignancies, including endometrial cancer (19-
20). Substituting carboplatin for cisplatin appears to reduce toxicity and increase ease of 
administration (21-25).
A recent Phase II pilot study of pelvic radiation therapy “sandwiched” between platinum/taxane-
based therapy in Stage I-IV USPC patients demonstrated that this regimen had excellent antitumor 
activity, but the majority of patients with advanced disease recurred during the three year study period 
(21). Phase III GOG data on advanced/recurrent endometrial cancers of all subtypes have 
demonstrated median progression-free survival (PFS) rates of 7-8 months and median overall survival 
(OS) rates of 15 months, despite treatment with platinum/taxane-based chemotherapy (16). Finally, 
two recent Phase III studies from the Japanese Gynecologic Oncology Group (GOG) and 
NSGO/EORTC, respectively demonstrated that patients with high-risk, early-stage endometrial 
cancers treated with chemoradiation had improved progression-free and overall survival when 
compared to patients treated with radiation therapy alone. Patients with USPC were included in these 
trials (26-27).
In addition to platinum/taxane-based chemotherapy, another reasonable approach to the treatment of 
USPC may lie in targeted therapy. Several studies have demonstrated that the human epidermal 
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growth factor receptor 2 gene (HER2, also known as c-erbB2 and HER2/neu), is over-expressed in 
18 to 80% of USPC and may contribute to USPC transformation and tumorigenesis (28-35).  In some 
of these studies, HER-2/neu overexpression has been identified as an independent variable associated 
with poor outcome in USPC patients, and one that occurs more frequently in African-American women 
than in Caucasian women (32,33). In a single institution study of 26 USPC samples evaluated by Santin 
et al, 62% exhibited HER2/neu overexpression (34). Protein overexpression and gene amplification 
were found to correlate in 100% (9/9) of the 3+ positive tumors but in only 2/7 (29%) of the 2+ 
positive tumors (34). Consistent with these results, in a recent exploratory immunohistochemical 
analysis of HER-2/neu expression in advanced endometrial carcinoma performed by the GOG, HER-
2/neu overexpression [either 2+ (moderate) or 3+ (strong)] was detected in 23 of 38 (61%) of the 
USPC tested in a centralized core lab facility (35). High HER-2/neu expression levels in USPC have 
also been reported by Diane-Montez et al. (36), with 12 of the 25 (48%) USPC cases in the John 
Hopkins’ series demonstrating HER-2/neu overexpression. Of interest, in this study, a significant 
association of HER-2/neu overexpression with surgical staging was detected, with 81.8% advanced 
stage disease vs. 28.6% early stage disease showing HER-2/neu overexpression (36). Taken all 
together, these results raise the possibility of therapeutic strategies that target HER2, such as using 
the anti-HER2 monoclonal antibody trastuzumab (Herceptin) may have significant therapeutic 
potential in USPC patients harboring advanced and/or recurrent disease.
Results from large randomized clinical trials for patients with HER-2 positive invasive breast cancer 
have shown that patients who received trastuzumab in combination with chemotherapy had a 
significant decrease in risk for breast cancer recurrence when compared with patients who received 
the same chemotherapy without trastuzumab (37). Importantly, clinical responses to trastuzumab used 
as single agent in breast cancer patients are reported on the order of 10-15%, while the overall 
response rate to trastuzumab in combination with chemotherapeutic agents may increase in the same 
patient populations to > 50% (37). On the basis of these results, a significantly higher clinical activity 
of trastuzumab when used in combination with chemotherapy may be expected in USPC patients 
harboring advanced and/or recurrent disease over expressing HER2/neu. While previous studies in 
HER2/neu positive breast cancer have demonstrated improved efficacy of trastuzumab and paclitaxel 
with the addition of carboplatin, there are no studies in the literature evaluating combination 
platinum/taxane chemotherapy with trastuzumab in USPC patients.
A Phase II study of single agent trastuzumab in advanced/recurrent endometrial cancer patients of 
any histology has recently been reported from the GOG (38). This study was not able to demonstrate 
single agent activity of trastuzumab against endometrial carcinoma patients harboring tumors with 
HER2/neu overexpression. Such results, however, have been recently challenged due to the many 
shortcomings in the design of the GOG181b study (39). Moreover, evidence of trastuzumab clinical 
activity in a handful of heavily pretreated endometrial carcinoma patients has been recently reported 
as case reports in the medical literature (40-42).
Clinical efficacy of trastuzumab has been postulated to depend on multiple direct or indirect action 
mechanisms that may produce cytostatic and/or cytotoxic antitumor cell effects. CD16 and natural 
killer (NK) cells appear to play a central role in mediating the anti-tumor effects of trastuzumab 
therapy, and an inherent resistance to trastuzumab has been noted in some HER2/neu positive breast 
cancer patients with specific polymorphisms of CD16 (43-44). To date, trastuzumab therapy and the 
immunologic basis for its putative activity (or inactivity) have not been studied in UPSC.
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Clearly, there is a critical need to determine the optimal chemotherapy regimens and whether targeted 
therapy may be beneficial in women with USPC over expressing HER2/neu. Therefore, the purpose 
of this study is to perform a randomized Phase II evaluation of Carboplatin/Paclitaxel with or without 
Trastuzumab (Herceptin®) in patients with HER2/neu+ advanced stage/recurrent disease with an 
emphasis on determining the progression free survival in USPC patients and assessing immunologic 
markers predictive of trastuzumab response.  
3.0
PATIENT ELIGIBILITY AND EXCLUSIONS
3.1
Eligible Patients 
3.1.1
Patients must have advanced (stage III-IV) or recurrent histologically confirmed USPC.   
3.1.2
Patients must harbor a tumor HER2/neu+ based upon IHC staining score of “3+” or 2+ 
with confirmed gene amplification by FISH to be included.
3.1.3
All patients diagnosed with recurrence must have measurable disease. In recurrent 
patients, paraffin embedded USPC tumor tissue must be available from either primary 
surgery, tumor purified from ascites or from CT-guided biopsy of recurrent disease. 
Measurable disease is defined as at least one lesion that can be accurately measured in 
at least one dimension (longest dimension to be recorded). Each lesion must be  20 
mm when measured by conventional techniques, including palpation or plain x-ray, or 
 10 mm when measured by spiral CT and/or MRI.
3.1.4
Patients with recurrence must have at least one “target lesion” to be used to assess 
response on this protocol as defined by RECIST v1.1.  Tumors within a previously 
irradiated field will be designated as “non-target” lesions unless progression is 
documented or a biopsy is obtained to confirm persistence at least 90 days following 
completion of radiation therapy.
3.1.5
Patients may be optimally or suboptimally debulked after surgery.
3.1.6
Patients with measurable recurrent disease of any previous substage (I-IV) are eligible 
to enrollment. 
3.1.7
The diagnosis must be histologically confirmed by a gynecologic pathologist as 
containing ≥10% uterine papillary serous (UPSC) adenocarcinoma in the specimen.
3.1.8
Patients must have adequate bone marrow function: WBC greater than or equal to 
3,000/ul, Platelets greater than or equal to 75,000/ul, Granulocytes greater than or equal 
to 1500/ul. Renal function: creatinine less than or equal to 2.0 mg/dL Hepatic function: 
Bilirubin < 1.5 X laboratory normal. SGOT < 3 X laboratory normal.
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3.1.9
Patients must be enrolled within 8 weeks of primary surgery or within 8 weeks after 
diagnosis of recurrent disease.
3.1.10 Patients must have an ECOG performance status of 0, 1 or 2.
3.1.11 Patients must have signed an approved informed consent
3.1.12 Patients with recurrent disease may have received prior treatment with carboplatin 
/paclitaxel but must have had a treatment free interval of > 6 months
3.1.13 Patients with recurrent disease may not have received more than three prior 
chemotherapies for treatment of their uterine cancer
3.1.14 Patients must have recovered from effects of recent surgery, radiotherapy or 
chemotherapy
3.1.15 Patients who have received prior doxorubicin may not have had more than 320 mg/m2 
total dose and must have a normal LVEF (≥ 45%).  (This includes Doxil or other 
liposomally encapsulated doxorubicin preparations.)
3.1.16 Patients of childbearing potential must have a negative serum pregnancy test within 7 
days prior to the study entry and be practicing an effective form of contraception.      
3.1.17 Patients must be at least 18 years of age. The safety and efficacy of trastuzumab in 
pediatric patients has not been established
3.2 
Ineligible Patients:
3.2.1
Patients with a history of other invasive malignancies, with the exception of 
non-melanoma skin cancers are excluded if there is any evidence of other 
malignancy being present within the last five years.  Patients are also excluded 
if their previous cancer treatment contraindicates this protocol therapy
3.2.2
Patients who have a significant history of cardiac disease, i.e., uncontrolled 
hypertension, unstable angina, uncontrolled congestive heart failure, or 
uncontrolled arrhythmias within 6 months of registration (NYHA 
classification III-IV).
3.2.3
Patients with any unstable medical issue (including cardiac issues as above,
 active treatment for pulmonary embolism, CVA, renal or hepatic 
insufficiency, active infection/sepsis requiring IV antibiotics). 
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3.2.4    Known brain/leptomengial involvement of the disease, active neurological                   
disease, dementia.
3.2.5
Patients who have received prior therapy with trastuzumab or any other anti-
epidermal growth factor type II receptor antibody.
3.2.6
Patients who have an uncontrolled seizure disorder, or active neurological 
disease.
3.2.7
Patients known to be seropositive for HIV and active hepatitis, even if liver 
function studies are in the eligible range.
3.2.8
Known hemorrhagic diathesis or active bleeding disorder.
3.2.9 Patients requiring supplemental oxygen.
3.3 Inclusion of Minorities:
3.3.1
As men do not have uteri, only women will be enrolled in this trial. 
Participating institutions will not exclude potential subjects from participating 
in this or any study solely on the basis of ethnic origin or socioeconomic status.  
Every attempt will be made to enter all eligible patients into this protocol and 
therefore address the study objectives in a patient population representative of 
the entire USPC population treated by participating institutions.
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4.0
 STUDY MODALITIES
             4.1 
Chemotherapy
4.11
 Paclitaxel (NSC #673089) 175 mg/m2 will be administered intravenously 
every 21 days for 6 cycles.  Additional cycles may be administered if the 
investigator feels that the subject would receive clinical benefit from continued 
chemotherapy treatment.
4.12 
 Formulation: Paclitaxel is a poorly soluble plant product from the western 
yew, Taxus brevifolia. Improved solubility requires a mixed solvent system 
with further dilutions of either 0.9% sodium chloride or 5% dextrose in water.
4.131  Supplier/How Supplied: Commercially available. A sterile solution 
concentrate, 6 mg/ml, in 5 ml vials (30 mg/vial) or 17 ml vials (100 mg/vial) 
in polyoxyethylated castor oil (Cremophor EL) 50% and dehydrated alcohol, 
USP, 50%. The contents of the vial must be diluted just prior to clinical use. 
4.132
Solution Preparation: Paclitaxel, at the appropriate dose, will be 
diluted in 500-1000 ml of 0.9% Sodium Chloride injection, USP or 5% 
Dextrose injection, USP (D5W) (500 mls is adequate if paclitaxel is a single 
agent). Paclitaxel must be prepared in glass or polyolefin containers due to 
leaching of diethylhexlphthalate (DEHP) plasticizer from polyvinylchloride 
(PVC) bags and intravenous tubing by the Cremophor vehicle in which 
paclitaxel is solubilized.
NOTE: Formation of a small number of fibers in solution (within acceptable 
limits established by the USP Particulate Matter Test for LVPs) has been 
observed after preparation of paclitaxel. Therefore, in-line filtration is 
necessary for administration of paclitaxel solutions. In-line filtration should 
be accomplished by incorporating a hydrophilic, microporous filter of pore 
size not greater than 0.22 microns (e.g.: IVEX-II, IVEX-HP or equivalent) 
into the IV fluid pathway distal to the infusion pump. Although particulate 
formation does not indicate loss of drug potency, solutions exhibiting 
excessive particulate matter formation should not be used.
4.133
Storage: The intact vials should be stored between 2-25°C (36-77°F).
4.134 Stability: Commercially available paclitaxel will be labeled with an expiration 
date. All solutions of paclitaxel exhibit a slight haziness directly proportional 
to the concentration of drug and the time elapsed after preparation, although 
when prepared as described above, solutions of paclitaxel (0.3-1.2 mg/ml) are 
physically and chemically stable for 48 hours.
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4.135 Intravenous Administration of Paclitaxel: Paclitaxel, at the appropriate dose 
and dilution, will be given as a 3-hour continuous IV infusion. Paclitaxel will 
be administered via an infusion control device (pump) using non-PVC tubing 
and connectors, such as the IV administration sets (polyethylene or polyolefin) 
which are used to infuse parenteral Nitroglycerin. Nothing else other than 0.9% 
sodium  chloride is to be infused through the line where paclitaxel is being  
administered.
4.136 Adverse Effects:
4.136.1
Hematologic: Myelosuppression
4.136.2
Gastrointestinal: Nausea and vomiting, diarrhea, stomatitis, mucositis, 
pharyngitis, typhlitis, ischemic colitis, neutropenic enterocolitis
4.136.3
Heart: Arrhythmia, heart block, ventricular tachycardia, myocardial 
infarction (MI), bradycardia, atrial arrhythmia
4.136.4
Pulmonary: Pneumonitis
4.136.5
Blood Pressure: Hypotension, hypertension (possibly related to 
concomitant medication--Dexamethasone)
4.136.6
Neurologic: Sensory (taste), peripheral neuropathy, seizures, mood 
swings, hepatic encephalopathy, encephalopathy
4.136.7
Skin: Infiltration: erythema, induration, tenderness, rarely ulceration, 
radiation-recall reactions, erythema multiforme (e.g., Stevens-Johnson 
syndrome, toxic epidermal necrolysis) 
4.136.8
Allergy: Anaphylactoid and urticarial reactions (acute),  flushing, rash, 
pruritus
4.136.9
Liver: Increased SGOT, SGPT, bilirubin and alkaline phosphatase, 
hepatic failure, hepatic necrosis 
4.136.10
Other: Alopecia, fatigue, arthralgia, myalgia, lightheadedness, 
myopathy
4.136.11
Other, Vision: Sensation of flashing lights, blurred vision, scintillating 
scotomata
4.136.12
*Refer to Package insert for additional information
4.2 
Carboplatin (Paraplatin® - NSC #241240) AUC 5 will be 
administered intravenously every 21 days for 6 cycles.  Additional 
cycles may be administered if the investigator feels that the subject 
would receive clinical benefit from continued chemotherapy 
treatment.
4.21
Formulation: Paraplatin® is supplied as a sterile lyophilized powder 
available in single-dose vial containing 50 mg, 150 mg and 450 mg of 
carboplatin for administration by intravenous infusion. Each vial contains 
equal parts by weight of carboplatin and mannitol.
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4.22
Preparation: Immediately before use, the content of each vial must be 
reconstituted with either sterile water for injection, USP, 5% dextrose in 
water, or 0.9% sodium chloride injection, USP, according to the following 
schedule:
Vial strength 
Diluent volume 
50 mg 
5 ml
150 mg 
15 ml
450 mg 
45 ml
These dilutions all produce a carboplatin concentration of 10 mg/ml. When 
prepared as directed, Paraplatin® solutions are stable for 8 hours at room 
temperature, since no antibacterial preservative is contained in the 
formulation it is recommended that Paraplatin® solutions be discarded 8 
hours after dilution.
NOTE: Aluminum reacts with Paraplatin® 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 Paraplatin®.
4.23
Storage: Unopened vials of Paraplatin® are stable for the life indicated on 
the package when stored at controlled room temperature and protected from 
light.
4.24
Adverse effects: 
Hematologic: Myelosuppression
Gastrointestinal: Nausea and vomiting, diarrhea, 
Neurologic: Peripheral neuropathy, central neurotoxicity 
Allergy: Anaphylactoid and urticarial reactions (acute), flushing, rash, 
pruritus
Liver: Increased SGOT, SGPT, bilirubin and alkaline phosphatase
Other: Fatigue, electrolyte imbalance, hypomagnesemia, hypocalcemia
 
4.25
Supplier: Commercially available. Bristol-Myers Squibb Oncology
4.26
Administration: Carboplatin AUC 5 IV Day 1 with a 30 minutes infusion 
time
4.27
* Refer to Package insert for additional information
4.3 Targeted Therapy
4.3.1
Trastuzumab (Herceptin®) 
4.3.1.1
On day 1, an 8 mg/kg loading dose of trastuzumab will be administered over a 90-
minutes period. Beginning on Day 21, patients will receive 6 mg/kg of trastuzumab, 
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administered intravenously every 21 days and continued indefinitely every 21 days 
after 6 cycles of cytotoxic therapy are completed and until progression of disease or 
prohibitive toxicities occur. Additional cycles may be administered if the investigator 
feels that the subject would receive clinical benefit from continued chemotherapy 
treatment.
4.3.1.2
How supplied: Trastuzumab, manufactured by Genentech and available commercially, 
is supplied as a freeze-dried preparation at a nominal content of 440 mg per vial for 
parenteral administration. This agent is formulated in histidine, trehalose, and 
polysorbate 20. Each vial of trastuzumab is packaged with one 30 ml vial of 
bacteriostatic water for injection, USP, 1.1% benzyl alcohol.
4.3.1.3             Preparation: Reconstitution with 20 ml of the supplied diluent provides a solution    
                        containing 21 mg/ml trastuzumab. The reconstituted solution is designed for multiple
                       uses and must be stored under refrigeration.  Reconstituted trastuzumab should be 
                       clear to slightly opalescent and colorless to pale yellow. The vial must be used within 
                       28 days after reconstitution. If a patient has a known allergy to benzyl alcohol, Sterile 
                      Water for injection without a preservative may be used. However, the reconstituted 
                     solution should be used immediately and the unused portion discarded.  Provided     
                     below are directions for reconstituting each vial of trastuzumab:
Using a sterile syringe, slowly inject 20 ml of the supplied diluent (or sterile 
water, if appropriate) into the vial. The stream of diluent should be directed 
into the lyophilized cake. Swirl the vial gently to aid reconstitution. 
Trastuzumab may be sensitive to shear-induced stress, e.g., agitation or rapid 
expulsion from a syringe.  DO NOT SHAKE. Vigorous handling of solutions 
of trastuzumab may result in aggregation of the protein and create cloudy 
solutions. Slight foaming of the product upon reconstitution is not unusual. 
Allow the vial to stand undisturbed for approximately 5 minutes. The 
solution should be essentially free of visible particles, clear to slightly 
opalescent and colorless to pale yellow.  Reconstituted trastuzumab should 
be further diluted in 250 ml of 0.9% Sodium Chloride for Injection, USP, 
prior to administration. Solutions for infusion prepared in polyvinylchloride 
(PVC) or polyethylene bags may be stored at 2-8°C (36-46°F) for up to 24 
hours prior to use. Dextrose 5% solution should not be used.
4.3.1.4              Administration: Trastuzumab is given by slow intravenous infusion only. A
typical dosing schedule is 6 mg/kg administered every 21 days. The initial 
dose of 8 mg/kg is infused over 90 minutes. If this is well tolerated, 
subsequent infusions may be given over 30 minutes. 
4.3.2
Storage and Stability: Trastuzumab is shipped from the Genentech Clinical   
Repository at ambient temperature via overnight courier but must be placed in 
a refrigerator at 2-8°C (36-46°F) immediately upon receipt to ensure optimal 
retention of physical and biochemical integrity. DO NOT FREEZE. When 
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stored appropriately, trastuzumab is stable through the date stamped on the vial 
label. Vials reconstituted with the provided diluent (Bacteriostatic Water for 
Injection) are stable for up to 28 days when stored refrigerated at 2-8°C (36-
46°F). 
4.3.3
Supplier: Genentech, Inc.  Commercially available for subjects enrolled at Yale 
under the standard of care.
4.3.4
Toxicities of trastuzumab: Hematologic toxicity is infrequent. Mild to 
moderate diarrhea has been observed. Pulmonary fibrosis has been reported. 
(During the first infusion with trastuzumab, a symptom complex most 
commonly consisting of chills and/or fever was observed in about 40% of 
patients. The symptoms were usually mild to moderate in severity and were 
treated with acetaminophen, diphenhydramine, and meperidine (with or 
without reduction in the rate of trastuzumab infusion). Trastuzumab 
discontinuation was infrequent. Other signs and/or symptoms may include 
nausea, vomiting, pain (in some cases at tumor sites), rigors, headaches,
 dizziness, dyspnea, hypotension, rash, and asthenia. The symptoms occurred 
infrequently with subsequent trastuzumab infusions.
4.3.4.1
  Cardiac Toxicities: Seven percent of patients receiving trastuzumab as 
single agent have been noted to develop any cardiac dysfunction; 5% of 
patients developed class III/IV heart failure.  94% of the patients had received 
prior anthracyclines.
4.3.5
Product Complaint: A product complaint is any written or oral information 
received from a complainant that alleges deficiencies related to identity, 
quality, safety, strength, purity, reliability, effectiveness or performance of a 
product after it has been released and distributed to the commercial market or 
clinical trial.
Product Complaints with an AE (adverse event) should be reported via 
email/fax to:
usds_aereporting-d@gene.com OR 650-238-6067
Product Complaints without an AE (adverse event) should be reported via 
email to:
kaiseraugst.global_impcomplaint_management@roche.com
All complaints must be filed within 15 calendar days for approved products. 
Complaints can be reported using a Medwatch, CIOMS or any Genentech-
approved reporting form (same as SAEs, AESI etc.).
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5.0 CORRELATIVE STUDIES 
5.1
Immunohistochemistry (IHC): Uterine or metastatic tumor sites will be 
collected at the time of primary staging surgery. The tumor will be processed and 
paraffin-embedded by a research technician in the surgical pathology department.  
Archival tumoral tissue or tumor cells isolated from ascites will be studied in patients 
with recurrent disease that do not go to surgery.  The Dako Hercep test will be 
performed as initial evaluation for HER2/neu protein over-expression in USPC 
samples.  Membranous staining for HER2/neu will be scored according to the Dako 
Hercep test criteria and scored as 0, 1+, 2+, 3+ (45-48). Uterine serous tumors showing 
a 3 + positive screening test are eligible for enrollment. USPC samples showing 2+ 
positivity by IHC for HER2/neu by Hercep test must also show gene amplification by 
fluorescent in situ hybridization (FISH) to be eligible for study enrollment. All IHC 
and FISH assays will be centrally reviewed in the Pathology Department at Yale 
University where confirmatory IHC and/or FISH review and/or testing will be 
performed. Patients will be allowed to initiate therapy prior to confirmation.
5.2
Fluorescence in-situ hybridization (FISH):  Only the cases with 2+ 
membranous staining on IHC will be submitted to confirmatory FISH analysis based 
on a known correlation established in breast cancer and recent reports in USPC (34,46-
48). Fluorescence in situ hybridization (FISH) is regarded as the best diagnostic test 
for detecting HER-2/neu amplification: it has high sensitivity (96.5%) and specificity 
(100%) for detecting amplification of HER-2/neu (45-48).  Fluorescence in situ 
hybridization (FISH) analysis will be performed on sections of paraffin-embedded 
tissue using dual-color DNA FISH probes. For the detection of HER2/neu 
amplification a Pathvysion LSI, Her-2 (17q11-12) probe labeled with Spectrum 
Orange will be used in combination with a CEP 17 centromeric probe labeled with 
Spectrum Green (Abbott) as previously reported by Santin et al., (34).
Of note: as concordance between HER2/neu protein expression by IHC and
gene amplification by FISH has not definitely been demonstrated in cases 
where IHC may be positive (3+) but gene amplification is negative, we shall 
use IHC as the gold standard test to determine patient eligibility to 
trastuzumab therapy.  
5.3
Exploratory Objectives 
5.3.1.1
Isolation of peripheral blood mononuclear cells and plasma to determine 
peripheral blood natural killer (NK) cell numbers, cytotoxic activity and 
circulating HER2/neu levels by ELISA.
5.3.1.2
  Anticoagulated vials of peripheral blood (i.e., 15 mL total in sodium 
heparin) will be collected from each patient prior to the first treatment with 
trastuzumab, after 3 and 6 cycles of therapy and after 3 months after the end 
of chemotherapy. Peripheral blood mononuclear cells (PBMCs) will be used 
in flow cytometry studies to identify CD56+CD3- NK cells, CD56+CD3+ 
NK-T cells and CD56+/CD16+ NK cells numbers and in cytotoxicity assays 
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against HER2/neu positive targets as previously described (44). Plasma 
levels of HER2/neu will be quantified by ELISA.
6.0
TREATMENT PLAN AND ENTRY PROCEDURE/REGISTRATION 
PROCEDURE
6.1
Study Entry
6.11
Patients will be screened and consented by the P.I. or a member of                         
the study staff at each respective institution.  Patient Randomization Form to 
be faxed and approved by Lead Institution PI prior to entry into trial.  NOTE: 
Do not perform MUGA/ECHO unless patient is randomized to Trastuzumab 
arm of study.
6.12
Treatment Plan
This is a two arm, randomized Phase II design with HER2/neu+ 
advanced/recurrent USPC disease. Patients with USPC meeting eligibility 
criteria will undergo immunohistochemistry for HER2/neu expression and/or 
fluorescence in situ hybridization (FISH) to detect amplified HER2/neu gene 
expression. 
6.121
HER2/neu+: Patients who have HER2/neu positive disease (i.e., 3+ USPC) 
by IHC and/or FISH + results will be randomized to receive six cycles of 
chemotherapy with carboplatin and paclitaxel with or without concurrent 
trastuzumab. They will also have peripheral blood drawn to perform in vitro 
studies to provide a basis for assessing the possible therapeutic contributions 
of immune mechanisms of action of trastuzumab.
The trastuzumab shall be continued indefinitely in these patients until disease 
progression of prohibitive toxicities occur.
6.122
CA-125 Exploratory Analysis: Of note, retrospective studies suggest
 that CA-125 may be a marker of active disease in women with USPC (49)  
Therefore, in an exploratory analysis, CA-125 will be drawn on 
each patient with other labs prior to treatment, after each cycle and then at 3 
month intervals if remission is achieved.
6.123
Chemotherapy: Carboplatin AUC 5 and Paclitaxel 175 mg/m2 (3 hours) 
every 21 days x 6 cycles will be given to all patients. Three weeks of therapy 
will be considered one cycle. Additional cycles may be administered if the 
investigator feels that the subject would receive clinical benefit from 
continued chemotherapy treatment.
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6.124.1 Methods of Chemotherapy Administration
Maximum body surface area used for dose calculations will be 2.0 m2 as per 
GOG Chemotherapy Procedures Manual.
6.124.2 Sequence and timing of drug administration: Carboplatin will be 
administered as a 30 minute infusion.  Carboplatin will be infused after 
Paclitaxel.
6.124.3 Paclitaxel will be administered as a 3-hour infusion on this study.  For all 
courses where paclitaxel is to be administered, it is recommended that a 
preparative regimen be employed to reduce the risk with hypersensitivity 
reactions. This regimen should include dexamethasone (either IV or PO), 
anti- histamine H1 (such as diphenhydramine) and anti-histamine H2 (such 
as cimetidine, ranitidine, or famotidine).
6.124.4 Antiemetic Regimens: It is anticipated that nausea and vomiting may be a 
significant side effect of chemotherapy. The following representative 
antiemetic regimens are suggested: Ondansetron 8-32 mg IV 30 minutes 
prior to administration of chemotherapy and dexamethasone 10-20 mg IV 30 
minutes prior to drug administration, or Granisetron 10 mcg/kg IV (or 2 mg 
PO) 30 minutes prior to chemotherapy, with or without lorazepam 0.5-2.0 
mg IV 30 minutes prior to chemotherapy or aloxi 0.25 mg IV 30 minutes 
prior to chemotherapy.
6.124.5 Dosing of Carboplatin
The dose will be calculated to reach a target area under the curve (AUC) of 
concentration x time according to the Calvert formula using an estimated 
glomerular filtration rate (GFR) from the Cockcroft-Gault formula. The 
initial dose of carboplatin must be calculated using GFR.  Institutional 
guidelines should be followed when calculating carboplatin dose.
In patients with an abnormally low serum creatinine (less than or equal to 0.7 
mg/dl), due to reduced protein intake and/or low muscle mass, the creatinine 
clearance should be determined using a minimum of 0.7 mg/dL.
Calvert Formula: Carboplatin dose (mg) = target AUC × (GFR +25)
For the purposes of this protocol, the GFR is considered to be
equivalent to the creatinine clearance. The creatinine clearance (Ccr) is 
estimated by the method of Cockcroft-Gault using the following formula:
Ccr=  [140-age(years)] x Weight (kg)x 0.85/(72 x Scr)
Where: Ccr = estimated creatinine clearance in ml/min
Age = patient's age in years (from 20-80)
Scr = serum creatinine in mg/dl
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In the absence of new renal obstruction or elevation of serum creatinine 
above 1.5 x ULN (CTC grade2), the dose of carboplatin will not be 
recalculated for subsequent cycles, but will be subject to dose modification 
for hematologic criteria and other events as noted.
The Maximum GRF according to the new NCI recommendations to be used 
in the Calvert Formula should not exceed 125 ml/min.  Therefore, the 
maximum allowed dose of carboplatin is 750 mg (AUC 5).
6.124.6 Dosing of Trastuzumab Therapy: 8 mg/kg of trastuzumab will be 
administered IV over a 90-minute period and on the same day as 
chemotherapy (but after the patient has received paclitaxel and carboplatin). 
The drug will be administered every 21 days thereafter at a dose of 6 mg/kg 
and if the patient tolerates the initial 90 minute infusion, a 30 minute infusion 
will be used for subsequent doses. Therapy will be continued on an every 21 
day basis until disease progression or adverse effects prohibit further 
treatment. Antiemetic pre-treatment is not required.
Trastuzumab will usually be administered in an outpatient setting. When 
study medication is administered to a patient, emergency resuscitation 
equipment must be available in the clinic. Patients must remain under 
medical supervision for 1 hour following completion of the first dose of 
trastuzumab administration.
If a Grade 3 or 4 toxicity occurs during an infusion of trastuzumab or during 
the post-infusion observation period, the infusion must be immediately 
stopped and the patient must be monitored for a minimum of 1 additional 
hour. If the toxicity does not resolve to ≤ grade 1 within an hour, the patient 
must be admitted to the hospital for additional monitoring. In most cases 
patients experiencing a reaction such as fever, rigors, or dyspnea with the 
initial trastuzumab infusion will not experience a recurrence, and may 
receive further treatment as scheduled. If the reaction was mild, the infusion 
may be restarted the same day. If the reaction was severe, pretreatment with 
diphenhydramine or prolongation of infusion duration may be employed at 
the discretion of the treating physician. Patients with underlying pulmonary 
pathology are at increased risk of severe or life-threatening pulmonary 
reactions and should be closely monitored. Such patients and their caregivers 
should be instructed to contact their nurse or physician or go to the nearest 
urgent care facility immediately if they develop clear discomfort after a 
treatment with trastuzumab.
6.124.7 Stage III-IV patients should receive systemic chemotherapy (i.e., carboplatin 
and paclitaxel with or without trastuzumab) followed by radiation therapy.  
Depending on pathologic findings, in addition to pelvic radiation, para-aortic 
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radiation and/or vaginal brachytherapy are allowed at the discretion of the 
treating oncologist. 
6.124.8 Surgical Procedures: There will be no surgical modifications.  Pelvic and para-
aortic node dissection is required for the purpose of this protocol unless gross 
extra-uterine disease is present at time of initial surgery.
7.0 TREATMENT  MODIFICATIONS
                7.1 Dose reduction levels: 
Drug
Initial dose (A)
Reduced dose (B)
Units
Paclitaxel
175
135
mg/m2
Carboplatin
5.0
4.0
AUC
7.2         Hematologic toxicity
7.21 Initial treatment modifications will consist of cycle delay and/or dose reduction as 
indicated below. The use of hematopoietic cytokines and protective reagents are restricted as 
noted:
7.21.1 Patients will NOT receive prophylactic growth factors  [filgrastim (GCSF), 
sargramostim (GM-CSF), pegfilgrastim (Neulasta)] unless they experience recurrent 
neutropenic complications after treatment modifications specified below.
7.21.2 Patients will NOT receive prophylactic thrombopoietic agents.
7.21.3 Patients may receive erythropoietin for management of anemia AFTER 
documentation of hemoglobin less than 10 g/dl (CTCAE v4.0 grade 2).
7.21.4 Treatment decisions will be based on the absolute neutrophil count (ANC) rather
than the total white cell count (WBC).
7.21.5 Subsequent cycles of therapy will not begin until the ANC is ≥ 1500 cells/microliter 
(CTCAE v4.0 grade 1) and the platelet count is ≥ 100,000/microliter. Therapy will be 
delayed for a maximum of two weeks until these values are achieved. Patients who fail to 
recover adequate counts within a two week delay will be removed from study therapy.
7.21.6 For first occurrence of febrile neutropenia, and/or documented grade 4 neutropenia 
persisting >7 days, reduce carboplatin and paclitaxel chemotherapy by one dose level on 
subsequent cycles.
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7.21.7 For recurrent febrile neutropenia, and/or recurrent documented grade 4 neutropenia 
persisting ≥7 days (after initial dose reduction), add prophylactic growth factors. In this 
circumstance, it is recommended that G-CSF at a dose of 5 microgram/kg/day* (or 
equivalent dosing of pegfilgrastim or sargramostim) will be administered subcutaneously 
starting the day after the last dose of chemotherapy (normally day 2-4) and continuing 
through hematopoietic recovery. Growth factors should not be used within 72 hours of a 
subsequent dose of chemotherapy.
7.21.8 Patients with grade 4 thrombocytopenia will have a 1 level dose reduction in the 
carboplatin only.
7.21.9 There will be no dose modifications on the basis of uncomplicated granulocyte
nadirs lasting less than 7 days.
7.3 Non-hematologic toxicity
7.31Neurotoxicity: Neurologic Toxicity Grade 2 (at the discretion of the investigator) 
or Grade 3 or greater peripheral neuropathy requires discontinuation of protocol 
therapy until symptoms resolve to Grade 1.  When treatment is resumed the carboplatin 
dose should be reduced to an AUC of 4 and paclitaxel should be reduced to level B.  
The protocol regimen will be discontinued in patients with recurrent Grade 3 or any 
Grade 4 neurologic toxicity. 
7.32 Gastrointestinal Adverse Effects: Grade 1-2 nausea/vomiting with chemotherapy 
or radiation therapy, and grade 1-2 diarrhea after radiation therapy may be expected.  
Patients may receive the investigator’s choice of drugs for the control of nausea and 
vomiting. Grade 4 gastrointestinal toxicity will require hospital admission for IV 
hydration. Stomatitis or diarrhea: If any mucositis is present on day 21 of a cycle, 
treatment should be withheld until the mucositis has returned to Grade 1. Grade 3 or 4 
mucositis or diarrhea; require a dose reduction of paclitaxel.
7.33 Genitourinary Adverse Effects: Increased frequency with dysuria may occur in 
some patients.  This may be treated symptomatically with antispasmodics and 
increased fluid intake.  Urinary tract infection should be ruled out if the symptoms 
persist.
7.34 Adjustments for Cardiac Toxicity: Asymptomatic bradycardia is not an indication 
for discontinuation of therapy.  
However, the Paclitaxel infusion should be 
discontinued for chest pain, clinically significant arrhythmia, hypotension, or serious 
allergic reaction.  Any arrhythmia that is felt to necessitate discontinuation of 
Paclitaxel should be discussed with the Study Chair as soon as possible.
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7.35 Dose Adjustments for > Grade 3 Non-Hematologic Toxicity: Decrease Paclitaxel 
and Carboplatin combination one dose level, and resume treatments after recovery to 
< grade 1 toxicity.
7.36 Paclitaxel hypersensitivity reaction: If hypersensitivity reactions to paclitaxel or 
its vehicle (Cremaphor) occur, it will usually be during the first few minutes of 
infusion.  Appropriate symptomatic therapy should be given.  Continued treatment 
may be considered if the reaction is not life-threatening; however, patients must be 
cautioned about potential recurrences of the reaction.  Should the patient decide to 
continue with treatment it is preferable that this be done on the same day of the 
occurrence. Patients will follow the institutional protocol for paclitaxel desensitation. 
A suggested procedure would be to administer the drug first with 1 ml of the original 
IV solution diluted in 100 ml over one hour, then 5 ml in 100 ml over one hour, then 
10 ml in 100 ml over one hour, and finally, the original solution at the original speed.  
7.37 Myalgias in the several days following paclitaxel treatment may be severe, and 
should receive aggressive symptomatic treatment, including narcotics or steroids as 
required.  They are not, however, an indication for dose reduction.
7.38 Hepatic toxicity: Bilirubin must return to within normal limits prior to further 
therapy. 
7.4 Trastuzumab: Although patients will undergo routine monitoring during 
therapy, organ-specific toxicities that require dose modification are not 
anticipated with trastuzumab, and there are no provisions for dose reduction. 
As noted above, infusion duration may be lengthened at the discretion of the
 treating physician.
7.41 Therapy with trastuzumab should be discontinued in patients with any
new cardiac symptoms or findings of cardiac dysfunction. Therapy should also 
be discontinued if the LVEF is documented to fall to a value ≤ 40% or decrease 
≥ 15 absolute percentage points, from baseline (for example, from a value of 
60% to 45%).
7.42 
Criteria for removal from trastuzumab treatment:
7.43 Inability to tolerate trastuzumab because of toxicity.
7.44 The patient may withdraw from the study at any time.
7.45 Patients with evidence of disease progression or significant side effects will  
             be removed from study treatment.
7.46 New cardiac toxicity as specified in exclusion criteria.
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8.0
STUDY PARAMETERS
8.1
Observations and Tests
The following observations and tests are to be performed and recorded before, during, 
and after treatment:
Parameter
Pre-
Treatment
(28 Days)
During
Chemotherapy
+/-Trastuzumab
During
Trastuzumab
Therapy
After Therapy (every 3 mo. 
X 2 yrs, then every 6 mo. X 
3 yrs, then yearly)
History, PE (including 
pelvic), Performance Status, 
Toxicity Evaluaton,weight
X
1
1
X
CBC /Diff/Platelets
5
1,7
1,7
2
Chemistries:Serum 
Cr,BUN,K,Mg,Bili
5
1,7
1,7
2
CA 125
5
3
3
X
Urinalysis
5
2
2
2
SGOT,SGPT,Alk Phos
5
1,7
2
2
Vital signs
X
1
1
2
EKG
X
2
2
2
Toxicity 
X
1
1
2
*Radiographic tumor 
evaluation and measurement 
(Chest/Abd/Pelvis)
6
6
6
X
LVEF
X
4
4
2
**PMBC collection for 
Translational Studies
        X
After the 3rd and 6th 
cycle
3 months after the end of 
carboplatin/taxol(both study 
arms)
1 
Patients should be seen/examined before each cycle of chemotherapy. A physical exam only needs to be 
completed every 3 months while on trastuzumab maintenance. 
2
Repeat only as clinically indicated.
3
Retrospective studies suggest that CA-125 may be a marker of active disease in women with USPC. 
Therefore, CA-125 will be drawn prior to treatment, after each cycle of chemotherapy and then per 
protocol
4
LVEF can be determined by gated cardiac scan (such as MUGA) or echo.  Repeat measurements should 
be obtained using the same technique after cycle 3, after cycle 6 and every 3 months while on 
Trastuzumab.  
5
Must be obtained within 14 days prior to initiating protocol therapy.
6
Must be obtained within 28 days prior to initiating protocol therapy, after cycle 3 and after cycle 6.  
To be obtained at the end of treatment and every 3 months x 2 years, then every 6 months x 3 years, then 
yearly until disease progression.
 7
CBC/Differential/Platelets and chemistries must be obtained within 4 days of re-treatment with protocol 
therapy or per institutional guidelines.
*
Repeat CT scan or MRI should use similar equipment and techniques to ensure consistent measurements
**
See Appendix D for collection and shipping information.
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8.2 
To be completed within 28 days prior to initiation of therapy
Documentation  of tumoral HER2/neu by IHC and /or FISH 
Medical history including list of current medications and dosing 
schedules.
History of previous therapies for current disease; any residual toxicity 
from prior therapies should be recorded by using the grading schema in 
NCI Common Toxicity Criteria v4.0.
A physical examination will be performed. A pelvic examination is 
required only if this method is used to evaluate measurable disease. All 
measurable disease will be documented with uni-dimensional tumor 
measurements if clinically possible.
ECOG performance status
CT of the chest, abdomen and pelvis or MRI
Baseline measurements of tumor size
PBMC to be used in flow cytometry (i.e., analysis of NK cells) and 
cytotoxic assays of NK activity against K-562 cells and HER2/neu + 
USPC-ARK2 and USPC-ARK3 cell lines (i.e., 15 mL in heparinized 
tubes of patient’s peripheral blood-see Appendix D).
Vital Signs (blood pressure, pulse, respiratory rate, temperature)
Baseline EKG
LVEF measurement by MUGA or Echo if randomized to receive 
Trastuzumab
8.3 
To be completed within 14 days of initiation of therapy
Complete blood count with leukocyte differential and platelet count
Serum chemistries to include magnesium, SGPT, SGOT, alkaline 
phosphatase, total bilirubin, BUN, serum creatinine and potassium. 
Serum CA-125
Urinalysis
8.4   To be obtained 1 week prior to each chemotherapy cycle  (approximately    
every 3 weeks) +/-7 days to allow for holidays/patient schedule issues: 
Weight
Vital Signs (blood pressure, pulse, respiratory rate, temperature)
A physical examination will be performed. A pelvic examination is 
required only if this method is used to evaluate measurable disease. All 
measurable disease will be documented with uni-dimensional tumor 
measurements if clinically possible. A physical exam only needs to be 
completed every 3 months while on trastuzumab maintenance.
ECOG performance status
Serum CA-125
Assessment of treatment related toxicities
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8.4.1
To be obtained within 4 days of retreatment with protocol therapy or 
per institutional guidelines:
Complete blood count and leukocyte differential and  
platelet count 
Serum chemistries (magnesium, SGPT, SGOT, total bilirubin, BUN, 
serum creatinine), electrolytes. These tests may be done up to 2 days 
prior to MD visit
8.5 
To be obtained after 3 cycles, after 6 cycles and every 3 months for 
patients randomized to receive Trastuzumab:
LVEF by MUGA or Echo performed every 3 months while on 
trastuzumab. Must use same method as baseline assessment.
8.5.1
To be obtained after 3 cycles, after 6 cycles and 3 months after 
completion of carboplatin/taxol chemotherapy:
PBMC to be used in flow cytometry (i.e., analysis of NK cells) and 
cytotoxic assays of NK activity against K-562 cells and HER2/neu + 
USPC-ARK2 and USPC-ARK3 cell lines (i.e., 15 mL in heparinized 
tubes of patient’s peripheral blood-see Appendix D)
8.6
To be obtained at the end of treatment and every 3 months x 2 years, 
then every 6 months x 3 years, then yearly until disease progression*:
Adverse events/toxicities-if study-related and ongoing 
Serum CA-125
A physical examination will be performed. A pelvic examination is 
required only if this method is used to evaluate measurable disease. 
CT of the chest abdomen and pelvis or MRI
Evaluation of tumor measurement 
*Note:  In order to more precisely determine time of progression, the investigator 
is encouraged to obtain radiologic assessments earlier than 3 months if there is a 
strong clinical suspicion of progression of disease to either confirm or refute the 
clinical impression. 
8.7     Patients will be followed every 3 months for survival only after confirmed 
disease progression.
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9.0
EVALUATION CRITERIA
9.1
Objective Response
The major parameters of response to be assessed include Progression-Free Survival, 
Overall Survival, documentation of Sites of Recurrence, and Treatment Related 
Toxicity.  Treatment response will be based on RECIST v1.1 Guidelines for 
Measurable Lesions.
9.11 Measurable Lesions- Only recurrent patients with measurable lesions will be 
enrolled in the study.  All target lesions must be assessed using the same 
technique as baseline.  Included in the evaluations are the following standard 
response criteria for target lesions:  

Complete Response (CR):  Disappearance of all target lesions.  No new 
lesions. Lymph nodes must be <10mm short axis.
 

Partial Response (PR):  At least a 30% decrease in the sum of the 
longest diameter of target lesions, taking as reference the baseline 
sum of the longest diameters.  No new lesions.

Progressive Disease (PD):  The appearance of a new lesion, or at 
least a 20% increase in the sum of the longest diameters of the 
target lesions, taking as the reference the smallest sum of the 
longest diameters recorded since treatment started, and at least 
5mm increase.

Stable Disease (SD):  Target lesions do not qualify for CR, PR, or 
progression.  No new lesions.  
All non-target lesions must be assessed using the same technique as 
baseline.  Included in the evaluations are the following standard 
response criteria for non-target lesions:

Complete Response:  The disappearance of all non-target lesions.

Incomplete Response/Stable Disease:  The persistence of one or more 
non-target lesion(s).

Progression Disease:  The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. provides cycle 
responses for all combinations of tumor responses in target and non-target 
lesions with or without new lesions. 
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9.12
 Progression-Free Survival will be defined as date from entry to a particular    
     protocol to date of reappearance or increasing parameters of disease on               
imaging (CT scan or MRI) or by clinical exam or death from any cause, or is 
     censored at date of last disease assessment. 
9.13
   Survival will be defined as observed length of life from entry to a particular 
protocol to death or, for living patients, date of last contact.
9.14
Sites of Recurrence will be assessed. Any clinical or radiological evidence for 
new tumor, preferably confirmed by pathology, will be considered as a 
recurrence. Pattern of relapse to be noted:
9.14.1 Pelvic (peritoneal, nodal)
9.14.2 Abdominal (peritoneal, nodal, visceral, ascites)
9.14.3 Diaphragmatic
9.14.4 Distant (nodal, parenchymal, liver, lungs, others)
9.14.5 Omental
9.14.6 Effusions (pleural, ascites)
9.15    Treatment Toxicity: The grade level of the various toxicities will be classified 
using the Common Toxicity Criteria, version 4 (CTC, v.4) guidelines. Acute 
toxicities will be scored if occurring </= 30 days from treatment completion, 
and chronic if > 30 days. Frequency and duration of treatment interruptions 
due to the treatment toxicity will be assessed.  
10.0
DURATION OF STUDY
10.1
This study will continue as long as treatment protocols remain activated.
10.2
The patient must be followed quarterly for two years and every six months for three 
additional years, and thereafter annually or at time of recurrence until death.
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11.0
STUDY MONITORING AND REPORTING PROCEDURES 
11.1 Personnel responsible for the safety review and its frequency:
The principal investigator will be responsible for monitoring the data, assuring protocol compliance, 
and conducting the safety reviews at the specified frequency which must be conducted at a 
minimum of every 6 months (including when reapproval of the protocol is sought).  During the 
review process, the principal investigator with the help of the Remote Monitoring Coordinator will 
evaluate whether the study should continue unchanged, require modification/amendment, or close to 
enrollment. Either the principal investigator, the IRB or the Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC) have the authority to stop or suspend the study or require 
modifications.
11.2 The risks associated with the current study are deemed moderate for the following 
reasons: 
1. We do not view the risks associated with the Trastuzumab as minimal.
2. We do not view the risks associated with the combined use of Carboplatin, Paclitaxel and 
Trastuzumab as minimal.
3. Given the now established safety and validity of studies performed using Trastuzumab 
(FDA approved since September, 1998), we do not view the proposed study as high risk.
4. Given our experience with the combined co-administration of Carboplatin, Paclitaxel and 
Trastuzumab, we do not view the proposed studies as high risk.
Although we have assessed the proposed study as one of moderate risk, the potential exists for 
anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it is not 
possible to predict with certainty the absolute risk in any given individual or in advance of first-
hand experience with the proposed study methods. Therefore, we provide a plan for monitoring the 
data and safety of the proposed study as follows:
11.3 Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and attributed to the 
study procedures / design by the principal investigator Dr. Alessandro Santin , according to the 
following categories:
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s).
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s).
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s).
d.) Unlikely: Adverse event is likely not to be related to the investigational procedures(s)/agent(s).
e.) Unrelated: Adverse event is clearly not related to investigational procedures(s)/agent(s).
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11.4 Plan for Grading Adverse Events:
The following scale will be used in grading the severity of adverse events noted during the study:
1. Mild adverse event
2. Moderate adverse event
3. Severe 
11.5 Plan for Determining Seriousness of Adverse Events:
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse 
Event.  Similarly, an adverse event may be graded as moderate but still meet the criteria for an SAE.  
It is important for the PI to consider the grade of the event as well as its “seriousness” when 
determining whether reporting to the IRB is necessary.
Refer to Section 12.0 of the protocol for guidelines
11.6 Plan for reporting Reportable Adverse Events and other unanticipated problems 
involving risks to subjects or others to the IRB
The principal investigator will report the following types of events to the IRB: a) adverse events 
that are serious or life-threatening AND unanticipated (or anticipated but occurring with a greater 
frequency than expected) AND possibly, probably or definitely related to the 
drug/device/intervention; and b)other unanticipated problems involving risks to subjects or others.
These adverse events or unanticipated problems involving risks to subjects or others will be 
reported to the IRB in accordance with IRB Policy 710, using the appropriate forms found on the 
website. This information is discussed in Section 12.0 of the protocol.
11.7 Plan for reporting adverse events to co-investigators on the study, as appropriate the 
protocol’s research monitor(s), e.g., industrial sponsor, Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC), Protocol Review Committee (PRC), DSMBs, study sponsors, 
funding and regulatory agencies, and regulatory and decision-making bodies.
For the current study, the following individuals, funding, and/or regulatory
agencies will be notified (choose those that apply):
X All Co-Investigators listed on the protocol.
X Yale Cancer Center Data and Safety Monitoring Committee (DSMC)
X Genentech, Inc. 
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The principal investigator Alessandro Santin will conduct a review of all adverse events upon 
completion of every study subject. The principal investigator will evaluate the frequency and 
severity of the adverse events and determine if modifications to the protocol or consent form are 
required.
11.8
ADVERSE EVENT REPORTING FOR COMMERCIAL DRUG STUDIES
Genentech Requirement for reporting:
This study will utilize the CTC version 4.0 for toxicity and Adverse Event Reporting.  A copy of the 
CTC version 4.0 can be downloaded from the CTEP home page.
Toxicity Grade
Typea
Local IRB
Study 
Coordinators
Via 
email/fax/phone
4,5
Unknown
Yes
Yes
5
Known
No
Yes*
2,3
Unknown
No
No
4 (non-myelo)
Known
No
No
4 (myelob)
Known
No
No
*  If clearly related to the commercial agent(s)
a  Type (Known or unknown) is based on toxicities included in the package insert or literature of 
known toxicities associated with the study drug(s).
 b Myelosuppression, which includes neutropenia, anemia, thrombocytopenia
11.9
ASSESSMENT OF SAFETY
11.9.1 SPECIFICATION OF SAFETY VARIABLES 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and 
serious adverse events (SAEs) that are considered related to Trastuzumab, all events of 
death, and any study specific issue of concern.
11.9.1.1 Adverse Events
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated 
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with the use of an investigational (medicinal) product or other protocol-imposed 
intervention, regardless of attribution.
This includes the following:
 AEs not previously observed in the subject that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with advanced recurrent 
uterine serous papillary carcinoma that were not present prior to the AE reporting period. 
See Section 11.10.
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations).
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention.
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period.
11.9.2 Serious Adverse Events
Refer to Section 12.0 of the study protocol.
11.9.3 Methods and Timing for Assessing and Recording Safety Variables
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, as outlined in Section 11.10 and 12.0 respectively, are collected 
and reported to the appropriate IRB(s), and Genentech, Inc. in accordance with  FDA 
regulations at 21CFR 312.32 (a)(IND Safety Reports). 
11.9.4 Adverse Event Reporting Period
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of study treatment and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is earlier.  
After this period, investigators should only report SAEs that are attributed to prior study 
treatment.
11.9.5 Assessment of Adverse Events
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
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during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately.
Each reported AE or SAE will be described by its duration (i.e., start and end dates), 
regulatory seriousness criteria if applicable, suspected relationship to the Trastuzumab  
(see following guidance), and actions taken.
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline:
Yes
There is a plausible temporal relationship between the onset of the AE and 
administration of the Trastuzumab and the AE cannot be readily explained by the 
subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE 
follows a known pattern of response to the Trastuzumab and/or the AE abates or 
resolves upon discontinuation of the Trastuzumab or dose reduction and, if 
applicable, reappears upon re-challenge.
No
Evidence exists that the AE has an etiology other than the Trastuzumab (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship to 
Trastuzumab administration (e.g., cancer diagnosed 2 days after first dose of study 
drug).
Expected adverse events are those adverse events that are listed or characterized in the Package 
Insert or current Investigator Brochure. 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current Investigator 
Brochure (I.B.) or not identified.  This includes adverse events for which the specificity or severity 
is not consistent with the description in the P.I. or I.B.  For example, under this definition, hepatic 
necrosis would be unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or 
hepatitis. Refer to Section 12.0 for further guidelines.
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11.10 PROCEDURES FOR ELICITING AND RECORDING  ADVERSE EVENTS
11.10.1
Eliciting Adverse Events
A consistent methodology for eliciting AEs at all subject evaluation time points should be 
adopted.  Examples of non-directive questions include: 
“How have you felt since your last clinical visit?
“Have you had any new or changed health problems since you were last here?” 
11.10.2
Specific Instructions for Recording Adverse Events
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  
Avoid colloquialisms and abbreviations.  All information will be recording using Oncore 
Clinical Trials Management System.
a. Diagnosis vs. Signs and Symptoms
If known at the time of reporting, a diagnosis should be reported rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, it is ok to 
report the information that is currently available.  If a diagnosis is subsequently established, 
it should be reported as follow-up information.
b. Deaths
All deaths that occur during the conduct of the research must be reported to the Yale 
Principal Investigator and the Remote Monitoring Coordinator  immediately (if possible) to 
ensure that all over site committees are properly informed.  All information will be entered 
into Oncore Clinical Trials Management System and updated appropriately.  Further 
determination regarding the need to submit to the subjects local IRB, Yale University HHRP 
following IRB Policy 710 for reporting Unanticipated Problems Involving Risk to Subjects 
and Genentech Drug Safety Committee will be reviewed. Specific information is outlined in 
section 12.0 of the protocol. 
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When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be reported as the single medical concept.  If the cause of death is unknown 
and cannot be ascertained at the time of reporting, report “Unexplained Death”.
c.
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the start of the study.  Such 
conditions should be reported as medical and surgical history.
A preexisting medical condition should be re-assessed throughout the trial and reported as 
an AE or SAE only if the frequency, severity, or character of the condition worsens during 
the study.  When reporting such events, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., “more frequent 
headaches”).
d. Hospitalizations for Medical or Surgical Procedures
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE.
If a subject is hospitalized to undergo a medical or surgical procedure as a result of an AE, 
the event responsible for the procedure, not the procedure itself, should be reported as the 
SAE.  For example, if a subject is hospitalized to undergo coronary bypass surgery, record 
the heart condition that necessitated the bypass as the SAE.
Hospitalizations for the following reasons do not require reporting:
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for preexisting conditions
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study or
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of 
the study.
e.
Pregnancy
If a female subject becomes pregnant while receiving investigational therapy or within 30 
days of awareness after the last dose of study drug, a report should be completed and 
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expeditiously submitted to the Genentech, Inc.  Follow-up to obtain the outcome of the 
pregnancy should also occur. 
Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as 
serious, and expeditiously reported as an SAE.  Similarly, any congenital anomaly/birth 
defect in a child born to a female subject exposed to the Trastuzumab should be reported as 
an SAE.
f.
Post-Study Adverse Events
The investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if attributed to prior Trastuzumab exposure.
If the investigator should become aware of the development of cancer or a congenital 
anomaly in a subsequently conceived offspring of a female subject who participated in the 
study, this should be reported as an SAE.
g.
Reconciliation  
The Sponsor agrees to conduct reconciliationfor the product.  Genentech and the Sponsor will agree 
to the reconciliation periodicity and format, but agree at minimum to exchange monthly line listings 
of cases received by the other party.  If discrepancies are identified, the Sponsor and Genentech will 
cooperate in resolving the discrepancies.  The responsible individuals for each party shall handle the 
matter on a case-by-case basis until satisfactory resolution. 
11.11 STUDY CLOSE-OUT REPORTS
Any Clinical Study Report (final study report), abstracts or literary articles that are a result 
of the study should be sent to Genentech for review.
Copies of such reports should be mailed to the assigned Medical Science Liaison (MSL) to 
the study: Christine Ryan, MSN, NP at cryan@gene.com
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12.0 PROCEDURES FOR REPORTING UNANTICIPATED PROBLEMS INVOLVING 
RISKS TO SUBJECTS OR OTHERS, INCLUDING ADVERSE EVENTS (UPIRSOs)
12.1 Expedited Reporting of UPISROs  Occuring at Yale
AEs classified as “serious” and “unexpected” that are possibly, probably, or definitely attributed 
to drug administration, or SAEs whose frequency exceeds expectations, require expeditious 
handling and reporting.
Serious Adverse Event (SAE)
Any adverse event that results in any of the following outcomes:  

death, 

a life-threatening experience, 

inpatient hospitalization or prolongation of existing hospitalization, 

a persistent or significant disability/incapacity, 

a congenital anomaly/birth defect, or

any other adverse event that, based upon appropriate medical judgment, may jeopardize 
the subject’s health and may require medical or surgical intervention to prevent one of 
the other outcomes listed in this definition. 
The PI will promptly investigate all safety information related to an adverse experience.  If the 
results of the PI’s investigation show an adverse drug experience not initially determined to be 
reportable (based on whether the event is serious, unexpected, and associated with drug 
administration) is so reportable, the PI will report such experience.  Follow-up information to a 
safety report shall be submitted as soon as the relevant information is available.
Reporting to the Yale Human Investigation Committee
Timeframe for Reporting 
1. Events that may require a temporary or permanent interruption of study activities by the 
Principal Investigator or sponsor to avoid potential harm to subjects should be reported to 
the IRB immediately (if possible), followed by a written report to the IRB using the 
UPIRSO Reporting Form (710 FR 4) no more than 5 calendar days after the Yale 
Principal Investigator becomes aware of the event. 
                                          
2. Internal Events (defined above) should be reported to the IRB using the UPIRSO Reporting 
Form (710 FR 4) within 5 calendar days of the Principal Investigator becoming aware of 
the event. 
3. External Events (defined above) should be reported to the IRB using the UPIRSO Reporting 
Form (710 FR 4) within 15 calendar days of the Yale University Principal Investigator (PI) 
becoming aware of the event ONLY IF either of the following are true:
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(a) The Yale PI has concluded that an immediate change to the protocol is necessary to 
address the risks raised by the event, OR 
(b) A monitoring entity (e.g., an external IRB at the site where the problem or event 
occurred, the sponsor, or the Data Safety Monitoring Board) has required 
modifications/amendments to the research protocol or consent documents as a result of 
the event. 
For all reports of external events, the UPIRSO Reporting Form (710 FR 4) must include the 
following information: 
(a) a clear explanation of why the event or series of events has been determined to meet 
criteria for reporting; 
(b) a description of the proposed protocol changes and  any corrective actions to be taken by 
the PI in response to the external event; and 
(c) any aggregated data and an analysis or summary from the sponsor or DSMB, when 
applicable and available, sufficient to explain the significance of the event or series of 
events in order to ensure the information is interpretable and relevant to the IRB’s task 
of protecting the rights and welfare of human participants. 
Reporting to Investigators at Collaborating Sites
             
The Yale PI will notify all participating investigators in a written safety report of any 
adverse experience associated with the use of the drug that is  both serious and 
unexpected as soon as possible and in no event later than 15 calendar days after the 
sponsor’s (PI’s) initial receipt of the information.  [21CFR312.32(c)]
12.2  SUB SITE INVESTIGATOR SAE REPORTING REQUIREMENTS
The collaborating investigator (Sub Site PI) in a multi-center trial will report serious, unexpected 
adverse events occurring at their site to the Yale Principal Investigator regardless of attribution 
immediately (if possible) of knowledge of the event.  Full written reports should be submitted to the 
Yale PI within 5 calendar days of initial knowledge of the report. A Medwatch 3500A shall be used 
for reporting this event following the instructions outlined in section 12.3.  This information will also 
need to be recorded in Oncore Clinical Trials Management System in the SAE section. Information 
entered into Oncore will directly reflect the Medwatch 3500A submission.  
Send SAEs to the Yale Principal Investigator:
Name: Alessandro Santin,MD
Phone: 203-737-4450
Email: alessandro.santin@yale.edu
Fax:203-737-4339
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12.3
SAE Reporting to Genentech
Investigators must report all SAEs to Genentech within the timelines described below to:
 
The completed Medwatch/case report should be faxed immediately upon completion to 
Genentech Drug Safety at:
(650) 225-4682
or
(650) 225-5288
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it 
becomes available.

Serious AE reports that are related to the Product will be transmitted to Genentech within 
fifteen (15) calendar days of the Awareness Date.

Serious AE reports that are unrelated to the Product will be transmitted to Genentech within 
thirty (30) calendar days of the Awareness Date.
 Additional Reporting Requirements to Genentech include the following.

Any reports of pregnancy following the start of administration with the Product will be 
transmitted to Genentech within thirty (30) calendar days of the Awareness Date. 

 All Non-serious Adverse Events originating from the Study will be forwarded in a quarterly 
report to Genentech.
  Note: Investigators should also report events to their IRB as required.
MedWatch 3500A Reporting Guidelines:
In addition to completing appropriate patient demographic and suspect medication information, the 
report should include the following information within the Event Description (section 5) of the 
MedWatch 3500A form:

Protocol description (and number, if assigned)

Description of event, severity, treatment, and outcome if known
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
Supportive laboratory results and diagnostics
Investigator’s assessment of the relationship of the adverse event to each investigational product 
and suspect medication
Follow-up information:  
Additional information may be added to a previously submitted report by any of the following 
methods:

Adding to the original MedWatch 3500A report and submitting it as follow-up

Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500A form 
Summarizing new information and faxing it with a cover letter including patient identifiers (i.e. 
D.O.B. initial, patient number), protocol description and number, if assigned, brief adverse 
event description, and notation that additional or follow-up information is being submitted  
(The patient identifiers are important so that the new information is added to the correct initial 
report)
Occasionally Genentech may contact the reporter for additional information, clarification, or current 
status of the patient for whom an adverse event was reported.  For questions regarding SAE 
reporting, you may contact the Genentech Drug Safety representative noted above or the MSL 
assigned to the study.  Relevant follow-up information should be submitted to Genentech Drug 
Safety as soon as it becomes available and/or upon request.
MedWatch 3500A (Mandatory Reporting) form is available at
http://www.fda.gov/medwatch/getforms.html 
At all times, the Remote Monitoring Coordinator is available to facilitate submissions and answer 
any questions regarding the process for all sub site staff.
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13.0  MULTI-SITE MANAGEMENT AND COORDINATION
13.1
Overview
This is a multi-site trial where Dr. Alessandro D. Santin is the lead Principal Investigator for Yale 
University and for all non-Yale sites. The Gynecological Oncology research team at Yale University 
consisting of a Multi-site Research Coordinator, Remote Monitoring Coordinator, Multi-site Data 
Manager, Clinical Research Nursing Coordinator, Specimen Procurement Coordinator and a Multi-
site Administrative Assistant will provide multicenter research support for all sites involved in this 
project.  The YCCI clinical trials management support staff will provide clinical database systems 
support and training through the use of Oncore Clinical Trials Management System. 
13.2
Initiation of Study
Once sub-site IRB approval has been obtained and all required start up documents have been 
submitted, Dr. Alessandro D. Santin will perform a Site Initiation Visit (SIV) prior to enrollment of 
study subjects.  This will be either on-site or via teleconference with each participating site PI and 
staff available.  Members of the Gynecologic Oncology research team will be available to answer all 
protocol questions.  Once this has taken place with the participating site they may enroll subjects into 
the protocol.  All pre and post SIV documents will be collected and stored in accordance with the 
Gynecologic Oncology Research SOP for collection of regulatory documents.
13.2.1  Investigational Site Training
Dr. Alessandro D. Santin or an appointed designee will provide investigational staff training prior to 
study initiation. Training topics will include but are not limited to: Good Clinical Practice (GCP), AE 
reporting, study details and procedure, study documentation, specimen procurement and shipping, 
informed consent, and enrollment. Sub sites are supplied with telephone and e-mail contact for all 
personnel and encouraged to contact with any questions regarding the conduct of the protocol. 
13.2.2  Data Collection
Sites will use Oncore Clinical Trials Management System for all data associated with the protocol. 
Data managers at participating centers will receive Oncore access once they are designated by the site 
PI, complete an Oncore access request and submit HIPAA training certification. Individuals will 
receive Oncore training by a member of the YCCI clinical trials management support staff.  Subjects 
entered into the system will be identified by a subject number assigned after randomization. The 
confidentiality of records that could identify subjects will be protected, respecting the privacy and 
confidentiality rules in accordance with the applicable regulatory requirement(s).  The database will 
be monitored by the Multi-site Data manager and the Remote-site Monitoring Coordinator to ensure 
that data is entered in a timely manner.    
13.3  Monitoring
Dr. Alessandro D. Santin or an appointed designee must be allowed to visit all study site locations 
periodically to assess the data quality and study integrity. On-site they will review study records and 
directly compare them with source documents, discuss the conduct of the study with the investigator, 
and verify that the facilities remain compliant.
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In addition, remote monitoring of data may be performed periodically requiring the site to submit de-
identified patient data for comparison to the Remote-site Monitoring Coordinator. The study may be 
audited by the Yale University DSMB internal auditors.  Yale University DSMB audit reports will be 
kept confidential.
13.4
Study Enrollment Procedures
Any modification of the original consent document provided to participating sites by the Coordinating 
Center must be approved in advance by the Coordinating Center. Rationale will be provided with any 
request for a change. A copy of each site’s IRB and Coordinating Center approved informed consent 
document must be on file at the Gynecological Oncology Regulatory office before subjects may be 
enrolled.  
To register eligible patients on this study, each site will contact the Multi-site Coordinator; Lisa Baker, 
RN (203-785-6398) or Martha Luther, RN (203-737-2781) and provide the signed and dated 
eligibility checklist, completed signature page of the consent form and additional source documents 
if requested by the Principal Investigator or Multi-site Coordinator. Once the Principal Investigator 
or Multi-site Coordinator verifies eligibility, the patient will be randomized and a unique subject study 
number will be issued.  The subject will not be identified by name. 
13.5
Responsibilities of the Lead Investigator Dr. Alessandro D. Santin: 
The lead investigator is responsible for the overall conduct of the study at all participating sites and 
for monitoring the safety and quality of the data as well as compliance to the protocol and with 
applicable federal regulations and Good Clinical Practice (GCP). 
The lead investigator will monitor accrual rates at all sites for adequate progress, ensure appropriate 
coordination, submission of documents and approval of the protocol as well as consent documents 
and any subsequent amendments at all sites. There will be only one version of these documents that 
will be used by all participating institutions and the lead investigator is responsible for assuring that 
the correct versions are used by all participating institutions.
No additional sites will be added to the study without a proposed amendment and review and approval 
by the Yale Cancer Center Protocol Review Committee and the Yale IRB (HIC). 
The lead investigator has the authority to suspend accrual at any site not complying with this protocol, 
including not submitting data in a timely manner. Any suspension of accrual will be reported to the 
Yale University Data Safety Monitoring Committee (DSMC) as well as to the Yale University HHRP. 
Site principal investigators must report the suspension to their IRB.
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13.6
Responsibilities of the Coordinating Center   
The coordinating center, under the direction of the lead investigator Dr. Alessandro D. Santin, MD, 
is responsible to ensure that each participating site has the appropriate assurance on file with the 
Office for Human Research Protection (OHRP) or their local/central Institutional Review Board 
(IRB). The coordinating center is responsible for obtaining copies of OHRP/IRB assurance for each 
site prior to enrollment of subjects at the site.
13.7   IRB Approvals
The Coordinating Center is responsible to ensure that no patients are entered on study without full 
IRB approval and that IRB re-approval is appropriately maintained. A copy of the IRB approval 
document from each participating institution will be obtained by the Coordinating Center prior to 
activation of the study at any site. Documentation of reapproval must be provided to the Coordinating 
Center in a timely manner or registration will be halted at any site in which a current continuing 
approval is not on file at the Coordinating Center.
13.8
Amendments and Consents
The Coordinating Center will maintain a copy of all amendments, consent forms, and approvals from 
each site. Consent forms will be reviewed and approved by the Coordinating Center to ensure 
consistency with the Yale IRB approved consent. Should changes to the protocol or consent become 
necessary, protocol amendments will be issued by the Coordinating Center to all sites for local site 
approval prior to implementation, unless there is an apparent immediate hazard to a subject or the 
subject’s best interest is endangered. Any such deviation from the approved protocol will be promptly 
reported to the lead investigator.  
13.9
Responsibilities of Participating Sites:
The principal investigator at each site is responsible for the overall conduct of the study at their site 
and for monitoring the safety and quality of the data as well as compliance to the protocol and with 
applicable federal regulations and (GCP). 
The principal investigator at each site is responsible for assuring that all the required data is collected 
and entered onto the e-CRFs using Oncore Clinical Trials Management Systems in accordance with 
study-specific requirements and that the data submission and reporting timelines are met. The 
coordinating center will perform onsite monitoring periodically to ensure adherence to the protocol 
as well as regulatory compliance. 
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14.0   STATISTICAL CONSIDERATIONS
14.1 Study design:  This will be a randomized, open-label Phase II multicenter study of 
advanced/recurrent UPSC patients, with an emphasis on identifying and treating women having 
HER2/neu+ disease. The incidence of HER2/neu+ USPC patients in the retrospective literature ranges 
from 18-80%. However, the percentage is known to increase with advancing stage, and most of these 
studies are small and are confounded by patients of various disease stages. In a recent GOG study of 
patients with largely advanced-stage USPC, HER2/neu expression rates (i.e., 2+ and 3+) were >60% 
(35). 
            With regard to sample-size planning, almost 100% of recurrences in women with advanced-
stage disease will happen within the first two years after diagnosis. Based upon historical Phase III 
data of outcomes in advanced or recurrent endometrial cancer patients treated with platinum/taxane-
based therapy (median PFS=~7.0-8.0 months) and retrospective data on advanced stage USPC 
patients (median PFS ~6 months), we would anticipate a 6-month median PFS in patients treated with 
chemotherapy alone.
14.2 Primary objective
To estimate whether the addition of trastuzumab to paclitaxel and carboplatin chemotherapy improves 
progression free survival (PFS) when compared to paclitaxel and carboplatin alone in USPC patients 
over expressing HER2/neu 
14.3 Secondary objectives
To assess objective response rate (ORR)
To assess overall survival (OS)
To assess the safety profile of Trastuzumab in USPC patients
14.4 Exploratory/correlative objectives
To determine peripheral blood natural killer (NK) cell numbers and activity in HER2/neu+ USPC 
patients to provide a basis for assessing the possible therapeutic contributions of immune mechanisms 
of action of trastuzumab.
To study HER2/neu extracellular domain (ECD) circulating levels in the plasma of USPC patients 
over expressing HER2/neu before, during and after treatment to elucidate whether changes in 
HER2/neu ECD would predict response to trastuzumab.
To determine whether CA-125 levels correlate with disease activity in persistent and/or recurrent 
disease.
14.5 Subjects will be stratified by (a) Study Site and (b) Disease Stage (i.e. Stage III or Stage IV or 
Recurrent Disease).  
Subjects will be assigned at a 1:1 allocation ratio to Arm A 
(Carboplatin+Paclitaxel) or Arm B (Carboplatin+Paclitaxel plus Trastuzumab) by randomization.
14.6 Primary endpoint.  Progression-free survival (PFS), defined as the length of time from 
randomization to disease recurrence, disease progression, or death for any reason.  Subjects who are 
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alive and who did not experience disease recurrence or progression by the end of the study will be 
censored for the primary endpoint at the date of their last contact. 
14.7 Statistical analysis plan for primary endpoint.  
Arm B (Carboplatin+Paclitaxel plus 
Trastuzumab) will be compared to Arm A (Carboplatin+Paclitaxel) for an increase in PFS by means 
of the log rank test, conducted using a one-sided alpha=0.10.  A single interim analysis for futility 
will be conducted when the observed number of recurrence/progression/death events reaches 26 or 
>30% of the required total of 85.  
 14.8 Statistical power requirement.  Under the analysis plan for the primary endpoint, the proposed 
study will be required to have 90% power to detect a 43% decrease in hazard of a 
recurrence/progression/death event in Arm B compared to Arm A (hazard ratio = 0.57).  This 43% 
decrease in hazard is equivalent to an increase in median PFS from 6 months in the control arm to 
10.5 months in the trastuzumab arm.  For the sample-size calculation, we will assume a median PFS 
of 6 months in the control arm.  For the interim-analysis adjustment, we will use the Lan-DeMets 
(O’Brien-Fleming) spending function to allocate Type II error.
14.9 Study design, sample size, and study duration.  The following study design meets the statistical 
power requirement:  

A total of 100 subjects will be accrued to the study, at a rate of five subjects 
per month for a total of 20 months.  

The 
interim 
analysis 
for 
futility 
will 
take 
place 
when 
26 
recurrence/progression/death events have occurred.  If the log-rank z-score has a value 
more negative than –1.328 (equivalent to a 1-sided P value greater than 0.908, and to 
an apparent 69% increase in hazard for trastuzumab compared to control), then the 
result will be taken as evidence of treatment futility, and the study will be terminated 
early, before reaching full accrual.  Based on an accrual rate of 5 subjects per month 
and a 6-month median PFS in the control arm, we expect to observe 26 events at 12.9 
months into the study, when cumulative accrual should be 65 subjects or fewer (<65% 
of 100).  
o
This early stopping rule has probability=0.0030 of Type II error 
(inappropriately causing early termination) when the true trastuzumab effect is a 
43% decrease in hazard compared to control.
o
The interim-analysis trigger point of 26 events was chosen to be early enough 
to allow a data monitoring board sufficient time to review the results and make a 
decision before final accrual of 100 subjects is reached.      

The final analysis for efficacy will take place when 85 recurrence/
progression/death events have occurred.   Based on an accrual rate of 5 subjects per 
month and a 6-month median PFS in the control arm, we expect to observe 85 events 
at 33.6 months of study duration.  
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o
The study is thus expected to last slightly more than 2.75 years under current 
assumptions of 100 subjects accrued at 5 per month and median PFS of 6 months 
in the control arm.  
o
Early drop-outs and ineligible subjects.  If an enrolled subject drops out of 
the study before receiving treatment, or is found to have been ineligible, she will 
be replaced.  Up to ten such early drop-outs and ineligibles will be replaced in this 
manner; thus, the study may enroll up to 110 subjects in order to assure the required 
sample size of 100.  If an enrolled subject drops out of the study after receiving 
treatment, she will not be replaced, and her time on study will be censored at the 
date of her study withdrawal.
14.10 Correlative studies in HER2/neu+ cohort
        Association of IHC, FISH, plasma HER2/neu levels and NK cell number and activity 
with PFS using Cox proportional hazards regression will be performed. 
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15.0
BIBLIOGRAPHY
1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010; 60:277-
300. 
2. Hendrickson M, Ross J, Eifel P, Cox R, Martinez A, Kempson R. Adenocarcinoma of 
the endometrium: Analysis of 256 cases with carcinoma limited to the uterine corpus. 
Gynecol Oncol 1982;13:373-392. 
3. Carcangiu M, Chambers J. Uterine papillary serous carcinoma: A study of 108 cases with 
emphasis on the prognostic significance of associated endometrioid carcinoma, absence 
of invasion, and concomitant ovarian cancer. Gynecol Oncol 1992;47:298-305.
4. Grice J, Ek M, Greer B, Koh W, Muntz H, Cain J et al. Uterine papillary serous 
carcinoma: Evaluation of long-term survival in surgically staged patients. Gynecol Oncol 
1998;69:69-73. 
5. Schwartz PE. The management of serous papillary uterine cancer. Curr. Opin. Oncol. 18: 
494-499; 2006. 
6.  Fader AN, Drake RD, Rose PG, Gehrig PA, Huh WK, Fader AN. Boruta D. Olawaiye 
AB. Gehrig PA. Current Opinion in Obstetrics & Gynecology. 22(1):21-9, 2010 
7. Cirisano F, Robboy S, Dodge R, Bentley R, et al. The outcome of stage I-I clinically and 
surgically staged papillary serous and clear cell endometrial cancers when compared with 
endometrioid carcinoma. Gynecol Oncol 2000;77:55-65.
8. Alektiar K, McKee A, Lin O, Venkatraman E, et al. Is there a clear difference in outcome 
between stage I-II endometrial cancer of papillay serous/clear cell and endometrioid 
FIGO grade 3 cancer? Int Jo Radiat Oncol Biol Phys. 2002;54:79-85.
9. Sutton G, Bundy B, Axelrod J, Roy T, Homesley H, Malfetano J, Mychalczak B, King 
M. Whole Abdominal Radiotherapy in Stage I-II Papillary Serous or Clear Cell Cancers 
of the Uterus (A GOG Study). Gyncol Oncol 2002;84:479-536 (SGO abstr# 205).
10. Goff B, Kato D, Schmidt R, Ek M, Ferry J et al. Uterine papillary serous carcinoma: 
Patterns of metastatic spread. Gynecol Oncol 1994;54:264-268.
11. Randall ME, Filiaci V, Mannel R, et al. Randomized phase III trial of whole-abdominal 
irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial 
carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 2006 Jan 1;24(1):36-44
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12. Burke T, Gershenson D, Morris M, Stringer A, Levenback C, Tortolero-Luna G, Baker 
V. Postoperative adjuvant cisplatin, doxorubicin, and cyclophosphamide chemotherapy 
in women with high-risk endometrial cancer. Gynecol Oncol 1994;55:47-50
13. Levenback C, Burke T, Silva E, Morris M, et al. Uterine papillary serous carcinoma 
treated with cisplatin, doxorubicin, and cyclophosphamide. Gynecol Oncol 1992;46:317-
321.
14. Ball H, Blessing J, Lentz S, Mutch D. A phase II trial of paclitaxel in patients with 
advanced or recurrent adenocarcinoma of the endometrium: A GOG study. Gynecol 
Oncol 1996;62:278-281
15. Lincoln S, Blessing J, Lee R, et al. Activity of paclitaxel as second-line chemotherapy in 
endometrial carcinoma: A Gynecologic Oncology Group study. Gynecol Oncol 
2003;88:277-281.
16. Fleming GF, Brunetto VL, Cella D, et al. Phase III trial of doxorubicin plus cisplatin with 
or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic 
Oncology Group Study. J Clin Oncol. 2004 Jun 1;22(11):2159-66
17. Ramondetta L, Burke T, Levenback, Bevers M, Bodurka-Beevers D, Gershenson D. 
Treatment of Uterine Papillary Serous Carcinoma with Paclitaxel. Gynecol Oncol 
2001;82:156-161
18. Hoskins P, Swenerton K, Pike J, et al. Paclitaxel and carboplatin, alone or with 
irradiation, in advanced or recurrent endometrial cancer: A phase II study. J Clin Oncol 
2001;19:4048-4053.
19. Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB:Surgical 
Pathologic Spread Patterns of Endometrial Cancer.  Cancer 1987;60:2035-2041.
20. Creutzberg C, van Putten W, Koper P, Lybert M et al. Surgery and postoperative 
radiotherapy versus surgery alone for patients with stage 1 endometrial carcinoma: 
multicenter randomized trial. Lancet 2000;355:1404-11.
21. Fields AL, Einstein MH, Goldberg G. Pilot phase II trial of radiation "sandwiched" 
between combination  paclitaxel/platinum chemotherapy in patients with uterine 
papillary serous carcinoma (UPSC). Gynecol Oncol 2008 Jan: 108(1):201-6
22.  Roberts J, Brunetto V, Keys H, Zaino R, Spirtos N, et al. A phase III study of surgery vs 
surgery plus adjunctive radiation therapy in intermediate risk endometrial 
adenocarcinoma. Gynecol Oncol 1998;68:135 (SGO abstr #258).
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23. Morrow CP, Bundy B, Homesley H, Creasman W, Hornback N, Kurman R, Thigpen T. 
Doxorubicin as an adjuvant following surgery and radiation therapy in patients with high-
risk endometrial cancer, stage I and occult stage II: A GOG study. Gynecol Oncol 
1990;36:166-171.
24. Green J, Green S, Alberts D, O’toole R, Surwit E, Noltimier J. Carboplatin therapy in 
advanced endometrial cancer. Obstet Gynecol 1990;75:696-700. 
25. Long H, Pfeifle D, Wieland H et al. Phase II evaluation of carboplatin in advanced 
endometrial cancer. J Natl Cancer Inst. 1988;80:276-278. 
26. Susumu N et al: Randomized phase III trial of pelvic radiotherapy versus cisplatin-based 
combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: 
a Japanese Gynecologic Oncology Group study. Gynecol Oncol. 2008 Jan;108(1):226-
33
27. Hoberg T et al: main plenary at ASCO Annual Meeting, June 2007
28. Santin AD, Bellone S, Palmieri M, Dunn D, Agha J, Gokden M, Roman JJ, Hutchins L, 
Pecorelli S, O’Brien T, Cannon MJ, Parham GP. Overexpression of HER-2/Neu in 
uterine serous papillary cancer.  Clin. Cancer Res. 8;1271-1279;2002.
29. Santin AD, Bellone S, Van Stedum S. et al. Amplification of c-erbB2 oncogene. Cancer 
2005; 104:1391
30. Rolitsky CD, Theil KS, McGaughy VR, et al. Her2/neu amplification and overexpression 
in endometrial carcinoma. Int J Gynecol Pathol 1999; 18:138
31. Slomovitz BM, Broaddus RR, Burke TW. Her2/neu overexpression and amplification in 
uterine papillary serous carcinoma. J Clin Oncol 2004; 22:2136.
32. Morrison C, Zanagnolo V, Ramirez N, et al.  HER-2 is an independent prognostic factor 
in endometrial cancer: association with outcome in a large cohort of surgically staged 
patients. J Clin Oncology. 24(15):2376-85, 2006.
33. Santin AD, Siegel ER, Bellone S, et al. Racial differences in overexpression of epidermal 
growth factor type II receptor (HER2/neu): a major prognostic indicator in Uterine Serous 
Papillary Cancer. Am. J. Obstet. Gynecol. 192;813-818;2005.
34.  Santin AD, Bellone S, Van Stedum VR, et al. Determination of HER2/neu status in 
uterine serous papillary carcinoma: Comparative analysis of immunohistochemistry and 
fluorescence in situ hybridization.  Gynecol Oncol. 2005 Jul;98(1):24-30 
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35. Grushko TA, Filiaci VL, Mundt AJ, Ridderstråle K, Olopade OI, Fleming GF; 
Gynecologic Oncology Group. An exploratory analysis of HER-2 amplification and 
overexpression in advanced endometrial carcinoma: a Gynecologic Oncology Group 
study. Gynecol Oncol. 2008 Jan;108(1):3-9.
 
36. Díaz-Montes TP, Ji H, Smith Sehdev AE, Zahurak ML, Kurman RJ, Armstrong DK, 
Bristow RE. Clinical significance of Her-2/neu overexpression in uterine serous 
carcinoma. Gynecol Oncol. 2006 Jan;100(1):139-44. Epub 2005 Sep 22. PMID: 
16182348 
37. Brufsky A. Trastuzumab-based therapy for patients with HER2-positive breast cancer: 
from early scientific development to foundation of care. [Review] [105 refs] American 
Journal of Clinical Oncology. 33(2):186-95, 2010
38. Fleming GF. Sill MW. Darcy KM. McMeekin DS. Thigpen JT. Adler LM. Berek JS. 
Chapman JA. DiSilvestro PA. Horowitz IR. Fiorica JV. Phase II trial of trastuzumab in 
women with advanced or recurrent, HER2-positive endometrial carcinoma: a 
Gynecologic Oncology Group study. Gynecologic Oncology. 116(1):15-20, 2010 
39. Santin AD. Letter to the Editor referring to the manuscript entitled: "Phase II trial of 
trastuzumab in women with advanced or recurrent HER-positive endometrial carcinoma: 
a Gynecologic Oncology Group study" recently reported by Fleming et al., (Gynecol 
Oncol., 116;15-20;2010). Gynecol Oncol. 2010 Feb 19. [Epub ahead of print].
40. Jewell E, Secord AA, Brotherton T, Berchuck A. Use of trastuzumab in the treatment of 
metastatic endometrial cancer. Int J Gynecol Cancer 2006;16:1370-3.
41. Villella JA. Cohen S. Smith DH. Hibshoosh H. Hershman D. HER-2/neu overexpression 
in uterine papillary serous cancers and its possible therapeutic implications. International 
Journal of Gynecological Cancer. 16(5):1897-902, 2006 
42. Santin AD. Bellone S. Roman JJ. McKenney JK. Pecorelli S. Trastuzumab treatment in 
patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu. 
International Journal of Gynaecology & Obstetrics. 102(2):128-31, 2008 
43. Koene HR, Algra J et al. Fc gammaRIIIa-158V/F polymorphism influences the binding 
of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-
48L/R/H phenotype. Blood. 1997 Aug 1;90(3):1109-14
44. Ruiz M, et al. Varchetta S. Gibelli N. Oliviero B. Nardini E. Gennari R. Gatti G. Silva 
LS. Villani L. Tagliabue E. Ménard S. Costa A. Fagnoni FF. Elements related to 
heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab 
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therapy for primary operable breast cancer overexpressing Her2. Cancer Research. 
67(24):11991-9, 2007
45.  Ruiz M, et al. Phase-II study of weekly schedule of trastuzumab, paclitaxel, and 
carboplatin followed by a week off every 28 days for HER2+ metastatic breast cancer.
                  Cancer Chemother Pharmacol. 2008 Mar 26 Cancer Res. 
46. Lopez-Guerro J, et al. Histological tumor grade correlates with HER2/c-erB-2 status in 
invasive breast cancer: a comparative analysis between immunohistochemical (CB11 
clone and Herceptest), FISH and differential PCR procedures. Arkh Patol. 2003 Jan-
Feb;65(1):50-5
47. Moatter T, Din ZU, et al. Immunohistochemical Her-2/ Neu expression with gene 
amplification by fluorescence in situ hybridization for assessment in breast carcinomas.
J Coll Physicians Surg Pak. 2007 Dec;17(12):726-30
48. Pauletti G, Dandekar S, Rong H, Ramos L, Peng H, Seshadri R, Slamon DJ. Assessment 
of methods for tissue-based detection of the HER-2/neu alteration in human breast 
cancer: a direct comparison of fluorescence in situ hybridization and immune-
histochemistry.  J Clin Oncol. 2000 Nov 1;18(21):3651-64
49. Olawaiye AB, Rauh-Hain JA, Withiam-Leitch M, Rueda B, Goodman A, Del Carmen 
MG. Utility of pre-operative serum CA-125 in the management of uterine papillary 
serous carcinoma. Gynecol Oncol. 110(3):293-8, 2008. 
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Appendix A: 
FIGO Surgical Stages for Endometrial Cancer
IA         Tumor confined to the uterus, no or < 50% myometrial invasion
IB         Tumor confined to the uterus, > 50%  myometrial invasion
II          Cervical stromal invasion, but not beyond uterus
IIIA      Tumor invades serosa or adnexa
IIIB      Vaginal and/or parametrial involvement
IIIC1    Pelvic node involvement
IIIC2    Para-aortic involvement
IVA       Tumor invasion bladder and/or bowel mucosa
IVB       Distant metastases including abdominal metastases and/or inguinal lymph nodes
 
Appendix B:
Performance Status Criteria
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ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence of 
disease.
0
Normal activity.  Fully active, able to carry 
on all pre-disease performance without 
restriction.
90
Able to carry on normal activity; minor signs 
or symptoms of disease.
80
Normal activity with effort; some signs or 
symptoms of disease.
1
Symptoms, but ambulatory.  Restricted in 
physically 
strenuous 
activity, 
but 
ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on normal 
activity or to do active work.
60
Requires occasional assistance, but is able to 
care for most of his/her needs.
2
In bed <50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities.  Up and about 
more than 50% of waking hours.
50
Requires 
considerable 
assistance 
and 
frequent medical care.
40
Disabled, 
requires 
special 
care 
and 
assistance.
3
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours.
30
Severely disabled, hospitalization indicated.  
Death not imminent.
20
Very sick, hospitalization indicated. Death 
not imminent.
4
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair.
10
Moribund, 
fatal 
processes 
progressing 
rapidly.
5
Dead.
0
Dead.
Appendix C:
Adverse Events to Study Agents
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Adverse Event List(s) for Commercial Agent(s)
Paclitaxel:
Hematologic: Myelosuppression
Gastrointestinal: Nausea and vomiting, diarrhea, stomatitis, mucositis, pharyngitis, typhlitis, 
ischemic colitis, neutropenic enterocolitis
Heart: Arrhythmia, heart block, ventricular tachycardia, myocardial infarction (MI), bradycardia, 
atrial arrhythmia
Pulmonary: Pneumonitis
Blood Pressure: Hypotension, hypertension (possibly related to concomitant medication--
Dexamethasone)
Neurologic: Sensory (taste), peripheral neuropathy, seizures, mood swings, hepatic 
encephalopathy, encephalopathy
Skin: Infiltration: erythema, induration, tenderness, rarely ulceration, radiation-recall reactions, 
erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) 
Allergy: Anaphylactoid and urticarial reactions (acute), flushing, rash, pruritus
Liver: Increased SGOT, SGPT, bilirubin and alkaline phosphatase, hepatic failure, hepatic necrosis 
Other: Alopecia, fatigue, arthralgia, myalgia, lightheadedness, myopathy
Other, Vision: Sensation of flashing lights, blurred vision, scintillating scotomata
(Please refer to package insert for the comprehensive list of adverse events.)
  Carboplatin:
Hematologic: Myelosuppression
Gastrointestinal: Nausea and vomiting, diarrhea, 
Neurologic: Peripheral neuropathy, central neurotoxicity 
Allergy: Anaphylactoid and urticarial reactions (acute), flushing, rash, pruritus
Liver: Increased SGOT, SGPT, bilirubin and alkaline phosphatase
Other: Fatigue, electrolyte imbalance, hypomagnesemia, hypocalcemia

Please refer to package insert for a comprehensive list of adverse events.
Trastuzumab:
ALLERGY/IMMUNOLOGY
Allergic reaction/hypersensitivity, (including drug fever)
Allergic rhinitis (including sneezing, nasal
stuffiness, postnasal drip)
Allergy/Immunology - Other
(Angioedema)
BLOOD/BONE MARROW
Hemoglobin 
Leukocytes (total WBC)
Neutrophils/granulocytes (ANC/AGC) 
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CARDIAC ARRHYTHMIA
Sinus tachycardia 
Supraventricular arrhythmia -
nodal/junctional
CARDIAC GENERAL
Cardiac General - Other (Cardiac arrest)
Cardiac General - Other
(Cardiomyopathy)
Cardiac troponin I (cTnI)
3Hypertension
Hypotension
Left ventricular systolic dysfunction 
Pericardial effusion (non-malignant)
Pericarditis
CONSTITUTIONAL SYMPTOMS
Fatigue (asthenia, lethargy, malaise) 
Fever (in the absence of neutropenia,
where neutropenia is defined as ANC <1.0x 10e9/L)
Rigors/chills 
DERMATOLOGY/SKIN
Rash/desquamation 
Rash: acne/acneiform
Ulceration
Urticaria (hives, welts, wheals)
GASTROINTESTINAL
Anorexia 
Diarrhea 
Mucositis/stomatitis
(functional/symptomatic) 
Nausea 
Vomiting 
INFECTION
Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented 
infection)(ANC <1.0 x 10e9/L, fever >=38.5 degrees C)
Infection - Other (Herpes simplex)
Infection with unknown ANC 
METABOLIC/LABORATORY
Alkaline phosphatase 
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AST, SGOT (serum glutamic oxaloacetictransaminase)
GGT (gamma-glutamyl transpeptidase) 
PAIN
Pain - abdomen NOS Pain – back
Pain – bone, joint, muscle
Pain - chest/thorax NOS Pain – head/headache 
Pain - neuralgia/peripheral nerve
Pain - tumor pain 
Pain NOS
PULMONARY/UPPER RESPIRATORY
Adult respiratory distress syndrome
(ARDS)
Bronchospasm, wheezing 
Cough 
Dyspnea (shortness of breath) 
Hypoxia 
Pleural effusion (non-malignant)
Pneumonitis/pulmonary infiltrates
Pulmonary - Other (Non-cardiogenic pulmonary edema)
Pulmonary fibrosis
Voice changes
SYNDROMES
Cytokine release syndrome/acute infusion reaction
Flu-like syndrome
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APPENDIX D
STUDY PI and Shipping address*:
Alessandro D Santin MD
Yale University School of Medicine
Department of Obstetrics, Gynecology & Reproductive Sciences,
333 Cedar Street, LSOG Bld. Room 305, PO Box 208063,
New Haven, CT, 06520-8063
Phone: 203-737-4450, Fax: 203-737-4339
E-mail: alessandro.santin@yale.edu
I.
Summary of Specimen Requirements
1) A) IHC stained slide(s) showing HER2/neu 3+, FISH + slides or 2+ expression along with an 
H&E stained slide of the primary/recurrent USC for Yale Pathology confirmatory assessment, 
B) Formalin-Fixed, Paraffin-Embedded Tumor Tissue Block or unstained slides 
2) Whole Blood Specimens (10 cc in Lithium Heparin and/or Sodium Heparin) and 5-7 cc 
EDTA (purple top tubes)
II.
Time Points Deadlines and Recommendations
1) IHC stained slides showing HER2/neu 3+, FISH + slides or 2+ expression along with an H&E 
stained slide of the primary/recurrent USC for Yale Pathology confirmatory assessment and 
formalin-fixed, paraffin-embedded primary or recurrent tumor (1st choice: block, 2nd choice: 
20 unstained sections), should be shipped to the Yale Department of Obstetrics & Gynecology 
at the time of patient enrollment in a FED-EX envelope for overnight delivery.  A preprinted 
FED-EX label will be provided.  In order to produce the label, a date of shipment is necessary.  
Please e-mail michele.montagna@yale.edu and martha.luther@yale.edu  with the date of 
shipment and a pre-printed label will be e-mailed back to you.  Please send all FISH slides 
in a light-protected case.
2) Whole blood (minimum 10 mL) drawn into dark green top (Lithium Heparin or Sodium 
Heparin) tubes and 5-7 cc EDTA (purple top tubes) for translational research studies will be 
collected before the first treatment (i.e., within 28 days of initiation of therapy), after the 3rd 
and 6th cycle of chemotherapy (at least 20 days from the chemotherapy infusion) and at 3 
months after the end of  carboplatin/paclitaxel chemotherapy. Blood samples should be 
shipped at room temperature to the Yale Department of Obstetrics & Gynecology the day the 
specimen is collected in a FED-EX envelope for overnight delivery.  A preprinted FED-EX 
label will be provided.  In order to produce the label, a date of shipment is necessary.  Please 
e-mail michele.montagna@yale.edu and martha.luther@yale.edu with the date of shipment 
and a pre-printed label will be e-mailed back to you.
NO BLOOD DRAWS OR SHIPMENTS ON FRIDAYS
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