Phase II Trial of Vaginal Cuff Brachytherapy Followed by Adjuvant Chemotherapy With Carboplatin and Dose Dense Paclitaxel in Patients With High-Risk Endometrial Cancer
Phase: PHASE2
Conditions: Endometrial Cancer, Papillary Serous, Clear Cell Endometrial Cancer
Sponsor: University of Oklahoma

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PHASE II TRIAL OF VAGINAL CUFF BRACHYTHERAPY FOLLOWED BY 
ADJUVANT CHEMOTHERAPY WITH CARBOPLATIN AND DOSE DENSE (Dd) 
PACLITAXEL IN PATIENTS WITH HIGH-RISK ENDOMETRIAL CANCER 
 
 
 
 
 
 
 
Principal Investigator 
Kathleen Moore, MD 
NCT# 03189446 
 

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SCHEMA 
 
Clinical Stage I-II endometrial cancer 
Surgery 
Stage I endometrioid with 3 high-intermediate risk (H-IR) features 
OR 
Stage II any histology 
OR 
Stage I-II Serous or Clear Cell 
Vaginal cuff brachytherapy 
 
Followed by 
Carboplatin (AUC 6) on day 1and Paclitaxel 
80 mg/m2 IV over 1 hour days 1, 8, and 15 
X 3 total cycles 
 
 

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TABLE OF CONTENTS 
PAGE 
1.0 
OBJECTIVES 
1 
2.0 
BACKGROUND AND RATIONALE 
2 
3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS 
11 
4.0 
STUDY MODALITIES 
13 
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 
17 
6.0 
TREATMENT MODIFICATIONS 
20 
7.0 
STUDY PARAMETERS 
24 
8.0 
EVALUATION CRITERIA 
26 
9.0 
DURATION OF STUDY 
27 
10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
28 
11.0 
STATISTICAL CONSIDERATIONS 
30 
12.0 
BIBLIOGRAPHY 
SUGGESTED PATIENT INFORMATION/INFORMED CONSENT 
33 

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1.0 
OBJECTIVES 
 
1.1 
Primary objectives 
 
1.11 
To determine the feasibility of treatment in patients with high risk 
endometrial cancer treated by vaginal cuff brachytherapy followed by 3 
cycles of dose dense paclitaxel and carboplatin chemotherapy. 
 
1.2 
Secondary objectives 
 
1.2.1 To determine the toxicity of vaginal cuff brachytherapy followed by 
carboplatin and dose dense paclitaxel chemotherapy. 
 
1.2.2 To describe sites of failure. 
 
1.2.3 To determine recurrence-free survival for patients treated with the 
proposed study 
 
1.2.4 To determine the contributing cause of death for patients with high risk 
endometrial cancer 
 
1.2.5 To determine overall survival 
 
 

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2.0 
BACKGROUND AND RATIONALE 
 
 
At the State of the Science in Endometrial Cancer Meeting in Manchester, England (Nov 
2006), sponsored by the NCI, an international group of investigators was charged with 
defining what would be considered standard therapies and potential investigational therapies 
that could be explored in the management of early stage endometrial cancer with high risk 
features for recurrence. Because of that meeting, a randomized phase III trial, GOG #249 
was developed and conducted comparing pelvic radiation therapy versus vaginal cuff 
brachytherapy (VCB) followed by 3 cycles paclitaxel/carboplatin (q 21 day, standard dosing) 
chemotherapy. The population evaluated included a broad group of “high-intermediate risk” 
patients based on prior experience with GOG #99 and PORTEC1. The initial results of GOG 
#249 have suggested that VCB + chemotherapy (VCB/C) is not superior to pelvic radiation 
alone1. In addition, the study also helped to further define subpopulations at risk for 
recurrence. 
The GOG #99 previously compared pelvic radiation therapy (PXRT) to observation in a 
group of intermediate risk, stage I-II patients with endometrial cancer with pathologic 
negative lymph nodes.2    A multi-institutional Dutch group evaluated the same two 
treatments in a group of intermediate risk (defined by tumor grade and depth of myometrial 
invasion) stage I-II patients who had not undergone a lymphadenectomy (PORTEC trial).3 
In both studies, PXRT reduced recurrences (principally by reducing pelvic failures), but did 
not statistically improve survival. One hypothesis generated from GOG #99 was that a higher 
intermediate risk (H-IR) patient population could be identified which accounted for 2/3 of 
the recurrences, and for whom PXRT should be considered. Similarly, PORTEC trial 
suggested that older patients and those with grade 3 tumors accounted for the highest risk of 
recurrence. Many have suggested that the patient populations in general enrolled in GOG 
#99 and PORTEC were at too low of a risk to demonstrate improved survival with radiation. 
For example, in GOG #99 only 1/3 of patients enrolled had H-IR features. Additionally, 
intercurrent deaths on both arms had an impact on the ability to detect differences in survival. 
GOG #249 demonstrated no difference between PXRT and VCB/C in a 600 patient 
randomized controlled trial. There was no difference in recurrence free survival (RFS) (82% 
vs. 84%) or overall survival (OS) (93% vs 92%) at the 24 month interval. There was however 
a change in the patterns of failure. Those receiving PXRT had excellent local control, with 
~2.5% pelvic failure rate and nearly 11% distant failure rate, while the VCB/C arm had a 
~7.5% pelvic failure rate and only 8% had distant failure. There were similar rates of non- 
hematologic toxicities, while the VCB/C as expected had significantly more grade 3/4 
hematologic toxicity. There were no treatment related deaths in either arm and completion 
of either regimen was high VCB/C-87% and PXRT 91%. Another important finding of GOG 
#249 was that most patients in this enriched population were at low risk for recurrence. Only 
those of with serous or clear cell carcinoma, stage II, or patients of any age with all 3 risk 
factors had a >15% chance of recurrence. In this population, neither therapy was effective 
in decreasing recurrences, suggesting this is a population who would benefit from a new 
strategy. 

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Several studies have looked at the potential benefit of weekly dose dense paclitaxel compared 
to q21 day infusions with promising results. GOG protocol #262 and #252 are both 
evaluating a Dd regimen in patients with ovarian cancer and a Dd regimen was demonstrated 
to be feasible in a cohort of patients with advanced endometrial cancer.4 Similar studies on 
ovarian cancer have shown controversial results. Katsumata et al. reported that dose-dense 
treatment of paclitaxel plus carboplatin offers better survival than conventional treatment 
and is a potential new standard of care for first-line chemotherapy for patients with advanced 
epithelial ovarian cancer5. A large phase 3 randomized trial reported that patients 
randomized to the weekly group had less frequency of grade 3-4 neutropenia, febrile 
neutropenia and thrombocytopenia when compared to those allocated paclitaxel plus 
carboplatin every 3 weeks6. A recent report showed that patients treated with weekly 
paclitaxel had a higher rate of grade 3 or 4 anemia and grade 2 to 4 sensory neuropathy but 
a lower rate of grade 3 or 4 neutropenia than did those treated with paclitaxel every 3 weeks7. 
This phase II trial attempts to build on evolving knowledge related to manipulations of 
paclitaxel/carboplatin backbone. Using a dose dense (Dd) strategy, we propose to conduct a 
pilot trial to evaluate the feasibility of carboplatin + Dd paclitaxel in this population of 
patients in an effort to understand ability to successfully complete the regimen, identify 
toxicity, and finally, assess efficacy. A piloted regimen which demonstrated feasibility could 
be advanced as an experimental arm into a larger cooperative group based clinical trial. 
 
A high risk population of early stage endometrial cancer patients exists: Despite the 
ability for surgical staging to define a low risk patient population for most patients with 
negative pelvic and para-aortic lymph nodes, certain subgroups of patients with stage I-II 
endometrial cancer have been shown to have a higher risk of recurrence. These patients may 
benefit from some form of post-operative adjuvant therapy. For example, in GOG #99 a 
subgroup of patients with “high-intermediate risk” (H-IR) could be defined which accounted 
for 66% of recurrences and cancer-related deaths. Risk criteria included grade 2-3 tumors, 
presence of lymphovascular space involvement (LVSI), and outer 1/3 myometrial invasion.2 
Patients were classified as H-IR if they were at least 70 years with any one factor, at least 50 
years with any 2 factors, or any age with all 3 factors. The cumulative risk of recurrence 
without therapy at 48 months was 27% for this group. Similarly, the PORTEC trial suggested 
that patients 60 years and older and those with grade 3 lesions had a higher hazard ratio for 
cancer related death (HR 3.1, p=0.02, HR 4.9, p= 0.0008, respectively).8 Patients with early 
staged uterine papillary serous (UPSC) or clear cell (CC) tumors also appear to have an 
elevated risk for recurrence.9 Huh reported on 60 patients with Stage I PS tumors who 
underwent complete surgical staging. Of the 40 patients who did not receive adjuvant 
therapy, the 5-yr disease-free survival rate was 66%.10 In GOG #94, for stage I-II patients 
treated with whole abdominal radiation therapy (WART), 5-yr PFS was 38% for UPSC 
patients, and 54% for CC patients.11 Creasman reported on data from FIGO that for stage I 
patients, 5-year survival (for surgery alone) was comparable between UPSC/CC (66%/77%) 
and grade 3 tumors (68%).12 Given the comparable outcomes between the patient 

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populations, patients with high risk endometrioid tumors will be combined with patients with 
UPSC/CC tumors. 
 
 
Unstaged patients may be included into high-risk, early stage models: In an effort to 
foster enrollment in clinical trials, the GOG has been charged by the Gynecologic Cancer 
Steering Committee reviewers to broaden eligibility in endometrial cancer clinical trials. The 
GOG has traditionally required comprehensive surgical staging for eligibility. Since 
gynecologic oncologists treat less than 1/3 of endometrial cancer patients, and most patients 
with endometrial cancer do not undergo complete surgical staging with assessment of pelvic 
and para-aortic nodes, a large pool of unstaged patients with H-IR features may exist, and 
who could be considered eligible for enrollment. The PORTEC trial, including a patient 
population considered to have low risk of nodal disease, found that in patients without nodal 
dissection, PXRT improved local control but did not impact survival. Many now consider 
patients with grade 1-2 tumors with < 50% invasion (and undissected nodes) to be at 
sufficiently low risk that routine adjuvant therapy is not recommended.13 Unstaged patients 
with grade 3 tumors or > 50% invasion are typically perceived to be at higher risk for 
recurrence, and are commonly offered PXRT to treat potential unrecognized nodal disease. 
For example, a review of the SEER data from a group of 21,249 patients with stage IA-IC 
endometrial cancer, of which only 43% had some form of nodal sampling, showed that 43% 
of patients with grade 3 tumors and 57% of stage IC patients received some form of post- 
operative radiation therapy.14  The potential for extrauterine disease spread is not 
insignificant in this patient population. For example, the GOG (GOG #33) found that 18% 
of grade 3 tumors and 25% of tumors with invasion into the outer 1/3 myometrium had 
pelvic nodal metastases.15 Clinically, the outcomes of unstaged patients with high risk factors 
have been reported in a subset analysis of patients registered and followed (but not eligible) 
within the PORTEC trial. Ninety-nine patients with stage IC, grade 3 endometrial cancers 
were treated with PXRT, and followed. Data showed local-regional failures occurred in 14% 
of patients (compared to 1-3% who were enrolled in the PORTEC trial), and distant failures 
occurred in 31% (compared to 3-8% who were enrolled in the PORTEC trial). While PXRT 
appears to improve local control in these cases (compared to no therapy), distant failures 
remain frequent and the authors concluded, “novel strategies for adjuvant therapy should be 
explored”. More recently, results of a randomized trial (ASTEC ) comparing surgical to 
clinical evaluation of nodal status have suggested a limited value of routine pelvic 
lymphadenectomy, particularly when patients receive post-operative PXRT regardless of 
node status (pathologically vs. clinically negative).16 
Hendrickson first reported the histologic criteria distinguishing UPSC from endometrioid 
variants in 1982.17 Since this time several investigators have reported their experiences with 
UPSC and demonstrated that this histologic type behaves differently than the more common 
endometrioid adenocarcinoma.18,19 Subsequent studies have classified CC tumors into a 
more aggressive subgroup as well.12 These two histologic variants are associated with a 
higher frequency of extrauterine disease spread, different patterns of failure, and poorer 
survival versus endometrioid types in most series.9,12,20 Both early staged and advanced 

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disease states appear to behave aggressively. In GOG #249 the UPSC/CC cohort accounted 
for 30% of the total PFS events with 22% of patients having an event. While patients with 
all 3 risk factors accounted for nearly half of the recurrence events in the study, with 18% 
(18/98) patients having an event. 
For patients with early stage disease, considerable controversy exists as to the optimal 
management of UPSC and CC tumors. A variety of treatments have been proposed for high- 
risk histologies. Patients with surgically staged Stage I UPSC/CC have been treated with no 
further therapy, WART, PXRT, radiation (pelvic or vaginal cuff) followed by chemotherapy, 
and chemotherapy alone. Retrospective studies have been inconsistent in reporting both high 
and low rates of recurrences in patients receiving no or a variety of adjuvant therapies. GOG 
#94 was a phase II study of patients with high risk endometrial cancers (Stage I-IV) treated 
by WART.  Data from the subgroup of 49 patients with Stage I-II UPSC/CC tumors, 
reporting on one of the largest surgically staged series of Stage I-II UPSC/CC patients, 
showed five- year disease-free survival (DFS) was only 35 %.11 By comparison, Stage I 
patients with endometrioid histologies in GOG #99, had two-year DFS between 86-92%, 
depending on the use of PXRT.9 Data from the annual FIGO report for Stage I uterine cancers 
(based on 148 UPSC, 59 CC tumors) for five-year DFS is shown below: 
 
Stage 
UPSC 
CC 
Ia 
74% 
83% 
Ib 
74% 
67% 
Ic 
46% 
64% 
 
Relatively few series reported in the literature have specifically evaluated surgically staged 
patients with UPSC/CC tumors. Most series describing patterns of failure or survival have 
come from groups of patients with and without complete staging procedures. Goff and 
colleagues demonstrated that when patients with UPSC cancers were surgically staged, 72% 
were found to have extrauterine disease at laparotomy.19 GOG #33 demonstrated that para-
aortic nodal disease was more common in patients with UPSC/CC tumors. The inclusion of 
unstaged patients into series of “early staged” UPSC patients reported in the literature has 
made it difficult to assess patterns of failure and determine appropriate therapies. In an effort 
to study a defined relatively homogenous patient population, all patients in this study must 
have complete surgical staging. 
The patterns of failure for Stage I-II UPSC/CC patients following whole abdominal radiation 
were described in GOG #94.11 The majority of failures occurred within the abdomen and 
pelvis, but distant failures were not uncommon. These findings indicate that radiation 
therapy alone has a limited role in the management of UPSC/CC. It is unclear to what extent 
complete surgical staging can define patterns of failure for Stage I-II patients. For patients 
with early staged endometrioid histologies, GOG #99 and the PORTEC trial showed that 
pelvic failure was the most common site, and could be reduced by the addition of pelvic 
radiation therapy. In the PORTEC study, pelvic radiation therapy led to a significant 
reduction in locoregional failures (4% vs 14%), but without improvement in overall 
survival.2,13 Radiation therapy seemed to impact vaginal recurrence risk more than pelvic 

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recurrence. The authors speculated that vaginal cuff brachytherapy might have controlled 
30/40 locoregional recurrences. In GOG #99, surgically staged patients with myometrial 
invasion were randomized to PXRT or no further therapy (NFT).This study found that PXRT 
significantly reduced pelvic failures. It was interesting to note however, that in the NFT 
group, 16/42 (38%) of failures were vaginal alone raising the suspicion that VCB may be a 
reasonable alternative. It remains to be seen whether similar patterns of failure would also 
be seen in patients with UPSC/CC tumors. As the data seem to suggest that post operative 
PXRT is most effective in controlling vaginal failures, it is hypothesized that VCB could do 
the same and with less morbidity. Data from GOG #99 and PORTEC1 are shown below: 
 
 
 
 
STUDY 
GOG #99 (NFT vs XRT) 
PORTEC (NFT vs XRT) 
Site of Failure 
Vagina 
7.4% vs 1.6% 
10.2% vs 2.3 % 
Pelvis 
4.0% vs 0.5% 
3.4% vs 2.0 % 
Distant 
5.5% vs 4.0% 
7.0% vs 7.9% 
 
 
Adjuvant treatment modalities should be based on risk and patterns of failure. Without 
adjuvant therapies, patterns of failure for surgically stage I endometrioid uterine cancers are 
predominantly in the vaginal cuff and at distant sites. Therapies, which address both local 
and systemic disease, may have the best chance to improve outcomes. In GOG #99, of 202 
patients who received no adjuvant therapy, recurrences were in the vaginal cuff (6.4%), 
pelvis (2.4%), and at distant sites (6.4%). Both the PORTEC and GOG #99 trials suggested 
that the primary benefit of PXRT is in its ability to reduce vaginal cuff failures. Indeed the 
conclusions of both studies suggested that similar reductions in risk might be obtained by 
substituting VCB for PXRT. The tolerability and lower toxicity compared to PXRT or 
WART is also desirable. Several studies have shown efficacy of VCB. Pearcey reviewed 
1800 cases with low-intermediate risk endometrial cancer treated with high dose VCB and 
reported a 99.3% vaginal control rate.21 Patients with higher risk stage I disease have also 
been treated with VCB. Chadha reported on 124 surgically staged patients with stage 
Ib/Grade 3, Ic, and occult II endometrial cancer and found no vaginal failures, and 3 extra-
pelvic failures (two abdomen, one abdomen + lung).13 No grade 3-4 bowel toxicity was 
reported, and two patients developed complete vaginal stenosis. Ng reported on 77 patients 
with Ib/Grade 3 and Ic patients treated by surgical staging and post-operative VCB. Median 
follow-up was 37 months and 11 patients (14%) have recurred including three distant 
failures.22 
 
While it is clear that these tumors are at an increased risk, no definite standard of care exists 
by which to manage them. It has been suggested that UPSC/CC tumors more closely 
resemble ovarian cancers than endometrial cancers. The high rates of intra-abdominal 

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disease spread and intra-abdominal failures reported support this concept, and have lead to 
the use of ovarian cancer-based chemotherapy regimens or WART as a treatment. It is 
interesting to note that regardless of the chemotherapy used, most regimens selected 
mirrored what was considered standard for ovarian cancer at that time. As more effective 
chemotherapeutic agents have been identified in endometrial cancer, combination regimens 
have demonstrated improved responses, and at least in populations with advanced disease, 
chemotherapy has shown superiority to radiation alone (GOG #122), chemotherapy as a 
front line treatment in endometrial cancer is supported.23 
 
 
Role of Chemotherapy 
 
The GOG and others have studied a variety of endometrial cancer patient populations in 
clinical trials utilizing chemotherapy. In GOG #34, surgically staged patients with high- risk 
factors (defined by positive adnexa, nodes, cervical extension or >50% myometrial invasion) 
were randomized to PXRT with or without post radiation adriamycin.24 The study found no 
difference in DFS or overall survival with the addition of adriamycin. The study evaluated a 
small group of patients with Stages I-III disease and lacked power to detect the magnitude 
of difference which was proposed. Chemotherapy alone in the management of early staged 
endometrial cancer has been evaluated. Burke reported on the 62 patients with high-risk 
endometrial cancer (21% with UPSC or CC histologies), including 33 patients with Stage I-
IIa disease treated with cisplatin, adriamycin, and cyclophosphamide following surgical 
staging.25 Three-year survival was 82% in patients without extrauterine disease. Levenback 
described 20 patients with UPSC, including 11 clinical stage I patients, treated with PAC 
chemotherapy and reported a 5 yr survival of 23%.26 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).27,28 Its combination with cisplatin and adriamycin was 
studied in GOG #177, and is now being evaluated sequentially with radiation in GOG#184, 
and is being compared to paclitaxel/carboplatin in GOG#209.29 
 
Paclitaxel has demonstrated activity in UPSC tumors as reported by Ramondetta and 
colleagues from the M.D. Anderson Cancer Center. They reported a 77% objective response 
rate in a small series of patients with advanced disease.30 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 UPSC tumors, the 
response rate was 60%, and 2/4 patients with recurrent disease responded to the regimen.31 
Carboplatin has demonstrated comparable activity to cisplatin in most gynecologic 
malignancies, including endometrial cancer. Substituting carboplatin for cisplatin appears to 
reduce toxicity and increase ease of administration. 
 
Recently, the Japan Gynecologic Oncology Group (JGOG) presented results of a phase III 
trial comparing whole pelvic irradiation to cyclophosphamide-doxorubicin-CDDP (CAP) 
chemotherapy in women with endometrial carcinoma with deeper than 50% myometrial 

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invasion.32 Of 385 eligible patients, 75% had surgical stage IC-IIB disease.  There were no 
statistically significant differences in PFS and OS between the 2 regimens. For all patients 
treated with CAP, only 3.7% recurred in the vaginal cuff. For stage IC patients, 5 yr survival 
was 89% in both treatment groups. The investigators suggested that adjuvant cisplatin-
based combined chemotherapy might have potential as an alternative to radiotherapy for 
intermediate risk endometrial cancer. Aoki evaluated 34 patients with stage I-II endometrial 
cancer who had 2 or more risk factors (grade 3, outer ½ DOI, LVSI, and cervix 
involvement).32 Of 26 patients treated with 3 cycles of CAP, 5 yr PFS and OS were 86% 
and 95% respectively. Of the 8 other patients treated by surgery alone, 5 yr PFS was 50%. 
By combining therapies (VCB/C), it is hoped to improve both local and distant control. 
 
 
 
Study 
Arms 
PFS Events 
OS Events 
Maggi 2006 
Chemo PXRT 
66 
59 
59 
59 
Susumu 2008 
Chemo PXRT 
30 
33 
22 
26 
GOG 249 
VCB/C PXRT 
43 
44 
23 
18 
Totals 
Chemo 
139/666= 
104/666= 
 
 
20.8% 
15.6% 
 
PXRT 
136/660= 
103/660= 
 
 
20.1% 
15.5% 
 
Japanese GOG presented their randomized controlled trial (JGOG 3016) at ASCO 2008, 
#550621 comparing paclitaxel 180 mg/m2 over 3 hours IV and carboplatin AUC 6 IV with 
weekly paclitaxel 80 mg/m2 days 1, 8, and 15 and carboplatin AUC 6 in ovarian cancer 
patients stages II-IV. The PFS was 17.2 months for the three week schedule and 28 months 
for the weekly schedule (p=0.0015 HR=0.714 [0.58) 1-0.879]). The two-year overall 
survival is 77.7% for the three-week schedule and 83.6% for the weekly schedule p=0.496 
HR=0.735 [0.540-1.0]). This data is encouraging for the weekly regimen, but there was only 
a 56% objective response in patients with measurable disease, only 47% completed 6 cycles, 
and 68 patients went off study for hematologic toxicity. The hematologic toxicity includes 
44% grade 3-4 thrombocytopenia, and 9% febrile neutropenia. There were 48% of dose 
dense participants who had at least one dose reduction and 76% who had at least one cycle 

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delay. Carboplatin dose was reduced for hematologic toxicity and paclitaxel dose was 
reduced only for neurotoxicity or abnormal liver functions. 
 
There is considerable support for weekly paclitaxel over the three-week schedule in the 
breast cancer literature. Sparano reported on the superiority of weekly paclitaxel for node 
positive or high risk node negative breast cancer patients with a HR=1.32 (p=0.01) when 
compared to every three week paclitaxel.33 CALGB23 protocol 9840 also demonstrated an 
advantage for weekly paclitaxel with response rate of 42% compared to 29% for the every 
three week schedule in breast cancer patients with metastatic disease. Neuropathy was more 
common in the weekly schedule (24% vs 12%). 
 
GOG #99 showed pelvic radiation was effective at reducing vaginal failures, with distant 
failures occurring in ~6% of patients. Radiation therapy as a single modality is thought to be 
less effective in a population enriched for risk for distant failure including only H-IR 
patients, those with stage II disease, or those with UPSC/CC histologies. For this reason 
chemotherapy is combined with radiation. The results of GOG #150, which included patients 
with Stage I-IV carcinosarcoma of the uterus, demonstrated better outcomes with 3 cycles 
of chemotherapy versus WART suggesting that an abbreviated course of chemotherapy may 
be adequate.34 Similarly, the median number of chemotherapy cycles used in the JGOG study 
was 3.35 Maggi et al reported no differences in survival of patients with high-risk endometrial 
carcinoma who were randomized to receive either pelvic radiation or 5 cycles of 
chemotherapy.36 Given the added expense, toxicity, and time to complete therapies with 6 
versus 3 cycles of therapy, the costs of extending the duration of chemotherapy to 6 cycles 
is balanced if 6 cycles results in superior RFS. If the risk of recurrence is not reduced by >/= 
40% with the use of 6 versus 3 cycles of therapy, then the value of additional chemotherapy 
will be judged to be not clinically relevant. This level of risk reduction is well within limits 
previously tested by the GOG. 
 
A phase II study evaluating surgically staged, stage I-II UPSC/CC and stage I-II endometrial 
carcinoma with high-intermediate features treated by VCB followed by three cycles of 
paclitaxel (175 mg/m2) and carboplatin (AUC 6) was performed. This regimen was well 
tolerated with 19/23 patients completing all prescribed therapy and 91% progression free at 
24 months.37 This led to GOG protocol #249 which randomized patients to VCB/C or PXRT 
in protocol. A total of 601 pts were accrued; PXRT was assigned to 301 (18 did not receive 
study treatment) and VCB/C to 300 (9 did not receive study treatment). The median age was 
63 years, 74% had stage I disease, and 89% underwent lymphadenectomy. Histology 
included 71% with endometrioid type, 15% UPSC, and 5% CC. Nearly all pts completed the 
prescribed therapy (91% PXRT, 87% VCB/C). Acute toxicity was more common with 
VCB/C.  Recurrence sites totaled to 5 vs 3 vaginal, 2 vs 19 pelvic, and 32 vs 24 distant 
failures with PXRT vs VCB/C. With a median follow-up of 24 months, the 24 month RFS 
was 82% vs 84% for PXRT and VCB/C and treatment hazard ratio was 0.97 (95% CI 0.635- 
1.43) (VCB/C relative to PXRT). The 24 month survival was 93% vs 92% for PXRT and 
VCB/C and treatment hazard ratio was1.28 (95% CI 0.689- 2.36) (VCB/C relative to PXRT). 

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There was no statistically significant treatment effect heterogeneity with respect to RFS 
among clinical- pathologic variables evaluated. Of interest, the group receiving VCB/C had 
more pelvic recurrences 19 vs 2, fewer distant failures 24 vs 32, while vaginal control was 
excellent for both 5 vs 3. GOG #249 also allowed further discrimination of patients at risk 
for recurrence, patients having grade 3 tumors or patients with outer half invasion, >70yo, 
and LVSI were at highest risk for recurrence.34 Recently, weekly paclitaxel in combination 
with tri-weekly carboplatin has demonstrated acceptable toxicity in patients with 
endometrial cancer, and is being evaluated in the phase III setting for ovarian cancer in GOG 
252 and 26232. Combining a dose dense paclitaxel regimen with VCB presents an ideal 
combination for achieving distant control while maintaining excellent vaginal control. 
 
 
 
2.1 
Inclusion of Women and Minorities 
 
The Stephenson Cancer center 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 
endometrial cancer population treated. 
 
 

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3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS 
3.1 
Inclusion Criteria 
3.11 
All 
patients 
must 
have 
undergone 
hysterectomy. 
Bilateral 
salpingooophorectomy is strongly encouraged but not mandatory. 
3.12 
Pelvic and para-aortic lymphadenectomy are optional, but strongly 
encouraged. Peritoneal washing are optional. 
The hysterectomy may be performed as per the surgeon’s preference 
including vaginally, laparoscopically, robotic, or open. A specific number 
of lymph nodes removed will not be utilized for eligibility, but the 
operative report should reflect that the procedure performed was 
consistent with the procedures described in the GOG Surgical Manual. 
3.13 
If either a bilateral salpingo-oophorectomy or nodal dissection was not 
performed, post-operative pre-treatment CT/MRI is required and must 
not demonstrate evidence suggestive of metastatic disease (adnexa, 
nodes, intraperitoneal disease). Post-operative, pre-treatment CT/MRI 
must be performed if a pelvic and para-aortic nodal dissection was not 
performed. 
3.14 
All patients will be staged according to the FIGO 2009 staging system 
and with endometrial carcinoma (endometrioid types) confined to the 
corpus uteri or with endocervical glandular involvement fitting one of the 
following high-intermediate risk factor categories: 
• 
age ≥18 years with 3 risk factors 
• 
Risk factors: 
a) Grade 2 or 3 tumor, (+) lymphovascular space invasion, outer ½ 
myometrial invasion. Patients with these risk criteria may be 
enrolled with either positive or negative cytology. 
b) Patients with Stage II endometrial carcinoma (any histology) 
with cervical stromal invasion (occult or gross involvement), 
with or without high- intermediate risk factors. 
c) Patients with serous or clear cell histology (with or without other 
high- intermediate risk factors) are eligible provided the disease 
is uterine- confined (with or without cervical stromal invasion or 
endocervical glandular involvement). 
3.15 
Patients must have GOG performance status 0, 1, or 2. 
3.16 
Patients must have adequate: 
3.181 Bone Marrow Function: 
Absolute neutrophil count (ANC) ≥ 1,500/mcl [equivalent to 
Common Toxicity Criteria (CTCAE v4.0) Grade 1]. Platelets ≥ 

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100,000/mcl (CTCAE v4.0 Grade 0). 
 
3.182 Renal Function: 
Serum creatinine ≤ institutional upper limit normal (ULN), 
CTCAE v 4.0 Grade 0. 
Note: If serum creatinine > ULN, a 24-hour creatinine 
clearance must be collected and must be >50 mL/min. 
 
3.183 Hepatic Function: 
Bilirubin ≤ 1.5 x ULN (CTCAE v4.0 Grade 0). SGOT and 
alkaline phosphatase ≤ 2.5 x ULN (CTCAE v4.0 Grade 0). 
 
3.184 Neurologic Function: Neuropathy (sensory and motor) ≤ CTCAE 
v4.0 Grade 1. 
 
3.17 
Patients who have met the pre-entry requirements specified in Section 
7.0; testing values/results must meet eligibility criteria specified in 
Section 3.1. 
3.18 
Patients must have signed an approved informed consent and 
authorization permitting release of personal health information. 
 
3.2 
Exclusion Criteria: 
Patients who meet any of the following criteria will not be eligible for this study: 
3.21 Patients with recurrent disease. 
3.22 Patients with GOG performance status of 3 or 4 
3.23 Greater than 12 weeks elapsed from surgery to enrollment 
3.24 Patients have prior pelvic or abdominal radiation therapy 
3.25 Known hypersensitivity to any component of study treatments that 
resulted in drug discontinuation 
3.26 Significant intercurrent illness including, but not limited to, unstable 
angina pectoris, and cardiac arrhythmia, or psychiatric illness/social 
situation that would limit compliance with study requirements 
3.27 Active pregnancy or lactation 
3.28 Prior malignancy requiring treatment within the last 3 years 
 
 

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4.0 
STUDY MODALITIES 
 
4.1 
Surgery 
Surgical therapy is an entry criterion, and not part of the experimental design of 
the study (See Sections 3.11-3.12). 
 
4.2 
Vaginal cuff brachytherapy (VCB) 
All patients will be assigned to VCB and chemotherapy; treatment will be 
delivered either by LDR or HDR brachytherapy. Treatment should commence 
within 12 weeks of the surgery/hysterectomy. Chemotherapy should start within 
3 weeks of initiating brachytherapy. 
 
4.21 
Intravaginal brachytherapy should be delivered with a vaginal cylinder 
(HDR or LDR) or colpostats (LDR). Given the variation in practice 
patterns and prescription routines, the treating physician must choose one 
of the following: 
 
A) HDR 6-7 Gy x 3 fractions, weekly, prescribed at a depth of 0.5 cm 
from the surface of the vagina. Dose optimization should be used in 
an effort to create reasonable homogeneity of dose at a depth of 5 mm 
from the surface of the applicator. 
 
B) HDR 10-10.5 Gy, x 3 fractions, weekly, prescribed at the vaginal 
surface. Dose optimization should be used in an effort to create 
reasonable homogeneity of dose around the surface of the applicator. 
 
C) HDR 6 Gy x 5 fractions, weekly, prescribed at the vaginal surface. 
Dose optimization should be used in an effort to create reasonable 
homogeneity of dose around the surface of the applicator. 
 
D) LDR 6500-7000 cGy prescribed at the vaginal surface in 1-2 
insertions at a dose rate of 40-100 cGy/hr. 
 
4.22 
The minimum vaginal length treated (length of the relevant isodose) is 3 
cm. The entire vagina is not required to be treated. 
 
4.23 
Expected Radiation Toxicities: Acute toxicity (occurring </= 30 days 
from completion of radiation) and Chronic toxicity (occurring > 30 days 
from completion of radiation) will be graded by the CTCAE v4.0. 
4.231 Expected short-term toxicities from brachytherapy include 
fatigue, diarrhea, rectal irritation, urinary frequency and dysuria, 
vaginal mucosal and vulvar irritation, and rarely urinary tract 
infection. 

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4.232 Possible long-term side effects may include shortening of the 
vagina, vaginal fibrosis, vaginal vault necrosis dyspareunia, 
rectal ulceration, dysuria, hematuria, bowel obstruction, chronic 
malabsorption, and fistula formation between pelvic tissues. 
 
Brachytherapy-related toxicities and time of onset will be 
recorded on data collection forms. Treatment delays and their 
reason must be documented. 
 
4.24 
Protocol Compliance: Minor violation includes a deviation of the 
intracavitary radiation dose of more than 15%, but less than 25%. A major 
deviation is defined as (1) a deviation of the intracavitary radiation dose 
of more than 25% from the protocol dose; (2) use of interstitial therapy, 
or brachytherapy applicators other than those specified by the protocol. 
 
4.3 
Chemotherapy: 
 
4.31 Paclitaxel (Taxol, NSC #673089) 
4.311 Formulation: Paclitaxel is a poorly soluble plant product from the 
western yew, Taxus brevifolia. Improved solubility requires a 
mixed solvent system with further dilutions of either 0.9% 
sodium chloride or 5% dextrose in water. Paclitaxel is supplied 
as a sterile solution concentrate, 6 mg/ml in 5 ml vials (30 
mg/vial) in polyoxyethylated castor oil (Cremophor EL) 50% and 
dehydrated alcohol, USP, 50%. The contents of the vial must be 
diluted just prior to clinical use. It is also available in 100 and 
300 mg vials. 
4.312 Solution Preparation: Paclitaxel, at the appropriate dose, will be 
diluted in 0.9% Sodium Chloride injection, USP or 5% Dextrose 
injection, USP (D5W) to a final concentration of 0.3 to 1.2 
mg/ml. Paclitaxel must be prepared in glass or polyolefin 
containers due to leaching of diethylhexlphthalate (DEHP) 
plasticizer from polyvinyl chloride (PVC) bags and intravenous 
tubing by the Cremophor vehicle in which paclitaxel is 
solubilized. NOTE: Formation of a small number of fibers in 
solution (within acceptable limits established by the USP 
Particulate Matter Test for LVPs) has been observed after 
preparation of paclitaxel. Therefore, in-line filtration is necessary 
for administration of paclitaxel solutions. In- line filtration 
should be accomplished by incorporating a hydrophilic, 
microporous filter of pore size not greater than 0.22 microns 
(e.g.: IVEX-II, IVEX-HP or equivalent) into the IV fluid 
pathway distal to the infusion pump. Although particulate 

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formation does not indicate loss of drug potency, solutions 
exhibiting excessive particulate matter formation should not be 
used. 
4.313 Storage: The intact vials can be stored in a temperature range 
between 20° – 25° C (68 – 77° F), protected from light. 
4.314 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 at room temperature (25° C) 
for 27 hours. 
4.315 Supplier: Commercially available from Bristol-Myers Squibb 
Company as well as generic manufacturers. 
4.316 Administration: Paclitaxel 80 mg/m2 IV over approximately 1 
hour days 1, 8, and 15 of a 21 day cycle x 3 total cycles will be 
given to all patients. Paclitaxel will be administered prior to 
carboplatin on day 1 of the infusion. Paclitaxel will be 
administered via an infusion control device (pump) using non-
PVC tubing and connectors, such as the IV administration sets 
(polyethylene or polyolefin) that are used to infuse parenteral 
Nitroglycerin. Nothing else is to be infused through the line 
where paclitaxel is being administered. See section 5.46. 
4.317 Adverse Effects: 
Hematologic: Myelosuppression 
Gastrointestinal: Nausea and vomiting, diarrhea, stomatitis, 
mucositis, pharyngitis, typhlitis, ischemic colitis, neutropenic 
enterocolitis 
Heart: Arrhythmia, heart block, ventricular tachycardia, 
myocardial infarction (MI), bradycardia, atrial arrhythmia 
Pulmonary: Pneumonitis 
Blood Pressure: Hypotension, hypertension (possibly related to 
concomitant medication--Dexamethasone) 
Neurologic: Sensory (taste), peripheral neuropathy, seizures, 
mood swings, hepatic encephalopathy, encephalopathy 
Skin: Infiltration: erythema, induration, tenderness, rarely 
ulceration, injection-recall reactions, erythema multiforme (e.g., 
Stevens-Johnson syndrome, toxic epidermal necrolysis) 
Allergy: Anaphylactoid and urticarial reactions (acute), flushing, 
rash, pruritus 
Liver: Increased SGOT, SGPT, bilirubin, alkaline phosphatase 
and triglycerides, hepatic failure, hepatic necrosis 

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Other: Alopecia, fatigue, arthralgia, myalgia, light-headedness, 
myopathy, headaches 
Other, Vision: Sensation of flashing lights, blurred vision, 
scintillating scotomata 
*See FDA- approved package insert for a comprehensive list of 
adverse events associated with paclitaxel. 
 
4.32 Carboplatin (Paraplatin®, NSC # 241240) 
4.321 Formulation: Carboplatin is supplied as a sterile, pyrogen-free, 
10mg/mL aqueous solution in multi-dose vials containing 
50mg/5mL, 150mg/15mL, 450mg/45mL or 600mg/60mL of 
carblplatin. 
4.322 Solution Preparation 
NOTE: Aluminum reacts with carboplatin causing precipitate 
formation and loss of potency. Therefore, needles or intravenous 
sets containing aluminum parts that may come in contact with the 
drug must not be used for the preparation or administration of 
carboplatin. 
4.323 Storage: Unopened vials of carboplatin are stable for the life 
indicated on the package when stored at controlled room 
temperature and protected from light. 
4.324 Stability: When prepared as directed, carboplatin solutions are 
stable for eight hours at room temperature. Since no antibacterial 
preservative is contained in the formulation, it is recommended 
that carboplatin solutions be discarded eight hours after dilution. 
4.325 Supplier: Commercially available from Bristol-Myers Squibb 
Company as well as generic manufacturers. 
4.326 Administration: Carboplatin IV will be administered over 
approximately 30 minutes at an AUC 6 q 21 days (Day1 of 21 
day cycle). See Section 5.224. 
4.327 Adverse effects: 
Hematologic: Myelosuppression 
Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain, 
constipation 
Neurologic: 
Peripheral 
neuropathy, 
ototoxicity, 
visual 
disturbances, change in taste, central nervous system symptoms 
Renal: Abnormal renal function test results including serum 
creatinine, blood urea nitrogen, and creatinine clearance 
Hepatic: Abnormal liver function tests including bilirubin, 
SGOT, and alkaline phosphatase 
Electrolyte Changes: Abnormally decreased serum electrolyte 

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values reported for sodium, potassium, calcium, and magnesium. 
Allergic Reactions: Rash, urticaria, erythema, pruritus, and rarely 
bronchospasm and hypotension. 
Injection Site Reactions: Redness, swelling, pain; necrosis 
associated with extravasation has been reported. 
Other: Pain, asthenia, alopecia. Cardiovascular, respiratory, 
genitourinary, and mucosal side effects have occurred in 6% or 
less of the patients. Cardiovascular events (cardiac failure, 
embolism, cerebrovascular accidents) were fatal in less than 1% 
of patients and did not appear to be related to chemotherapy. 
Cancer- associated hemolytic-uremic syndrome has been 
reported rarely. 
Malaise, anorexia, and hypertension have been reported as part 
of post-marketing surveillance. 
 
*See FDA-approved package insert for a comprehensive list of 
adverse events associated with carboplatin. 
 
 
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 
 
 
5.1 
Treatment Plan 
Patients with endometrial cancer meeting eligibility criteria will receive vaginal 
cuff brachytherapy followed by three cycles of chemotherapy with carboplatin 
and paclitaxel. Either LDR or HDR brachytherapy will be permitted, but must 
be specified at enrollment. 
 
5.21 
Radiation Therapy: Within 12 weeks of surgery (within 2 weeks of 
enrollment) all patients must start vaginal cuff brachytherapy. The use of 
LDR or HDR therapy must be specified at enrollment. 
 
5.22 
Chemotherapy: Carboplatin IV, AUC 6, on day 1 of a 21 day cycle and 
Paclitaxel 80 mg/m2 IV days 1, 8, and 15 (of a 21 day cycle) x 3 cycles 
will be given to all patients. Chemotherapy will begin within 3 weeks of 
completion of brachytherapy. 
 
5.221 Methods of Chemotherapy Administration 
 
Maximum body surface area used for dose calculations will be 
2.0 m2. 
The dose will be based on the patient’s actual weight at baseline 

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(Day 1 of Cycle 1). It is not necessary to recalculate the dose 
unless the patient has ≥10% weight changes during the study. 
5.222 Sequence and timing of drug administration: 
 
Paclitaxel will be administered per institution guidelines over 
approximately 1 hour. Paclitaxel will be administered prior to 
carboplatin. 
All patients should be pre-medicated per institution standard 
practice. See Section 5.223. 
Carboplatin will be administered per institution guidelines over 
approximately 30 minutes. Carboplatin will be infused after 
Paclitaxel. 
5.223 Antiemetic Regimens: It is anticipated that nausea and vomiting 
may be a significant side effect of chemotherapy. It is 
recommended to administer prophylactic anti-emetics per 
institution standard practice. For all courses where paclitaxel is 
administered, it is recommended that a preparative regimen be 
employed prior to the treatment regimen, to reduce the risk 
associated with hypersensitivity reactions to this drug. This 
regimen may include standard dose(s) of dexamethasone (either 
IV or PO), an anti-histamine H1 (diphenhydramine 25-50 mg IV 
or orally, or an equivalent dose of an alternate H1 blocker such 
as loratadine or fexofenadine), and a standard dose of anti-
histamine H2 IV (such as cimetidine, ranitidine, or famotidine). 
 
5.224 Dosing of Carboplatin: 
The carboplatin dose will be calculated to reach a target area under the 
curve (AUC) according to the Calvert formula using an estimated 
glomerular filtration rate (GFR) from the Cockcroft-Gault formula. The 
initial dose of carboplatin must be calculated using GFR. In the absence 
of renal toxicity greater than or equal to CTCAE Grade 2 (serum 
creatinine >1.5 x ULN) or toxicity requiring dose modification, the dose 
of carboplatin will not need to be recalculated for subsequent cycles, but 
will be subject to dose modification for toxicity as noted in the protocol. 
Carboplatin doses will be based on the subject’s weight at baseline and 
will remain the same throughout the study. However, the doses will be 
recalculated if the patient has a weight change of greater than or equal to 
10% from baseline. In patients with an abnormally low serum creatinine 
(less than 0.7 mg/dl), the creatinine clearance should be estimated using 
a minimum value of 0.7 mg/dl. If a patient is currently being dosed 
using a creatinine value less than 0.7 mg/dl, adjust dose with next 
planned treatment. For trials where patients enter and are treated within 
less than or equal to 12 weeks of surgery: If a more appropriate (higher) 

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baseline creatinine value is available from the pre-operative period 
(within 4 weeks of surgery date), that value may also be used for the 
initial estimation of GFR. 
 
CALVERT FORMULA: 
Carboplatin dose (mg) = target AUC x (GFR + 25) 
NOTE: the GFR used in the Calvert formula should not exceed 125 
ml/min. 
Maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 
ml/min. 
The maximum allowed doses of carboplatin are: 
AUC 6 = 900 mg 
AUC 5 = 750 mg 
AUC 4 = 600 mg 
For the purposes of this protocol, the GFR is considered to be equivalent 
to the estimated creatinine clearance. The estimated creatinine clearance 
(ml/min) is calculated by the method of 
Cockcroft-Gault using the following formula: 
Creatinine Clearance (mL/min) = {[140-Age (years)] x Weight (kg) 
x 0.85} / [72 x serum creatinine (mg/dl)] 
Notes: 
1) Weight in kilograms (kg): 
a. 
Body Mass Index (BMI) should be calculated for each patient. A 
BMI 
calculator 
is 
available 
at 
the 
following 
link: 
http://www.nhlbisupport.com/bmi/ 
b. 
Actual weight should be used for estimation of GFR for patients 
with BMI of less than 25. 
c. 
Adjusted weight should be used for estimation of GFR for patients 
with BMI of greater than or equal to 25. 
d. 
Adjusted weight calculation: 
Ideal weight (kg) = (((Height (cm)/2.54) – 60) x 2.3) + 45.5 
Adjusted weight (kg) = ((Actual weight – Ideal weight) x 0.40) + Ideal 
weight 
e. 
If a patient with BMI of greater than or equal to 25 is currently being 
dosed using actual weight, adjust dose with next planned treatment. 
2) The Cockcroft-Gault formula above is specifically for women (it 
includes the 
0.85 factor). 
At the time of a dose modification for toxicity: 
1) If the creatinine at the time of a dose modification is lower than the 
creatinine used tocalculate the previous dose, use the previous (higher) 
creatinine; if the creatinine at the time of a dose modification is higher 
than the creatinine used to calculate the previous dose, use the current 
(higher) creatinine. This will ensure that the patient is actually receiving 

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a dose reduction. 
 
6.0 
TREATMENT MODIFICATIONS 
 
6.1 
Radiotherapy Procedures: There will be no modifications for radiotherapy. 
 
6.2 
Chemotherapy Modifications: Treatment decisions will be based on the absolute 
neutrophil count (ANC) rather than the total white cell count (WBC). 
 
6.21 Chemotherapy – Day 1 of a subsequent cycle of cytotoxic chemotherapy 
will not be administered until the ANC is ≥ 1,000 cells/mcl and the platelet count 
is ≥ 75,000/mcl. All treatment will be delayed for a maximum of three weeks 
until these values are achieved. Patients who fail to recover adequate counts 
within a three-week delay will no longer receive protocol-directed cytotoxic 
therapy. 
 
6.22 Chemotherapy- Day 8 and 15 paclitaxel dose will not be given unless the 
ANC is at least 500 cells/mcl and the platelet count is at least 50,000/mcl. If not 
given, these doses are omitted and not made up. 
 
6.23 Use of Hematopoietic Cytokines and Protective Agents: It is anticipated that 
myelosuppression may be a significant side effect of dose dense chemotherapy. 
Myeloid growth factors can be used (it is recommended that NCCN and/or 
ASCO guidelines be consulted)38. If myeloid growth factors are used, it is 
recommended that filgrastim (dose according to institutional standard) will be 
administered daily subcutaneously starting 24-72 hours after the last dose of 
chemotherapy and continuing through hematopoietic recovery Administration 
of growth factors on the same day as chemotherapy is not recommended. 
Pegfilgrastim is not recommended for chemotherapy regimens given less than 
every 2 weeks. 
6.3 
Modifications for Hematologic Toxicity (Nadirs) 
6.31 
Initial occurrence of dose-limiting neutropenia (defined in 6.32) or dose 
limiting thrombocytopenia (defined in 6.33) will be handled according 
to Tables A 
6.32 
Dose-Limiting Neutropenia (DLT-ANC) is defined by the occurrence of 
• febrile neutropenia(disorder characterized by an ANC <1000/mcl and a 
single temperature of >38.3 degrees C (101 degrees F) or a sustained 
temperature of ≥38 degrees C (100.4 degrees F) for more than one hour) 
• Grade 4 neutropenia persisting ≥ 7 days, 
• delay of treatment for more than 7 days because of neutropenia, 
• ANC<1000cells/mcl on day 1, 
• or omission of day 8 or day 15 paclitaxel because of neutropenia. 

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6.33 
Dose-limiting thrombocytopenia (DLT-PLT) is defined by any 
occurrence of: Grade 4 thrombocytopenia (<25,000/mcl) 
• bleeding associated with Grade 3 thrombocytopenia (25,000 to 
• <50,000/mcl), 
• delay of treatment on day 1 of a cycle by more than 7 days because of 
thrombocytopenia, 
• platelet count of <75,000/mcl on day 1, 
• or inability to give day 8 or day 15 paclitaxel on Regimen II due to 
thrombocytopenia. 
 
There will be no modifications for uncomplicated Grade 3 thrombocytopenia 
except as above. 
 
 
 
Table A: Modification Instructions for Dose-Limiting Hematologic Toxicity Regimen 
DLT 
ANC 
DLT 
PLT 
First 
Occurrence 
Second 
Occurrence 
(06/20/2011) 
Third 
Occurrence 
Yes 
No 
Reduce 
carboplatin 
one AUC unit 
Omit day 15 
paclitaxel and 
administer G- 
CSF 
starting 
after 
day 
8 
paclitaxel 
Reduce 
caboplatin one 
AUC, and give 
G-CSF after day 
8 paclitaxel. 
Fourth 
occurrence: 
Discontinue 
Part A Protocol 
Directed 
Cytotoxic 
Therapy. 
Yes 
Yes 
Reduce 
carboplatin 
one AUC unit 
Omit day 15 
paclitaxel and 
administer G- 
CSF 
starting 
after day 8 
paclitaxel 
Discontinue 
Part A Protocol- 
Directed 
Cytotoxic 
Therapy** 
 
6.4 
Non-hematologic Toxicity: Patients, whose treatment is delayed > 21 days 
because of toxicity should have protocol therapy discontinued. 
 
6.41 Table B should be used for dose level modifications for non-hematologic 
toxicity only as indicated specifically in the sections below. 

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6.42 Paclitaxel hypersensitivity reaction: If hypersensitivity to paclitaxel or its 
vehicle Cremophor occurs, it will usually be during the first few minutes of 
infusion. If severe hypersensitivity occurs, stop infusion and do not 
rechallenge. Minor hypersensitivity reactions (such as flushing, skin 
reactions, dyspnea, hypotension, or tachycardia) do not require 
interruption of treatment. However appropriate symptomatic therapy should 
be given; 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 occurrence and re-titrated. A suggested procedure 
would be to administer the drug first with 1 cc of the original IV solution diluted 
in 100 cc over one hour, then 5 cc in 100 cc over one hour, then 10 cc in 100 cc 
over one hour, and finally, the original solution at original speed. Patients who 
elect not to have continued treatment with paclitaxel after experiencing a 
hypersensitivity reaction will discontinue study treatment, and be treated 
according to the physician’s recommendations. 
 
6.43 Neuropathy. Grade 2 (or greater) peripheral neuropathy requires reduction 
of one dose level in paclitaxel and delay in all subsequent protocol-directed 
therapy for a maximum of three weeks until recovered to Grade 1. If peripheral 
neuropathy fails to recover to Grade 1 by a maximum delay of three weeks from 
time therapy is due, or recurs, then the patient will be discontinued from study. 
 
6.44 Renal toxicity (associated with reduction in GFR) is not expected as a direct 
complication of chemotherapy in this untreated patient population using the 
prescribed dose and schedule of each regimen. As such, there are no specific 
dose modifications for renal toxicity. However, the target AUC dose of 
carboplatin must be recalculated each cycle in any patient who develops renal 
insufficiency, defined by serum creatinine greater than 1.5 x institutional upper 
limit normal (ULN). 
 
6.45 Hepatic toxicity is not expected as a direct complication of chemotherapy 
in this untreated patient population using the prescribed dose and schedule for 
each regimen. However, the development of Grade 3 (or greater) elevations in 
SGOT (AST), SGPT (ALT), alkaline phosphatase or bilirubin requires reduction 
of one dose level in paclitaxel and delay in subsequent therapy for a maximum 
of three weeks until recovered to Grade 1. 
 
6.46 There will be no dose modifications for alopecia, nausea, or constipation. It 
is recommended that routine medical measures be employed to manage nausea, 
constipation. Grade 3 diarrhea on day of planned treatment will require holding 
of paclitaxel in patients on weekly paclitaxel. Any grade 3 diarrhea in patients 
on weekly paclitaxel will mandate a one dose level reduction of paclitaxel in 
future cycles. If the diarrhea is clearly infectious and has resolved, the above 

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mandated dose reductions do not apply. 
 
Table B: Modifications for Non-Hematologic Toxicity 
Drug 
Regimen 
Starting Dose 
Regimen 
-1 Level 
Regimen 
-2 level 
Paclitaxel 
(weekly) 
80 mg/m2 
70 mg/m2 
60 mg/m2 
Carboplatin 
6.0 
5.0 
4.0 
 
 
 

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7.0 
STUDY PARAMETERS 
 
7.1 
Observations and Tests- The following observations and tests are to be 
performed and recorded on the appropriate form(s). 
 
 
Parameter 
Pre- 
Therapy 
(within 14 
days of 
start) (see 
Section 3.1 
for specific 
eligibility 
criteria) 
Weekly 
Prior to 
Each 
Cycle 
Following 
completion 
of therapy 
History & Physical 
X 
X 
X1 
ECOG PS 
X 
X 
X 
Toxicity Assessment 
X 
X 
X 
X4 
CBC/Differential/Platelets 
X 
X 
X 
X 
Electrolytes, BUN, creatinine, calcium 
(Ca), magnesium (Mg), phosphate 
(PO4), Urinalysis 
X 
X 
X 
Bilirubin, SGOT, SGPT, 
Alkaline Phosphatase 
X 
X 
Chest x-ray 
(CT of chest should be obtained if CXR 
is abnormal/suspicious) 
X2 
X4 
CT scan abdomen/pelvis 
X3 
X4 
 
 
 
1 Follow up starts within 4 weeks after completing or discontinuing study therapy, then every 3 
months to assess for survival status until death, withdrawal of consent, or until 2 years from 
the date of registration. 
2 Within 28 days prior to enrollment. 
3 Patients who did not have a bilateral pelvic and para-aortic lymphadenectomy performed must 
have a pretreatment (within 28 days prior to initiating treatment) CT/MRI demonstrating 
negative/non-suspicious lymph nodes. It is suggested that for CT scans, a spiral CT with an 

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intravenous/oral contrast and ≤ 5mm slice thickness be used where possible. MRI should be 
performed with gadolinium and include both T2W and T1W sequences; the minimum possible 
slice should be obtained for all sequences, depending on the size of the patient. 
4 Within 4 weeks after completing or discontinuing study therapy. 
 
 

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8.0 
EVALUATION CRITERIA 
 
8.1 
Objective Response 
 
The major parameters of response to be assessed include Progression-Free 
Interval, Overall Survival, documentation of Sites of Recurrence, and Treatment 
Related Toxicity. 
 
8.11 
Measurable Lesions- All patients in this study will have completely 
resected disease at enrollment. Response rate will not be measured. 
 
8.12 
Progression-Free Interval will be defined as date from entry to a 
particular protocol to date of reappearance or increasing parameters of 
disease or to date of last contact. 
 
8.13 
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 
(regardless of whether or not this contact is on a subsequent protocol). 
 
8.14 
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: 
8.14.1 Pelvic (peritoneal, nodal) 
8.14.2 Abdominal (peritoneal, nodal, visceral, ascites) 
8.14.3 Diaphragmatic 
8.14.4 Distant (nodal, parenchymal) 
8.14.5 Omental 
8.14.6 Effusions (pleural, ascites) 
 
8.15 
Treatment Toxicity: The grade level of the various toxicities will be 
classified using the Common Toxicity Criteria, version 4 (CTCAE 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. 
 
 

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9.0 
DURATION OF STUDY 
 
9.1 
This treatment of this study is approximately 4 months. 
 
9.2 
Following completion of therapy, the patient will be followed and data 
captured every 3 months to assess for survival status until death, withdrawal of 
consent, or until 2 years from the date of registration. 
 
 

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10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
 
 
10.1 
Safety oversight will be performed by Stephenson Cancer Center’s (SCC) 
internal Data and Safety Monitoring Committee (DSMC). The DSMC is 
composed of individuals with the appropriate expertise in adult and pediatric 
hematology and medical oncology, radiation oncology, translational and 
correlative science, pharmacy, nursing and biostatistics. The DSMC operates 
under the rules of an approved data safety monitoring plan which complies with 
the National Cancer Institute (NCI) guidelines published as Essential Elements 
of a Data and Safety Monitoring Plan for Clinical Trials Funded by NCI as of 
January 2005 and the “NIH Policy for Data and Safety Monitoring,” NIH Guide 
for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-
084.html. 
The Data Safety Monitoring Committee is charged with oversight of participant safety, 
study conduct and the validity and integrity of data for clinical trials at SCC. While the 
focus of the DSMC is to monitor interventional investigator initiated trials (IITs) that 
are not subject to external monitoring, it has the authority to monitor any SCC protocol 
when potential concerns are identified. The DSMC also has the authority to suspend or 
close a study until the principal investigator addresses any issues that may cause harm 
or increase risks to subjects. The DSMC reports all findings to the Institutional Review 
Board (IRB). 
Under the direction of the DSMC chair, a full board meeting is convened on a biannual 
basis to review the accumulated safety data, accrual information, and additional 
information as stated in the DSMC plan. 
 
DSMC Auditing 
In addition to monitoring, the DSMC oversees an internal auditing process to ensure 
subject safety and data quality. All cancer-related clinical trials active at the SCC are 
eligible for audit; however, priority is placed on those clinical trials that are not 
monitored or audited by an outside entity. If an external entity conducts an audit of a 
clinical trial at the SCC, then the findings of that audit are reported to the DSMC, either 
through the formal audit report provided by the external auditing entity, if available, or 
from the PI, who will report any findings communicated during the audit process. 
Using the existing DSMC structure of the SCC, a DSMC will be conveyed (using the 
SCC CTO SOP’s) to assess toxicity. We will review cohorts of 5 patients enrolled for 
frequency and severity of grade 2-3-4 toxicities and compare to data reported for 
standard regimens. Following a review of the DSMC meetings, information will be 
provided to the IRB. 
 

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10.2 
A patient consent form must be signed by the patient or guardian prior to study 
entry. 
 
10.3 
ADVERSE EVENT REPORTING FOR COMMERCIAL DRUG STUDIES 
 
This study will utilize the CTCAE v4.0 for toxicity and Adverse Event 
Reporting. 
 
 
Toxicity Grade 
Typea 
OUHSC IRB 
via mail 
4,5 
Unknown 
Yes 
5 
Known 
No 
2,3 
Unknown 
No 
4 (non-myelo) 
Known 
No 
4 (myelob) 
Known 
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 
 
10.31 AE will be reported to the IRB as per policy. 
A serious adverse event (SAE) is any sign, symptom or medical 
condition that emerges during treatment or during 30 days post-treatment 
follow-up period that was not present at the start of treatment and it is 
not a chronic condition that is part of the patient’s medical history, OR 
(2) was present at the start of treatment or as part of the patient’s medical 
history but worsened in severity and/or frequency during therapy, AND 
that meets any of the following regulatory serious criteria: 
• Results in death 
• Is life-threatening 
• Requires or prolongs inpatient hospitalization 
• Is disabling 
• Is a congenital anomaly/birth defect 
• Is medically significant or requires medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
All SAEs should be recorded on SAE report Form and reported to: SCC-
IIT-Reporting@ouhsc.edu or fax # (405)-271-1416 AND: 
IRB Contact information phone # (405) 271-2045 and fax # (405) 271-

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1677 
 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Study design overview and registration: This study is designed as a phase II 
clinical trial. This design will provide a direct assessment of the feasibility 
associated with 3 cycles of adjuvant combination carboplatin and Dd paclitaxel 
chemotherapy and VCB compared to historically demonstrated outcomes of 
surgery followed by pelvic radiation therapy in patients with high-risk early stage 
endometrial carcinoma. 
 
11.2 
Data collection: The principal parameters to be collected, analyzed and reported 
to determine the relative therapeutic effect of the two treatment regimens are: 
 
11.21 Outcome variables 
11.211 Primary: Completion of 3 cycles of chemotherapy and VCB 
11.212 Secondary: duration of recurrence-free survival, toxicity related 
to vaginal brachytherapy and combination carboplatin and 
paclitaxel, sites of failure, contributing cause of death, overall 
survival. 
 
11.22 Tumor characteristics: FIGO stage determined after definitive surgery, 
histologic cell type, tumor grade, depth of myometrial invasion, 
lymphatic- vascular space involvement (LVSI) of tumor. 
 
11.23 Host characteristics: age at entry, performance status, and race. 
 
11.24 Adverse effects: frequency and severity of adverse effects graded by 
CTCAE v 4.0. 
 
11.25 Treatment: total dose of radiation received; the number of cycles and 
total dose of protocol directed therapy administered; for those not 
completing study therapy, the reason for not completing the assigned 
treatment 
 
Accrual: 
Based on the experience with GOG 249 (randomized trial), 46 patients from the 
Stephenson Cancer Center were enrolled over a 5 year period. Of the total patients 
enrolled in GOG 249, the eligibility criteria as restricted in this study would account for 
73% of the total number of patients with recurrence. 
 

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A similar investigator initiated pilot study (single arm) conducted at the Stephenson 
Cancer Center enrolled 23 patients in 2 years.37 Based on our prior experience with this 
population we anticipate enrollment of 10 patients per year. 
 
 
11.3 
Hypotheses and sample size: 
 
Primary Hypothesis: This study will evaluate the effect of vaginal 
brachytherapy and 3 cycles of carboplatin and Dd paclitaxel following surgery 
verses historical controls who underwent surgery followed by pelvic radiation 
therapy. The primary endpoint for this evaluation is recurrence-free survival. 
The design of this study will provide evidence of benefit with regard to 
recurrence-free survival. The type I error level will be set at 0.05 (one tail test). 
 
Assumptions: It is anticipated based on available data from the recently 
completed prospective study GOG, patients treated with surgery and pelvic 
radiation (control arm of GOG 249): 
18% of patients with stage I endometrioid tumors and 3+ risk factors recurred, 
and 36 mo PFS was 75% 
15% of patients with patients with stage II endometrioid tumors with or without 
other risk factors recurred, and 36 mo PFS was 80% 
22% of patients with patients with stage I-II serous or clear cell tumors with or 
without other risk factors recurred and 36 mo PFS was 70%. 
These 3 patient populations accounted for 73% of all recurrences/deaths in the 
study. 
 
Sample Size: It is anticipated that 10 patients per year will be accrued for a total 
of 46 patients in a 5 year period. Based on the 87% and 91% completion of 
therapy rates in the GOG 249 protocol arms, the regimen will be considered 
feasible if 85% of enrolled patients complete the study, or 39/46. 35 
 
11.4 
Study Duration: The planned sample size is 46 patients. It is anticipated that 
this study will require approximately 60 months of accrual assuming a uniform 
accrual rate of 10 patients per year.  
 
11.5 
Interim Analyses: There will be one planned interim analysis of recurrence-
free survival data. The planned interim analysis will occur when at least 20 
failures (recurrence or death) have been reported. A log rank test will be used to 
test the independence of treatment and recurrence-free survival. The type I error 
spent at the interim analysis will be 0.005. If additional interim analyses are 
warranted, then the error spent at each interim analysis will be 0.005.  The 
number of patients with UPSC/CC histology that have been included in the study 
will also be determined at this time. It may be necessary to accrue more patients 
than originally anticipated in order to ensure that adequate numbers of patients 

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with UPSC/CC histology are included. 
 
Additionally, a futility analysis will be carried out. If the observed recurrence or 
death rate of the experimental arm is greater than the observed recurrence or 
death rate of the control arm, then accrual termination will be considered (if still 
active) with a conclusion that an advantage for the experimental arm has not 
been established. The increase in type II error due to this interim analysis is 
negligible. Under the null hypothesis, this procedure has a 50% chance of 
resulting in early termination. 
 
 
 

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