Clinical trial NCT02744898
Conditions: Endometrial Cancer
Keywords: uterus gynecological corpus uteri
Sponsor: NYU Langone Health
Start date: 2016-07-01; Completion date: 2020-03-01
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety of treatment with carboplatin and Abraxane in this patient population and determine the nature and degree of toxicities following treatment. The single stage open label Phase II feasibility study is designed to estimate the proportion of patients who can tolerate the proposed regimen for 6 cycles with no more than two dose level reductions.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Carboplatin AUC intervention 2: Abraxane
Intervention descriptions: intervention 1: None intervention 2: 100mg/m2

Protocol documents:
Prot_SAP_000.pdf: 
Version 10; October 09, 2017 
 
Page 1 of 44 
 
TITLE:  A Phase 2 Feasibility Study of Abraxane and Carboplatin in Epithelial 
Neoplasms of the Uterus 
 
NYU Study #: s15-01156 
 
Version date: Version 10, December 19, 2017 
 
Coordinating Center: 
     NYU Langone Medical Center 
 
     Cancer Institute 
 
 
160 East 34th St 
 
 
New York, NY 10016 
 
 
 
*Principal Investigator: 
 
Name: Franco Muggia, MD 
 
 
462 First Avenue, Building CD, Room 556 
 
 
New York, NY 10016 
Telephone: 212-263-6485 
Fax: 212-263-8210 
 
 
Email address: franco.muggia@nyumc.org 
 
Co-Principal Investigator:     Name: Bhavana Pothuri, MD 
 
 
550 First Ave 
 
 
New York, NY 10016 
Telephone: 212-731-6455 
Fax: 212-263-8210 
 
 
Email address: bhavana.pothuri@nyumc.org 
 
 
 
 
 
 
 
 
 
Co-investigator/Biostatistician:     Name: Judith D. Goldberg, Sc.D.  
650 First Avenue, 534 
Division of Biostatistics 
 
 
Telephone: 212-263-0314 
 
 
 
Fax: 212-263-8570 
           Email address: jd.goldberg@nyumc.org 
 
 
 
 


Version 10; October 09, 2017 
 
Page 2 of 44 
 
Contents 
1.0  Background ............................................................................................................................ 4 
1.1  Endometrial Cancer: ......................................................................................................... 4 
1.2  Experience with Carboplatin and Paclitaxel: ................................................................ 4 
1.3  Abraxane ............................................................................................................................ 5 
1.4  Rationale Behind Abraxane + Carboplatin in Endometrial Cancer .......................... 8 
2.0  Objectives ............................................................................................................................... 9 
2.1  Primary Endpoint ............................................................................................................. 9 
2.2  Secondary Endpoints ........................................................................................................ 9 
3.0  Study Design ........................................................................................................................ 10 
3.1-3.2  Description and Rationale for Study Design ........................................................ 10 
3.3  Outcome Measures ......................................................................................................... 10 
3.3.1  Primary Outcome Measures ................................................................................... 10 
3.3.2  Secondary Outcome Measures ............................................................................... 10 
3.3.3  Safety Outcome Measures ...................................................................................... 10 
4.0  Safety Plan ............................................................................................................................ 11 
4.1  Plan to manage safety ..................................................................................................... 12 
5.0  Study Subjects ...................................................................................................................... 13 
5.1  Subject Selection .............................................................................................................. 13 
5.2  Inclusion Criteria ............................................................................................................. 13 
5.3  Exclusion Criteria ............................................................................................................ 14 
6.0  Study Design ........................................................................................................................ 15 
6.1  Treatment Plan ................................................................................................................ 15 
7.0  Study Medications .............................................................................................................. 16 
7.1  Abraxane Dosage and Formulation ............................................................................. 16 
7.1.2  Abraxane Storage and Administration ................................................................. 17 
7.1.3  Abraxane Dose Modification and Toxicity Management .................................. 20 
7.2  Carboplatin Dosage and Formulation  (Paraplatin® - NSC #241240) .................... 23 
7.2.1  Administration ......................................................................................................... 23 
7.2.2  Storage ....................................................................................................................... 23 
7.2.3  Carboplatin dose modifications and toxicity management: .............................. 24 
7.3  Concomitant medications: ............................................................................................. 25 
8.0  Clinical and Laboratory Evaluations ............................................................................... 25 
8.1  Pre-Treatment evaluations:............................................................................................ 25 
8.2  In-Treatment Evaluations .............................................................................................. 25 
8.3  Post-Treatment Evaluations .......................................................................................... 26 
8.3.1 Imaging Follow-Up: .................................................................................................. 26 
8.3.2 Clinical Evaluation Follow-Up: ............................................................................... 26 
9.0 Risks of Participation ........................................................................................................... 26 
10.0 Potential Benefits of Treatment: ....................................................................................... 28 
11.0  Subject discontinuation from treatment ........................................................................ 28 
12.0  Study discontinuation ...................................................................................................... 28 
13.0  Statistical Methods ............................................................................................................ 28 


Version 10; October 09, 2017 
 
Page 3 of 44 
 
13.1  
Determination of sample size ................................................................................ 29 
14.0  Safety Reporting Of Adverse Events.............................................................................. 29 
14.1  Adverse Events Reporting and Definitions .............................................................. 29 
14.2  NYU Data Safety Monitoring Committee. ................................................................ 30 
14.3  Celgene Drug Safety Contact Information: ............................................................... 32 
14.4  Safety Reporting Requirements .................................................................................. 32 
15.0 Retention of Records .......................................................................................................... 33 
15.1  Confidentiality ............................................................................................................... 33 
15.2  Source Documents ........................................................................................................ 34 
15.3  Data and Source Documentation ................................................................................ 34 
16.0 Costs Incurred to Patients on Study ................................................................................ 35 
17.0 References: .......................................................................................................................... 36 
Appendix 1:  Study Schema ...................................................................................................... 39 
Appendix 2:  Treatment Schema .............................................................................................. 40 
Appendix 3:  Common NCI Toxicity Criteria ........................................................................ 41 
Appendix 4:  FDA Medwatch .................................................................................................. 42 
Appendix 5:  NYHA Guidelines .............................................................................................. 43 
Appendix 6:  Dose Reduction Levels ...................................................................................... 44 
 
 


Version 10; October 09, 2017 
 
Page 4 of 44 
 
1.0  Background 
 
1.1  Endometrial Cancer: 
 
Endometrial cancer is the most common gynecologic cancer in the United States, 
affecting more than 60,000 women annually [1].  This disease generally afflicts women 
that are postmenopausal with median ages older than those seen with ovarian cancer. 
Importantly, the disease is increasing in incidence as its etiology is linked to obesity, 
diabetes, and hypertension. Although 80% of women are diagnosed at an early stage 
and are curable with locoregional treatment [1], few effective treatment options exist for 
women who recur, which occurs with frequency in high-risk histologic subtypes 
(papillary serous carcinoma, clear cell carcinoma, grade 3 endometrioid carcinomas and 
carcinosarcomas). Chemotherapy has become a key part of the treatment for patients 
diagnosed with advanced disease, as well as for those with high-risk disease in both the 
adjuvant and recurrent disease settings. Trials that improve the ‘chemotherapy 
backbone’ with a focus to decrease potential toxicity and improve outcomes are 
important in parallel with the development of new therapies. This protocol describes a 
feasibility trial to verify the tolerability of a more optimal taxane schedule and formulation 
in endometrial cancer.   
 
1.2  Experience with Carboplatin and Paclitaxel: 
 
The systemic treatment of endometrial carcinoma was first developed around 
progestins and Adriamycin (doxorubicin) and then mostly evolved from Phase III studies 
by the Gynecologic Oncology Group (GOG) performed since the 1970s [2]. An 
additional study, GOG122, demonstrating the superiority of one of these regimens, 
doxorubicin + cisplatin, to whole abdominal radiation [3], served as a powerful stimulus 
for extending the curative potential of adjuvant systemic therapy to earlier stages of this 
disease. The rationale to treat endometrial cancer with systemic chemotherapy is 
supported by recent data from the Cancer Genome Atlas (TCGA), which characterizes 
high-risk subtypes of endometrial cancer as carcinomas marked by genetic instability 
and hypermutations, not unlike subsets of ovarian and breast cancers that are highly 
susceptible to chemotherapy [4]. In addition, the use of taxanes in endometrial cancer is 
associated with markedly improved survival for women with recurrent disease [5].  
 
More recently, GOG 209 demonstrated the non-inferiority and more favorable 
toxicity profile of the doublet of carboplatin + paclitaxel over doxorubicin, cisplatin and 
paclitaxel (plus G-CSF) in a phase III study of advanced endometrial cancers 
(references with Table 1: summary of GOG studies in advanced stage and recurrent 
endometrial cancers). Since then, carboplatin and paclitaxel have been considered the 
standard systemic chemotherapy backbone for patients with advanced presentations or 
recurrent disease [2]. Data in ovarian cancer (replicating prior data in breast cancer) is 
supportive of weekly dosing of paclitaxel as being associated with an improved survival 
benefit over every 21 day dosing (JGOG3016) albeit at greater myelosuppression 


Version 10; October 09, 2017 
 
Page 5 of 44 
 
(requiring blood transfusions) and neurotoxicity leading to greater dose attenuation and 
discontinuation [6]. Divided dose paclitaxel has been studied in the endometrial cancer 
population in a phase II study published by the Leuven Group [7]. This group utilized 
dose-dense day 1, 8 of both paclitaxel (90 mg/m2) and carboplatin (AUC 4) 
administered every 21 days to 42 patients. The median age was 63.9 years (range, 41-
81 years). The main histopathologic types were serous/clear cell (n = 27) and 
endometrioid (n = 13). The patients were divided in 2 groups: chemotherapy-naïve 
group (n = 28, group 1) and a group with previous chemotherapy (n = 14, group 2). The 
responses for group 1 were as follows: 11 (39 %) complete response, 9 (32%) partial 
response, and 2 (7%) stable disease. The responses for group 2 were 1 (7%) complete 
response, 2 (14%) partial response, and 6 (43%) stable disease. Treatment-related 
death occurred in 1 patient (7%) because of neutropenia and nephrotoxicity. 
Progression-free survival for group 1 was 10 months (range, 4-19 months). At time of 
analysis, 57% of the patients were still alive after a median follow-up of 10 months 
(range, 4-21 months). Progression free survival for group 2 was 11 months (range, 4-19 
months). Because of grade 3 and 4 hematologic toxicity, treatment adjustments were as 
follows: 49 (18%) and 18 (19%) dose reductions (carboplatin AUC, 2-3), 35 (13%) and 
14 (15%) dose delays, and 8 (3%) and 6 (6%) treatments were not administered on day 
8 for groups 1 and 2, respectively.  The authors concluded that while activity was 
impressive, the regimen was not suitable for eventual phase III study. Our proposed 
study employs a similar ‘divided dose’ for nab-paclitaxel only with carboplatin at the 
customary AUCs every 3 weeks – a regimen we have analyzed retrospectively [Musa F, 
Kudlowitz D, Velastegui A et al 2014 SGO abstract, manuscript in preparation]. 
 1.3  Abraxane 
 
Abraxane is a novel formulation of paclitaxel, where nanoparticles of the parent drug 
are bound to albumin. The smart nanoparticle formulation of paclitaxel uses tumor 
biology against itself, promoting the direct delivery of paclitaxel to the tumor and 
concentrating the drug where it is most needed. The pharmacokinetics of Abraxane are 
favorable over paclitaxel given its 43% higher clearance rate, no need for co-
administration with the solvent Cremophor (responsible for Taxol-associated reactions, 
which limit its use) and 53% higher volume of distribution [8].  The combination of 
Abraxane and carboplatin has been studied in non-small cell lung cancer, metastatic 
breast cancer and metastatic pancreatic cancer leading to the FDA approval of 
Abraxane for these indications. Data from phase III trials suggest the combination is 
safe and effective with significantly decreased grade ≥ 3 neuropathy, neutropenia, 
arthralgia and myalgia in the Abraxane arm. Importantly, with the high prevalence of 
glucose intolerance and diabetes in our study population, obviating glucocorticoid pre-
medication would be expected to remove or reduce complications associated with 
chemotherapy.  In addition, the decreased neuropathy seen with Abraxane would be 
especially important to patients with pre-existing diabetic neuropathy.   
 
 
 


Version 10; October 09, 2017 
 
Page 6 of 44 
 
Review of Clinical Studies with Abraxane [8] 
Every-Three-Week (Q3W) Schedule in Metastatic Breast Cancer 
In a phase I study, the maximum tolerated dose (MTD) of Abraxane was determined to 
be 300 mg/m2 by 30 minute infusion Q3W, without premedication or G-CSF support[9]. 
No severe hypersensitivity reactions occurred with Abraxane despite the absence 
of premedication.  Dose-limiting toxicities included sensory neuropathy, stomatitis, and 
superficial keratopathy, which occurred at a dose of 375 mg/m2.  
 
Two multicenter phase II studies have evaluated 2 dose levels of Abraxane (300 mg/m2, 
n = 63, and 175 mg/m2, n = 43) in patients with metastatic breast cancer [10]. The 
overall response rates in these 2 phase II trials were 40% (95% CI 25-54%) for the 175 
mg/m2 dose, and 48% (95% CI 35-60%) for the 300 mg/m2 dose.  Of 39 patients 
receiving 300 mg/m2 as first-line therapy for metastatic breast cancer, 64% (95% CI 49-
79%) responded. This was contrasted with a 45% response rate in similar patients at 
the lower dose level. Grade 4 neutropenia was noted in 24% of patients at the higher 
dose level, occurred primarily during the first cycle and resolved rapidly.   
 
A Phase III trial in patients with metastatic breast cancer compared Abraxane 260 
mg/m2 (n = 229) to Taxol 175 mg/m2 (n = 225) given Q3W [11].  Efficacy analyses were 
based on the ITT population. The ORR was significantly greater for Abraxane than for 
Taxol for all patients (33% v 19%, respectively; P = 0.001), patients who received first-
line therapy (42% v 27%, respectively; P = 0.029), patients who received second-line or 
greater therapy (27% v 13%, respectively; P = 0.006), and patients who had received 
prior anthracycline therapy in either the adjuvant/metastatic setting (34% v 18%, 
respectively; P = 0.002) or the metastatic setting only (27% v 14%, respectively; P = 
0.010). Tumor response rate was also significantly higher for Abraxane than for Taxol in 
patients with visceral dominant lesions (34% v 19%, respectively; P = 0.002) and in 
patients aged younger than 65 years (34% v 19%, respectively; P < 0.001). ORR also 
was greater for Abraxane compared with standard paclitaxel in patients with nonvisceral 
dominant lesions (34% v 19%, respectively) and in patients  65 years old (27% v 19%, 
respectively), but the results did not reach statistical significance because of the small 
number of patients in these subsets. 
 
Median time to progression was significantly longer with Abraxane than with Taxol for all 
patients (23.0 v 16.9 weeks, respectively; hazard ratio [HR] = 0.75; P = 0.006).   
 
There was a trend for greater median survival for all patients treated with Abraxane than 
with Taxol (65.0 v 55.7 weeks, respectively; P = 0.374). Although no difference in 
survival was observed in first-line patients, the difference was statistically significant in 
patients who received Abraxane, compared to Taxol, as second-line or greater therapy 
(56.4 v 46.7 weeks, respectively; HR = 0.73; P = .024) [11].  
 
The incidence of hypersensitivity reactions (any grade) was low for both arms (1% for 
Abraxane and 2% for Taxol). No severe (grade 3 or 4) treatment-related hypersensitivity 
reactions occurred in any of the patients in the Abraxane group despite the absence of 
premedication. In contrast, grade 3 hypersensitivity reactions occurred in the Taxol 


Version 10; October 09, 2017 
 
Page 7 of 44 
 
group despite standard premedication (chest pain, two patients; allergic reaction, three 
patients). Per protocol, corticosteroids and antihistamines were not administered 
routinely to patients in the Abraxane group; however, premedication was administered 
for emesis, myalgia/arthralgia, or anorexia in 18 patients (8%) in the Abraxane group in 
2% of the treatment cycles, whereas 224 patients (> 99%) in the Taxol group received 
premedication in 95% of the cycles. 
 
Although the patients in the Abraxane group received an average paclitaxel dose-
intensity 49% greater than that received by patients in the Taxol group, the incidence of 
treatment-related grade 4 neutropenia was significantly lower in the Abraxane group 
than in the Taxol group (9% v 22%, respectively; P < 0.001), with a higher mean 
neutrophil nadir (1.67 v 1.31 x 109/L, respectively; P = 0.046), suggesting that 
polyethylated castor oil may have contributed to this toxicity in patients who received 
standard (solvent-based) paclitaxel.  
 
As expected with a higher dose of paclitaxel, treatment-related grade 3 sensory 
neuropathy occurred more frequently in the Abraxane arm than in the Taxol arm (10% 
v 2%, respectively; P <  0.001); however, these episodes improved with interruption of 
treatment to grade 2 or 1 in a median 22 days and were easily managed with treatment 
interruption and dose reduction. By day 28 after its first occurrence, the number of 
patients with persistent grade 3 sensory neuropathy was the same (n = 4) in both study 
arms. No episodes of motor neuropathy or grade 4 sensory neuropathy were reported in 
either group.  
 
The only clinical chemistry value that was notably different between the two treatment 
arms was higher serum glucose levels in the Taxol–treated patients, who also had a 
higher incidence of hyperglycemia reported as an adverse event compared with 
Abraxane–treated patients (7% v 1% respectively; P = 0.003).  
 
Subgroup analyses revealed that the safety profiles of Abraxane (n = 97) and Taxol (n = 
30) in patients who received the drugs as first-line therapy were similar to those in the 
overall study population. In subgroup analyses by age, the reported AEs were similar in 
patients less than 65 years old and patients  65 years old in both groups. Of the 
patients  65 years old, the incidences of the following AEs were notably lower in the 
Abraxane group (n = 30) than in the Taxol group (n = 32): neutropenia (23% v 59%, 
respectively), leukopenia (10% v 31%, respectively), nausea (20% v 38%, respectively), 
hyperglycemia (0% v 19%, respectively), and flushing (0% v 16%, respectively). These 
data indicate no additional safety concerns for elderly patients, and stimulated the 
development of combinations for NSCLC including stratification for age <70 and >70 
years (see below). 
  
Weekly (QW) Schedule with Carboplatin in advanced Non-small cell Lung (NSCLC) 
Cancer 
A combination of Abraxane at 100mg/m2 on days 1, 8 and 15 of a 21 day cycle in 
combination with carboplatin AUC 6 every 21 days was studied in NSCLC, and led to 
the FDA approval of the combination for this particular indication. Overall response 


Version 10; October 09, 2017 
 
Page 8 of 44 
 
rates (ORR) for the Abraxane combination were statistically significantly increased over 
the Taxol/carboplatin arm (33% vs 25% P = 0.005, with the secondary endpoint of 
progression free survival favoring the Abraxane combination. Treatment Emergent AEs 
(TEAEs) in the Abraxane combination were alopecia, neutropenia, anemia, and 
thrombocytopenia; peripheral sensory neuropathy, arthralgia and myalgia were 
significantly more often TEAEs in the Taxol combination; TEAEs frequency and 
distribution did not differ by the age stratification (see Table 2, section 4.0). However, 
the incidence of TEAEs resulting in taxane delay/dose not given was higher for the 
Abraxane combination (71%) as opposed to the Taxol combination (41%). On the other 
hand, the improvement in ORR for Abraxane/carboplatin was achieved without 
significant increase in Serious AEs (SAEs) over Taxol/carboplatin (18% vs 15%). The 
toxicity experience in the 1052 patients (521 receiving Abraxane) enrolled in this trial 
provides the major rationale for dropping the day 15 dose of Abraxane in this 
feasibility/toxicity reduction feasibility study.  
1.4  Rationale Behind Abraxane + Carboplatin in Endometrial Cancer   
 
A major impetus behind our clinical trial is verifying the activity of a more optimal 
and potentially less toxic taxane schedule and formulation than GOG 209. While in 
ovarian cancer trialists have switched to weekly regimens (based on results from Phase 
III Japanese GOG and experience with divided dose Taxol for recurrences and 
metastatic breast cancer), results obtained by the GOG every-3-week carboplatin + 
Taxol doublet regimen are the only available Phase III clinical data for endometrial 
cancer. Accordingly, a regimen of carboplatin and divided dose (D1 and D8) Abraxane 
is worthy of a study in patients with high-risk histologic subtypes, advanced stage (III 
and IV) or recurrent endometrial cancer. Once feasibility across 6 cycles is established, 
a phase III trial versus the standard Taxol/carboplatin every 3 weeks is justified – not 
only because of toxicity reduction but also the possibility of improved efficacy from the 
divided dose taxane schedule. Thus, we propose a phase II feasibility design for 
Abraxane 100 mg/m2 on days 1 and 8 + carboplatin AUC 6 every 3 weeks given for 6 
cycles in previously untreated patients with endometrial cancer who meet eligibility 
criteria. This day 1, 8 dosing seeks toxicity reduction (and a reduction of dose delays 
and doses not given that were seen in 71% in the day 1, 8, 15 dosing in the NSCLC 
trial) for endometrial cancer patients who are generally older with a high percentage of 
comorbidities, and also pretreated with pelvic and/or vaginal radiation. In summary, the 
better hematologic tolerance of Abraxane vis-à-vis paclitaxel when given together with 
carboplatin, and the omission of day 15 dosing in our regimen (as opposed to the 
NSCLC study summarized in 1.3) support the feasibility testing of this regimen in 
advanced and/or recurrent endometrial cancer. If declared feasible, it would be an 
alternative doublet to Taxol/carboplatin every 3 weeks in a phase III study.  
 
 
 
 
 
 


Version 10; October 09, 2017 
 
Page 9 of 44 
 
Table 1: Summary of GOG studies in advanced stage and recurrent endometrial 
cancers 
 
Trial and 
reference 
Years of 
accrual 
Regimen 
N^ 
% RR 
(CR) 
Median 
PFS 
(m) 
Median  
OS (m) 
GOG 
48[16] 
1979-
1985 
Doxorubicin 
Doxorubicin/cyclophosphamide 
132 
144 
22(5) 
30(13) 
3.2 
3.9 
6.7 
7.3 
GOG 
107[17] 
12/1988-
12/1991 
Doxorubicin 
Doxorubicin/cisplatin 
150 
131 
25(8) 
42(19) 
3.8 
5.7 HR 
= 
0.736* 
9.2 
9.0     
GOG 
139[18] 
3/1993-
8/1996 
Doxorubicin/cisplatin 
Doxorubicin/circadian cisplatin 
173 
169 
49(15) 
46(17) 
5.9 
6.5  
13.2 
11.2     
GOG 
163[19] 
8/1996-
11/1998 
Doxorubicin/cisplatin  
Doxorubicin/paclitaxel/G-CSF 
 
157 
160 
40(NR) 
43(NR) 
7.2 
6.0  
12.6 
13.6 
 
GOG 
177[20] 
12/1998-
8/2000 
Doxorubicin/cisplatin 
Doxorubicin/cisplatin/paclitaxel/ G-
CSF (i.e., ‘TAP’ regimen) 
129 
134 
34(7) 
57(22) 
5.3 
8.3 HR 
= 0.60* 
12.3 
15.3     
HR = 
0.75* 
GOG 
209[21] 
8/2003-
4/2009 
Carboplatin/paclitaxel 
Doxorubicin/cisplatin/paclitaxel/G-
CSF (TAP) 
663 
642 
NR 
NR 
14 
14 
32 
38 
 
2.0  Objectives 
 
This is a feasibility study of a day 1, 8 dose-schedule of Abraxane given in combination 
with carboplatin every 3 weeks in patients with newly diagnosed or recurrent 
endometrial cancer.  
 
2.1  Primary Endpoint 
 
The primary endpoint is the percent completion of 6 cycles of therapy on this protocol. 
Completion is defined as completing 6 cycles of the doublet (including pre-specified up 
to two dose level reductions).    
 
2.2  Secondary Endpoints  
 
1. To determine percent progression free survival at 6, 12,18, 24 months from onset of 
study treatment with carboplatin and Abraxane in patients with high-risk histologic 
subtypes, advanced, or recurrent endometrial cancer.   


Version 10; October 09, 2017 
 
Page 10 of 44 
 
 
2. To determine objective response rates by RECIST 1.1 (in patients with measurable 
disease) at the above time points.    
 
3. To evaluate the safety of treatment with carboplatin and Abraxane in this patient 
population and determine the nature and degree of toxicities following treatment.  
 
3.0  Study Design  
3.1-3.2  Description and Rationale for Study Design  
The single stage open label Phase II feasibility study is designed to estimate the 
proportion of patients who can tolerate the proposed regimen for 6 cycles with no 
more than two dose level reductions.  
3.3  Outcome Measures  
3.3.1  Primary Outcome Measures  
The tolerability of the regimen is the primary outcome. Tolerability for an individual 
patient will be defined as remaining on the study for 6 cycles with two or fewer dose 
reductions.  
3.3.2  Secondary Outcome Measures 
The percent of patients without disease progression or death at 6, 12, 18, 24 months 
since start of treatment will be determined by CT scans at baseline compared to at 
the above specified time points (+/- 2 weeks). Responses at those time intervals will 
be assessed by the RECIST 1.1 criteria in those patients with measurable disease at 
baseline (but will not require objective responses to be confirmed by subsequent 
imaging). Patients who enroll following complete cytoreduction for advanced disease 
will not be evaluable for response, but will be evaluated for progression-free survival 
data.  
3.3.3  Safety Outcome Measures 
Toxicity will be assessed with each dosing visit while on protocol and at the 30 day 
post-treatment visit. Signs and symptoms will be characterized into grade as per the 
CTCAE protocol. Treatment limiting toxicities will include grade 3 and 4 non-
hematologic toxicities lasting more than 1 week (excluding fatigue, alopecia or 
aggravation of pre-existing problems) as well as grade 4 thrombocytopenia and 
febrile neutropenia as defined by the NCI-CTCAE. 
 


Version 10; October 09, 2017 
 
Page 11 of 44 
 
4.0  Safety Plan  
 
Dosing Abraxane on days 1 and 8 without day 15 should be able to circumvent many of 
the hematologic toxicities observed in the NSCLC trial cited at the end of section 1.3 
and summarized in Table 2. During post marketing surveillance, rare cases of severe 
hypersensitivity reactions have occurred [23]. The overall rate of grade 3 and 4 toxicities 
were low and comparable to that of solvent based Taxol with the exception of 
significantly less grade ≥ 3 neuropathy, neutropenia, arthralgia and myalgias in the 
Abraxane arm. On the other hand an increase in grade 3 and 4 thrombocytopenia and 
anemia was associated with use of Abraxane versus paclitaxel at 175 mg/m2. The 
omission of day 15 dosing makes it likely that this Abraxane/carboplatin doublet will 
prove feasible within the statistical framework established in this protocol.   
 
 
Table 2. Toxicity of Weekly Abraxane + Carboplatin in NSCLC Trial  
Most Common Treatment-Related Grade ≥ 3 AEs According to NCI-
CTCAE 
AE 
nab-PC (%) (n = 514) sb-PC (%) (n = 524) 
P 
Grade 3 
Grade 4 
Grade 3 
Grade 4 
Hematologic AEs 
 
 
 
 
 
    Neutropenia 
33 
14 
32 
26 
< .001* 
    Thrombocytopenia 
13 
5 
7 
2 
< .001† 
    Anemia 
22 
5 
6 
< 1 
< .001† 
    Febrile neutropenia 
< 1 
< 1 
1 
< 1 
N/S 
Nonhematologic AEs 
 
 
 
 
 
    Fatigue 
4 
< 1 
6 
< 1 
N/S 
    Sensory neuropathy 3 
0 
11 
< 1 
< .001* 
    Anorexia 
2 
0 
< 1 
0 
N/S 
    Nausea 
< 1 
0 
< 1 
0 
N/S 
    Myalgia 
< 1 
0 
2 
0 
  .011* 
    Arthralgia 
0 
0 
2 
0 
  .008* 
 
Abbreviations: AE, adverse event; nab-PC, 130-nm albumin-bound paclitaxel + 
carboplatin (PC); NCI-CTCAE, National Cancer Institute Common Terminology 
Criteria for Adverse Events;  
 
N/S, not significant; ↵* P < .05 in favor of nab-PC. 
 
† P < .05 in favor of sb-PC. 
 
Treatment limiting toxicities for this protocol will be grade 3-4 non-hematologic toxicities 
lasting more than one week (with exception of alopecia, fatigue or aggravation of pre-
existing problems) as well as grade 4 thrombocytopenia and febrile neutropenia.  
Patients experiencing a treatment limiting toxicity will be dose reduced according to the 
protocol treatment schema described below 
 


Version 10; October 09, 2017 
 
Page 12 of 44 
 
4.1  Plan to manage safety  
 
A number of measures will be taken to ensure the safety of patients participating in this 
trial. These measures will be addressed through exclusion criteria (see Section 5.3) and 
routine monitoring as follows. 
Patients enrolled in this study will be evaluated clinically and with standard laboratory 
tests before and at regular intervals during their participation in this study.  Safety 
evaluations will consist of medical interviews, recording of adverse events, physical 
examinations, blood pressure, and laboratory measurements. Patients will be evaluated 
for adverse events (all grades), serious adverse events, and adverse events requiring 
study drug interruption or discontinuation at each study visit for the duration of their 
participation in the study. Patients discontinued from the treatment phase of the study 
for any reason will be evaluated ~30 days (28–42 days) after the decision to discontinue 
treatment (see Section 7.1.3).   
Specific monitoring procedures are as follows: 
 Hematologic toxicity: a complete blood count with differential will be obtained at the 
start of each treatment cycle. Any hematologic toxicity will be noted and followed 
closely. If a grade 4 toxicity is identified, the treatment will be held until the laboratory 
value reaches the parameters for treatment and the dose will be adjusted according to 
the protocol stated below. If a patient requires two dose reductions over the duration of 
the trial and still incurs a treatment limiting toxicity, the patient will be discontinued from 
the study and counted as unable to complete the prescribed dose.   
 Non-hematologic toxicity: this will likely be identified in the pre-treatment interview, 
physical examination and/ or other laboratory tests obtained prior to each cycle of 
chemotherapy (complete metabolic panel). Again, any toxicity will be noted and followed 
closely. If a grade 3 or above toxicity is identified, treatment will be held and restarted 
once the toxicity has recovered to a grade 1 or lower. When the treatment is restarted, 
the dose will be reduced as specified below: 
Dose Reduction Levels  
Initial Treatment Dose 
Dose Level -1 
Dose Level -2 
Abraxane 100mg/m2 IV D1, 8 
Abraxane 75mg/m2 IV D1, 8 
Abraxane 60/m2 IV D1, 8 
Carboplatin AUC 6 IV D1  
Carboplatin AUC 5 IV D1 
Carboplatin AUC 4 IV D1 
 
 
Dose Reduction Levels for Patients with Prior Whole Pelvic Radiation 
Initial Treatment Dose 
Dose Level -1 
Dose Level -2 
Abraxane 75mg/m2 IV D1, 8 
Abraxane 60mg/m2 IV D1, 8 
Abraxane 50/m2 IV D1, 8 
Carboplatin AUC 5 IV D1  
Carboplatin AUC 4 IV D1 
Carboplatin AUC 3 IV D1 
 


Version 10; October 09, 2017 
 
Page 13 of 44 
 
Again, if a patient requires two dose reductions over the duration of the trial and still 
incurs a treatment limiting toxicity, the patient will be discontinued from the study and 
counted as unable to complete the prescribed dose.   
5.0  Study Subjects 
5.1  Subject Selection 
 
General Guidelines 
Patients will be recruited from the offices of gynecologic oncologists and medical 
oncologists at the NYU Perlmutter Clinical Cancer Center as per selection criteria 
below. The patients will be identified by the treating physician and referred to the 
research nurse for trial eligibility. Physicians and/or Co-investigators will explain the 
informed consent document to the patient. Any questions or concerns will be addressed 
by doctors and or study staff. Once all questions are addressed, the patient will sign the 
consent form. At the start of trial an H&P, basic vital signs and GOG performance status 
will be noted on the patient’s medical record.   
 
Registration Process 
Patients must sign an informed consent prior to any screening procedures. Registration is 
done centrally by the NYU Perlmutter Cancer Institute’s Clinical Trial Office (CTO).  
Documents required upon registration include last page of signed informed consent, 
eligibility checklist form (signed by PI or sub-investigator) and documentation confirming 
eligibility (including labs, history, availability of tissue specimen).   
 
5.2  Inclusion Criteria  
1 Female patients must have high risk resected stage I  or 2 disease (papillary serous, 
clear cell, carcinosarcoma histology or Grade 3), advanced stage (III or IV, all 
histologies) or recurrent endometrial cancer (all histologies). Patients do not need 
measurable disease and can enroll following surgery. 
 
2 Patients may not have received prior cytotoxic chemotherapy. However, 
nonplatinum/non-taxane chemotherapy used for radiation sensitization is 
allowed. Patients may have received prior radiation therapy (including whole 
pelvic or vaginal brachytherapy), hormonal therapy, or therapy with biologic 
agents, but such therapy must be discontinued at least 2 weeks prior to entry on 
this study. 
 
3 If patients underwent surgery, and chemotherapy is indicated after surgery either 
as adjuvant or to treat residual disease, study treatment should be initiated within 
8 weeks of surgery.  


Version 10; October 09, 2017 
 
Page 14 of 44 
 
 
4 In patients who have received prior radiation, at least 4 weeks should have 
elapsed since the completion of radiation therapy involving the whole pelvis or 
over 50% of the spine.  If vaginal brachytherapy is planned with chemotherapy, it 
should be done before or after completion of chemotherapy treatment.  
5 Poorly differentiated histology, uterine papillary serous carcinoma, clear cell 
carcinoma or carcinosarcoma is acceptable as long as the predominant metastatic 
component is epithelial (versus sarcomatous).  
 
6 Patients may have synchronous endometrial and ovarian cancer primaries.  
7 Patients must have a GOG performance status of 0, 1, or 2 
8 Patients must be at least 18 years of age. 
9 Patients must understand and willingly sign an approved informed consent, and 
authorization permitting release of personal health information. 
10 Patients must have adequate liver function: AST and ALT ≤ 2.5 X upper limit of 
normal (ULN), and bilirubin ≤ 1.5mg/dL. 
11 Patients must have adequate bone marrow function: platelets ≥ 100,000 cells/mm3 
(transfusion independent, defined as not receiving platelet transfusions within 7 days 
prior to laboratory sample), hemoglobin > 9.0g/dl and ANC ≥ 1,500 cells/mm3. 
12 Patients must have adequate renal function: creatinine < 1.5 mg/dL is 
recommended; however, institutional norms are acceptable. 
13 Patients must have < grade 2 pre-existing peripheral neuropathy (per CTCAE). 
 
5.3  Exclusion Criteria  
1. Other prior malignancies within 3 years, except non-melanoma skin cancers and 
synchronous ovarian primaries. 
 
2. Eligibility to a higher priority trial for first line or recurrent endometrial cancer (unless 
patient is unwilling to participate in such a trial). 
 
3. Patients with concomitant medical illness such as serious uncontrolled infection, or 
uncontrolled angina, which in the opinion of the treating physician, make the 
treatments prescribed on this study unreasonably hazardous for the patient. 
 
4. Patients who are pregnant or breastfeeding. 


Version 10; October 09, 2017 
 
Page 15 of 44 
 
 
5. Patients with third degree or complete heart block are not eligible unless a 
pacemaker is in place. Patients on medications, which alter cardiac conduction, such 
as digitalis, beta-blockers, or calcium channel blockers, or who have other 
conduction abnormalities or cardiac dysfunction could be entered at the discretion of 
the investigators. 
 
6. Patients with history of myocardial infarct within 6 months before enrollment, New 
York Heart Association (NYHA) class II or greater heart failure or symptoms 
suspicious for congestive heart failure are not eligible unless a LVEF in the past 6 
months is documented to be 50% or greater. Patients who have had a LVEF 
(performed for any reason) that is less than 50% in the past 6 months are ineligible. 
 
6.0  Study Design 
6.1  Treatment Plan  
In a phase II open-label tolerability study, women with high-risk histologic subtypes, 
advanced or recurrent endometrial cancer will be treated with Abraxane 100mg/m2 IV 
and carboplatin AUC 6 on day 1 and Abraxane 100mg/m2 IV on day 8 of a 21 day cycle 
for 6 cycles. Subjects will undergo pre-treatment evaluation within 4 weeks of enrolling 
into the study (as described in section 8.1). Clinical and laboratory evaluation will be 
performed as described is section 8.2. Imaging studies will be performed within 4 weeks 
of enrollment and at the 6, 12, 18, 24 month after start of treatment while on study. 
Dose reductions and modifications for toxicity are described below.  
 
Subjects who received whole pelvic radiation therapy or greater than 50% spine, will 
start at a reduced dose. (see section 4.1). Subjects must wait at least 4 weeks after 
completion of whole pelvic or >50% spine radiation prior to starting chemotherapy. If 
vaginal brachytherapy is planned with chemotherapy, it may be performed before 
starting or after completion of chemotherapy at the discretion of the treating physician. 
Subjects DO NOT need to start at a reduced dose if they received only vaginal 
brachytherapy.  Vaginal brachytherapy may not be performed in the middle of 
chemotherapy treatment.  
 
For subjects who underwent surgery and for whom chemotherapy is indicated after 
surgery, either as to treat adjuvantly or to treat residual disease, the study treatment 
should be administered within 8 weeks of surgery. For subjects who have recurrent 
disease and have had prior surgery, study treatment does not need to be initiated within 
8 weeks of surgery.  
 
 


Version 10; October 09, 2017 
 
Page 16 of 44 
 
7.0  Study Medications 
 7.1  Abraxane Dosage and Formulation 
 
ABRAXANE for Injectable Suspension (also known as ABI-007, nab-paclitaxel, 
paclitaxel protein-bound particles for injectable suspension) is an albumin-bound form of 
paclitaxel with a mean particle size of approximately 130 nanometers. Paclitaxel exists 
in the particles in a non-crystalline, amorphous state. ABRAXANE is supplied as a white 
to yellow, sterile, lyophilized powder for reconstitution with 20mL of 0.9% Sodium 
Chloride Injection, USP prior to intravenous infusion. Each single-use vial contains 100 
mg of paclitaxel and approximately 900mg of human albumin. Each milliliter (mL) of 
reconstituted suspension contains 5mg paclitaxel. ABRAXANE is free of solvents.   The 
active agent in ABRAXANE is paclitaxel.  
 
ABRAXANE is a biologically interactive albumin-bound paclitaxel combining a protein 
with a chemotherapeutic agent in the particle form. This composition provides a novel 
approach of increasing intra-tumoral concentrations of the drug by a receptor-mediated 
transport process allowing transcytosis across the endothelial cell. This albumin-specific 
receptor mediated process involves the binding of albumin to a specific receptor (gp60) 
on the intralumminal endothelial cell membrane, resulting in activation of a protein 
(caveolin-1), which initiates an internalization process in the endothelial cell through the 
formation of caveolae, with transport of the intact albumin-bound chemotherapeutic 
complex via these caveolae to the underlying tumor interstitium [18] A protein 
specifically secreted by the tumor (SPARC) binds albumin, allowing release of the 
hydrophobic drug to the tumor cell membrane [19]. ABRAXANE is the first biologically 
interactive nanoparticle product leveraging this gp-60/caveolin-1/caveolae/SPARC 
pathway to increase intra-tumoral concentration of the drug and reducing toxic effects in 
normal tissue. 
 
Preclinical studies comparing ABRAXANE to Taxol® (paclitaxel Cremophor® EL solvent-
based, BMS) demonstrated lower toxicities, with an MTD approximately 50% higher for 
ABRAXANE compared to Taxol.  At equal doses there was less myelosuppression and 
improved efficacy in a xenograft tumor model of human mammary adenocarcinoma.  At 
equitoxic doses of paclitaxel, ABRAXANE treated groups showed more complete 
regressions, longer time to recurrence, longer doubling time, and prolonged survival. At 
equal dose, tumor paclitaxel area under the curve was 33% higher for ABRAXANE 
versus solvent based paclitaxel, indicating more effective intratumoral accumulation of 
ABRAXANE[18].  
 
 
 
The dose used in this protocol is extrapolated from the phase III clinical trial of the 
combination of carboplatin and Abraxane for non-small lung cancer. In that study, the 
Abraxane was dosed weekly (days 1, 8, 15 of a 21 day cycle), however, in this study we 
will use a divided dose of Abraxane (days 1 and 8) and no treatment will be 
administered on day 15 in preparation for the initiation of the following cycle on day 1/ 
21. As in the NSCLC trial, the recommended dose of Abraxane is 100mg/m2 


Version 10; October 09, 2017 
 
Page 17 of 44 
 
administered as an intravenous infusion over 30 minutes on days 1 and 8 of a 21 day 
cycle. Standardizing the order of Abraxane and Carboplatin administration has no effect 
on patient toxicity; however, administration of Abraxane before Carboplatin is preferred 
but not required. 
 
 
7.1.2  Abraxane Storage and Administration  
Use caution when handling cytotoxic drugs. Closely monitor the infusion site for 
extravasation and infiltration.  
 
Packaging, Labeling, and Storage of Study Drug 
Availability 
ABRAXANE will be supplied by Celgene Corporation.  Each single-use vial contains 
100mg of paclitaxel and approximately 900mg of human albumin. Each milliliter (mL) of 
reconstituted suspension contains 5mg paclitaxel.  
Storage and Stability 
Storage: Store the vials in original cartons at 20ºC to 25ºC (68º F to 77ºF). Retain in the 
original package to protect from bright light.  
Stability: Unopened vials of ABRAXANE are stable until the date indicated on the 
package when stored between 20ºC to 25ºC (68ºF to 77ºF), in the original package. 
Neither freezing nor refrigeration adversely affects the stability of the product.  
Stability of Reconstituted Suspension in the Vial  
Reconstituted ABRAXANE should be used immediately, but may be refrigerated at 2ºC 
to 8ºC (36ºF to 46ºF) for a maximum of 24 hours if necessary. If not used immediately, 
each vial of reconstituted suspension should be replaced in the original carton to protect 
it from bright light. Discard any unused portion.  
Stability of Reconstituted Suspension in the Infusion Bag  
The suspension for infusion when prepared as recommended in an infusion bag should 
be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) and 
protected from bright light for a maximum of 24 hours. 
The total combined refrigerated storage time of reconstituted ABRAXANE in the vial and 
in the infusion bag is 24 hours. This may be followed by storage in the infusion bag at 
ambient temperature (approximately 25°C) and lighting conditions for a maximum of 
4 hours. Discard any unused portion. 
 
Study Medication Administration 
ABRAXANE is injected into a vein [intravenous (IV) infusion] over 30 minutes.  The use 
of an in-line filter is not recommended.  
Following administration, the intravenous line should be flushed with Sodium Chloride 
9mg/ml (0.9%) solution for injection to ensure complete administration of the complete 
dose, according to local practice.  
 
 
 


Version 10; October 09, 2017 
 
Page 18 of 44 
 
Reconstitution and use of ABRAXANE 
1. Calculate the patient’s body surface area at the beginning of the study and if the 
weight changes by >10% by using the formula provided in the study manual. 
2. Calculate the total dose (in mg) to be administered by:  
𝑇𝑜𝑡𝑎𝑙 𝐷𝑜𝑠𝑒 (𝑚𝑔) = 𝐵𝑆𝐴(𝑚2) × 𝑆𝑡𝑢𝑑𝑦 𝐷𝑜𝑠𝑒 (𝑚𝑔
𝑚2) 
3. Calculate the total number of vials required by: 
𝑇𝑜𝑡𝑎𝑙 𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑉𝑖𝑎𝑙𝑠= 𝑇𝑜𝑡𝑎𝑙 𝐷𝑜𝑠𝑒 (𝑚𝑔)
100 ( 𝑚𝑔
𝑣𝑖𝑎𝑙)
 
Round up the number of vials to be reconstituted to the next higher whole number when 
a fractional number of vials is obtained by the above formula (e.g., if the total number of 
vials = 4.05 or 4.5, then 5 vials would be reconstituted).  
4. Using sterile technique, prepare the vials for reconstitution. 
5. Swab the rubber stoppers with alcohol. 
6. Aseptically, reconstitute each ABRAXANE vial by injecting 20mL of 0.9% Sodium 
Chloride Injection, USP.  
 Slowly inject the 20mL of 0.9% Sodium Chloride Injection, USP, over a 
minimum of 1 minute, using the sterile syringe directing the solution flow onto 
the inside wall of the vial. 
 DO NOT INJECT the 0.9% Sodium Chloride Injection, USP solution directly 
onto the lyophilized cake as this will result in foaming. 
 Once the injection is complete, allow the vial to sit for a minimum of 5 (five) 
minutes to ensure proper wetting of the lyophilized cake/powder.   
 Gently swirl and/or invert the vial slowly for at least 2 minutes until complete 
dissolution of any cake/powder occurs.  Avoid generation of foam.  Rapid 
agitation or shaking will result in foaming. 
 If foaming or clumping occurs, stand solution for at least 15 minutes until 
foam subsides. 
 Each ml of reconstituted product will contain 5 mg of paclitaxel. 
7. Calculate the exact total dosing volume of 5 mg/ml suspension required for the 
subject: 
𝐷𝑜𝑠𝑖𝑛𝑔 𝑉𝑜𝑙𝑢𝑚𝑒 (𝑚𝑙) = 𝑇𝑜𝑡𝑎𝑙 𝑑𝑜𝑠𝑒 (𝑚𝑔)
5 (𝑚𝑔
𝑚𝑙)
 
8. The reconstituted suspension should be milky and homogeneous without visible 
particulates.  If particulates or settling are visible, the vial should be gently 
inverted again to ensure complete resuspension prior to use. Discard the 
reconstituted suspension if precipitates are observed.  


Version 10; October 09, 2017 
 
Page 19 of 44 
 
9. Once the exact volume of reconstituted ABRAXANE has been withdrawn from 
the vials, discard any excess solution left over in accordance with standard 
operating procedures. 
10. Further dilution is not necessary. Inject the calculated dosing volume of 
reconstituted ABRAXANE suspension into an empty sterile, standard PVC IV bag 
using an injection port.  Inject perpendicularly into the center of the injection port to 
avoid dislodging plastic material into the IV bag.   
11. Administer the calculated dosing volume of reconstituted ABRAXANE 
suspension by IV infusion over 30 minutes. The use of in-line filters is not 
recommended because the reconstituted solution may clog the filter.  
  
Drug Distribution and Destruction 
a. Supplier 
Celgene Corporation 
86 Morris Avenue 
Summit, NJ  07901 
 
Industry Contact: 
Norma Powers 
Director, Medical Operations 
Celgene Corporation 
86 Morris Avenue 
Summit, NJ  07901 
Mobile: 267-337-2720 
Fax: 908-673-2779 
Email: npowers@celgene.com 
 
b. Drug Distribution 
ABRAXANE® will be distributed by Celgene Corporation.  No supplies will be 
shipped to any site until regulatory approval has been obtained.  Investigational sites 
will be supplied with ABRAXANE® upon identification and screening of a potential 
trial subject.   
Upon identification of a potential subject, sites must fax a completed Drug Request 
Form to Celgene Corporation.  Allow at least 5 working days for drug shipment.  
There are no shipments on Fridays or holidays. 
For re-supply of drug, please complete and fax the Drug Request Form to Celgene 
Corporation at 908-673-2779. 
 
c. Drug Return and Destruction 
If the investigational site does not have a policy, procedure or SOP detailing the 
process to follow for study drug destruction, the study drug must then be returned to 
Celgene using the Drug Return Form provided in the package containing the study 
drug.  The following information must be recorded on the site’s pharmacy drug 


Version 10; October 09, 2017 
 
Page 20 of 44 
 
accountability log: quantity of vials to be returned, expiration date and lot number.  A 
copy of the Drug Return Form and the study drug should be returned to Celgene 
Clinical Supplies Dept. using the mailing address on the packaging slip that came 
with the original study drug order.  A copy of the Drug Return Form should be 
retained at the clinical site.  In the event of study completion or termination, a copy 
of all pharmacy records (drug dispensing log, drug accountability log and any 
destruction memos) must be mailed to Celgene Medical Operations. 
If the investigational site has a policy, procedure or SOP detailing the process to 
follow for study drug destruction, the pharmacist or designee can choose to destroy 
the study drug on site.  The following information must be recorded on the site’s 
pharmacy drug accountability log: quantity of vials destroyed, expiration date and lot 
number.  The pharmacist must document that the study drug was destroyed in 
accordance with their institution’s drug destruction policy or SOP.  A drug destruction 
memo and the site’s drug destruction SOP/policy should be sent to Celgene Medical 
Operations Dept.  A copy of the drug destruction memo should be retained at the 
clinical site.  In the event of study completion or termination, a copy of all pharmacy 
records (drug dispensing log, drug accountability log and any destruction memos) 
must be mailed to Celgene Medical Operations. 
7.1.3  Abraxane Dose Modification and Toxicity Management  
Hematologic toxicity 
Initial protocol treatment will only occur if ANC ≥ 1500 cells/mm3 and platelet count is ≥ 
100,000 cells/mm3 on day 1. Subsequent cycles of therapy (i.e. Day 1 treatment) will 
not begin until the ANC is ≥ 1000 cells/mm3 and the platelet count is ≥ 100,000/mm3. 
Therapy will be delayed for a maximum of three weeks until these values are achieved. 
Subjects who fail to recover adequate counts within a three-week delay will be removed 
from study. For day 8, ANC must be ≥ 500 cells/mm3 and the platelet count must be ≥ 
75,000/mm3. If day 8 dosing criteria are not met, the dose will be held until the following 
cycle, if toxicity has resolved and start the next cycle at one dose level reduction.  
 
- 
For subjects with ≥ grade 3 neutropenia or thrombocytopenia, treatment will be 
withheld until counts recover to ANC ≥ 1000 cells/mm3 and platelet count is ≥ 
100,000 cells/mm3 on day 1 or ANC ≥ 500 cells/mm3 and platelet count is ≥ 
75,000 cells/mm3 on day 8 of the cycle.  
- 
If treatment is withheld, upon resumption of dosing, Abraxane and carboplatin 
dosing will be permanently reduced as per the following guidelines: 
 
1. Dose Reduction of one dose level 
- 
Febrile neutropenia  
- 
Nadir ANC < 500 cells/mm3 persistent for more than one week 
- 
Nadir platelet count < 50,000 cells/mm3  
- 
Delay of next cycle (D1 treatment) by more than 7 days for nadir ANC < 1000 
cells/mm3 
- 
If unable to give D8 treatment  
- 
Dose is held for neutropenia or thrombocytopenia 


Version 10; October 09, 2017 
 
Page 21 of 44 
 
 
2. Dose Reduction of two dose levels 
- 
If any of the above listed conditions re-occurs following first dose reduction, 
except for thrombocytopenia see note below* 
 
If the conditions listed above reoccur following reduction of two dose levels, the 
treatment will NOT be further reduced, but instead will be discontinued. 
 
*IMPORTANT: Thrombocytopenia – if nadir platelet levels drop below 50,000 cells/mm3, 
the treatment will be withheld until the levels recover to 100,000 cells/mm3 for day 1 or 
50,000 cells/mm3 on day 8 and the dose will be reduced one dose level. If the levels are 
noted to drop below 50,000 cells/mm3 again, the treatment will not be further reduced 
and instead will be discontinued. 
 
Non-hematologic toxicity 
1. Neuropathy 
   
Grade 2 (or greater) peripheral neuropathy requires reduction of one dose level  
and delay in subsequent therapy for a maximum of 3 weeks until recovered to 
grade 1.  If recurrent neuropathy to ≥ grade 2 occurs after 1 dose reduction, 
treatment will be held until resolution of symptoms to ≤ grade 1, and treatment 
will be reinitiated at a second dose reduction.  
 
 2. Renal 
  
Grade 2 (or greater) renal toxicity requires reduction of one dose level and delay 
in subsequent therapy for a maximum of 3 weeks until recovered to grade 1.  
 
3. Hepatic 
-    Subjects with bilirubin levels above the ULN will be excluded from this clinical 
trial.  
- 
For subjects with moderate hepatic impairment (AST < 10 x ULN and bilirubin > 
1.5 to ≤ 3 x ULN): the Abraxane dose will be reduced one dose level (see section 
4.1), and subsequent therapy delayed for a maximum of 3 weeks until recovered 
to grade 1. 
- 
For severe hepatic impairment (AST < 10 x ULN and bilirubin > 3 - ≤ 5 x ULN): 
the Abraxane dose will be reduced to two dose levels, and subsequent therapy 
delayed for a maximum of 3 weeks until recovered to grade 1. 
- 
Any subjects with very severe hepatic impairment  (AST > 10 x ULN OR bilirubin 
> 5 x ULN) will be taken off trial.  
 
4.  Alopecia  
There will be no dose modifications for alopecia. 
 
5.   GI 
  
It is expected that subjects with nausea, emesis, diarrhea, or constipation will 
receive appropriate medical management without dose modification. However, 
subjects with persistent (greater than 24 hours) ≥ grade 3 toxicity in spite of 


Version 10; October 09, 2017 
 
Page 22 of 44 
 
optimal medical management require reduction of one dose level and delay in 
subsequent therapy for a maximum of 3 weeks until recovered to grade 1.  
 
6.   Other 
  
Non-hematologic toxicities with an impact on organ function of ≥ grade 2 require 
reduction of one dose level and delay in subsequent therapy for a maximum of 2 
weeks until recovered to grade 1, or pre-therapy baseline.  
 
7. 
Hypersensitivity 
  
Routine premedication to prevent hypersensitivity, nausea, or vomiting is not 
required. However, Abraxane contains paclitaxel, and hypersensitivity reactions 
have been observed in some patients treated to date. Mild hypersensitivity 
reaction (Grade 1 or 2 such as flushing, pain, urticaria, drug fever, and 
asymptomatic bronchospasm) can often be successfully treated with slowing or 
interrupting the infusion of Abraxane and administering antihistamines and 
antipyretics (such as diphenhydramine, promethazine, acetaminophen). 
Frequently, per investigator discretion, the infusion can be restarted and 
completed after the symptoms have abated. Injectable steroids and epinephrine 
should be immediately available to provide prompt treatment of any severe 
hypersensitivity reactions that may occur during or following study treatment.  
Subjects with grade 3 hypersensitivity reactions can be retreated after standard 
paclitaxel premedication at the discretion of the investigator. Pre-medicated 
subjects with grade 3 hypersensitivity reaction and all subjects with grade 4 
hypersensitivity reaction should not be retreated. 
    
 
Important – Abraxane contains albumin, a derivative of human blood and    
should not be administered to subjects who object to receiving blood products.   
 
Overdose 
Overdose, as defined for this protocol, refers to ABRAXANE® alone or in combination 
dosing only.   
 
On a per dose basis, an overdose is defined as the following amount over the protocol-
specified dose of ABRAXANE® assigned to a given subject, regardless of any 
associated adverse events or sequelae.  
PO 
any amount over the protocol-specified dose 
 
IV 
10% over the protocol-specified dose  
 
SC 
10% over the protocol-specified dose 
 
On a schedule or frequency basis, an overdose is defined as anything more frequent 
than the protocol required schedule or frequency.   
 
On an infusion rate basis, an overdose is defined as any rate faster than the protocol-
specified rate.  For nab-paclitaxel, an infusion completed in less than 25 minutes may 


Version 10; October 09, 2017 
 
Page 23 of 44 
 
increase Cmax by approximately 20%, therefore a nab-paclitaxel infusion completed in 
less than 25 minutes will meet the infusion rate criterion for an overdose. 
 
Important: We will conduct strict education with all co-investigators and infusion 
nurses to ensure infusion should not be completed in less than 25 minutes. 
 
Complete data about drug administration, including any overdose, regardless of 
whether the overdose was accidental or intentional, should be reported in the case 
report form.   
 
Concomitant Medications 
Supportive care, including but not limited to anti-emetic medications, may be 
administered at the discretion of the Investigator.  Concurrent treatment with 
bisphosphonates is allowed.  Erythropoietin and G-CSF may be administered at the 
discretion of the investigator, consistent with institutional guidelines.  
 
7.2  Carboplatin Dosage and Formulation  (Paraplatin® - NSC #241240) 
 
Carboplatin is supplied as a sterile, pyrogen-free, 10mg/mL aqueous solution in multi-
dose vials containing 50mg/5mL, 150mg/15mL,450mg/45mL, or 600g/60mL of 
carboplatin. Commercially available both from Bristol-Myers Squibb Oncology as well as 
generic manufacturers. Consult the American Hospital Formulary Service Drug 
Information guide, Facts and Comparisons, or the package insert for additional 
information. Carboplatin is given per standard of care, FDA-approved dosing. 
7.2.1  Administration  
Carboplatin aqueous solution can be further diluted to concentrations as low as 
0.5mg/mL with 5% Dextrose in Water or 0.9% Sodium Chloride for Injection, USP. 
When prepared as directed, carboplatin aqueous solutions are stable for 8 hours at 
room temperature (25°C / 77°F). Since no antibacterial preservative is contained in the 
formulation, it is recommended that carboplatin solutions be discarded 8 hours after 
dilution. Institutional pharmacy policy may allow refrigeration and longer storage. 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. 
7.2.2  Storage  
Unopened vials of carboplatin are stable to the date indicated on the package when 
stored at 25°C (77°F). Excursions from 15 to 30°C (59 to 86°F) are permitted. Protect 
from light. Carboplatin multi dose vials maintain microbial, chemical, and physical 
stability for up to 14 days at 25°C following multiple needle entries. 
 


Version 10; October 09, 2017 
 
Page 24 of 44 
 
 
7.2.3  Carboplatin dose modifications and toxicity management:  
Dose Calculations  
Carboplatin is dosed by AUC calculated as per the GOG calculator on www.gog.org. 
For subject safety GOG clinical research studies limit GFR values to less than or equal 
to 125ml/min. For GFR greater than 125, 125 is used to calculate the carboplatin dose. 
Therefore for GOG studies, the maximum dose is capped at 450mg for AUC 3, 600mg 
for AUC 4, 750mg for AUC 5 and 900mg for AUC 6. Calvert Formula: Carboplatin dose 
(mg) = (Target AUC) x (GFR + 25).  For the purposes of this calculation, the GFR will be 
considered to be equivalent to the estimated creatinine clearance (Ccr). The estimated 
creatinine clearance is calculated by the method of Cockcroft-Gault. The Cockcroft-
Gault formula for calculating the estimated creatinine clearance for women is: 
 
𝐶𝑐𝑟 ( 𝑚𝑙
𝑚𝑖𝑛) = (140 −𝐴𝑔𝑒(𝑦𝑒𝑎𝑟𝑠)) × 𝑊𝑒𝑖𝑔ℎ𝑡(𝑘𝑔)
72 × 𝑆𝑒𝑟𝑢𝑚 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 (𝑚𝑔
𝑑𝑙)
× 0.85 
 
For this study carboplatin will be dosed at AUC 6 IV (or AUC 5 if prior radiation therapy).  
 
Dose modifications will occur as follows:  
 
Dose level -1: Carboplatin IV AUC 5 (with Abraxane at 75mg/m2 IV) 
 
Dose level -2: Carboplatin IV AUC 4 (with Abraxane at 60mg/m2 IV) 
 
If the subject had prior whole pelvic radiation therapy, dose modifications will occur as 
follows: 
 
Dose level -1: Carboplatin IV AUC 4 (with Abraxane at 60mg/m2 IV) 
 
Dose level -2: Carboplatin IV AUC 3 (with Abraxane at 50mg/m2 IV) 
 
There will be no third dose reduction level for carboplatin, instead treatment will be 
discontinued.  
 
There will be no treatment modifications for grade 1 or grade 2 non-hematologic 
toxicities or grade 1 or 2 hematologic toxicities. For grade ≥ 3 non-hematologic 
toxicities, the treatment will be withheld until the toxicity has improved to ≤ grade 1 and 
restarted at dose level -1 (as specified above). For recurrent toxicity, the treatment will 
once again be held until the toxicity has improved to ≤ grade 1 at which point it will be 
restarted at dose level -2 (as specified above). 
 
Hepatic, neurologic and hematologic toxicities are treatment limiting in this study, please 
see description above (under Abraxane) for instructions on dose reductions for specific 
scenarios. When a dose reduction is undertaken, both the abraxane and carboplatin will 
be dose reduced.  
 


Version 10; October 09, 2017 
 
Page 25 of 44 
 
Important: severe and sometimes fatal hypersensitivity reactions, including anaphylactic 
reactions have been reported. Subjects who experience a severe hypersensitivity to 
carboplatin should not be rechallenged with the drug.  
7.3  Concomitant medications:  
 
No premedications are necessary with Abraxane administration. For cycle day 1 we 
suggest decadron 10mg IV once prior to carboplatin administration. Carboplatin is an 
emetogenic chemotherapy. Support with antiemetics is encouraged.  
 
Caution should be exercised when administering ABRAXANE concomitantly with 
medicines known to inhibit or induce either CYP2C8 or CYP3A4. 
8.0  Clinical and Laboratory Evaluations  
All treatments performed throughout the study are considered standard of care, with the 
exception of Abraxane, which will be provided by the manufacturer. Administration of 
drugs (both Carboplatin and Abraxane) will be considered standard of care. 
8.1  Pre-Treatment evaluations: 
 Vital signs, including blood pressure, height, weight, and performance status (within 
14 days) 
 History and physical examination (within 14 days) 
 CT-scan of chest, abdomen and pelvis should be performed (within 30 days). The 
imaging study performed during pre-treatment evaluation will be repeated at 6 months.  
 Complete blood count, basic metabolic panel (including magnesium), liver function 
test, CA-125 (within 14 days); approximately 9mL of blood will be collected. 
8.2  In-Treatment Evaluations 
 
Every 3 weeks: 
 Vital signs, including blood pressure, performance status, blood pressure, and weight 
(within 4 days of treatment) 
 History and physical examination (within 4 days) 
 Complete blood count, basic metabolic panel, liver function test (within 4 days). CA-
125 level is optional and will be drawn at the discretion of the provider. Approximately 
9mL of blood will be collected. 
⁯ 
Interval imaging (CT scans) will not be routinely performed during treatment. However, if 
done for medical reasons in order to assess signs and symptoms that have arisen 
during treatment warranting evaluation, such scan may be used to determine early 
progression during treatment. 


Version 10; October 09, 2017 
 
Page 26 of 44 
 
8.3  Post-Treatment Evaluations 
8.3.1 Imaging Follow-Up: 
Evaluations by CT will take place at 6, 12, 18, 24 months (+/- 2 weeks) after initiation of 
protocol treatment or until disease progression: 
 ⁯At 6, 12, 18, 24 months (+/- 2 weeks), imaging (CT scan) will be performed. Imaging 
may be performed earlier than set intervals for medical reasons in order to assess signs 
and symptoms that have arisen during treatment warranting evaluation. If at any time 
point progressive disease is noted, the subject will be followed up to the 24 month 
landmark only for survival. All samples collected during the study will be destroyed at 
the end of the study. No samples will be stored for future research.  
 
8.3.2 Clinical Evaluation Follow-Up: 
Evaluations will take place at 3, 6, 9, 12, 15, 18, 21, 24 months (± 2 weeks) after End of 
Treatment visit or until disease progression: 
 History and physical examination, assessment of performance, survival status 
 Complete blood count, basic metabolic panel (without magnesium) 
 CA-125 (approximately 3mL of blood) 
 Toxicity assessment 
 
9.0 Risks of Participation  
Taking Abraxane may cause the subject to have one or more of the side effects listed 
below.  The FDA considers the use of Abraxane to be investigational for treating 
endometrial cancer. Because this is a research study about Abraxane not all side 
effects are known. There may be rare and unknown side effects. Some of these side 
effects may be severe enough to cause death. 
 
Below is a list of the most common side effects of Abraxane: 
 Hair loss 
 Numbness, tingling, pain, or weakness in the hands or feet 
 Abnormal heart beat 
 Tiredness 
 Joint and muscle pain 
 Changes in your liver function tests, which may indicate liver problems 
 Rash 
 Low red blood cell count (anemia) which can cause fatigue and shortness of 
breath 
 Nausea and vomiting  
 Infections 
 Diarrhea 


Version 10; October 09, 2017 
 
Page 27 of 44 
 
 Loss of body fluid (dehydration) 
 Swelling in the hands or feet 
 
Below is a list of potential serious side effects of Abraxane: 
 Decreased blood counts. Abraxane can cause a severe decrease in neutrophils  
 Numbness, tingling, pain, or weakness in the heads or feet (neuropathy) 
 Severe infection (sepsis) 
 
Below is a list of other potential side effects of Abraxane: 
 Treatment with Abraxane can make liver problems worse. If you have liver 
problems, your starting dose of Abraxane should be lowered or withheld. 
 Abraxane contains albumin (human), a product of human blood 
 
As with any drug, an allergic reaction can occur. Allergic reactions can be mild or more 
serious and can even result in death. Common symptoms of an allergic reaction are 
rash, itching, skin problems, swelling of the face and throat or trouble breathing.  
 
It is also important to note the potential side effects when using Carboplatin, as these 
reactions are unknown when using Carboplatin and Abraxane together to treat 
endometrial cancer. The following is a list of potential side effects with Carboplatin: 
 
Likely side effects while using Carboplatin: 
 Low white blood cell counts  
 Low platelet count  
 Low red blood cell count 
 Tiredness 
 Loss of appetite and weight loss 
 Diarrhea, constipation, nausea and vomiting, and abdominal pain 
 Complete hair loss 
 Skin rash 
 Changes in taste 
 Changes in electrolytes (salts) in the blood such as magnesium and potassium 
 
Less Likely, but serious: 
 Numbness or tingling in fingers or toes 
 Ringing in the ears and hearing loss 
 Allergic reactions 
 Chills and fever with aches and pains 
 Decrease in kidney or liver function 
 Sores in mouth and throat (that can lead to difficulty swallowing and dehydration) 
 Altered vision 
 
Rare, but serious: 
 Seizures 
 Secondary cancers such as acute leukemia 
 Kidney failure requiring dialysis 


Version 10; October 09, 2017 
 
Page 28 of 44 
 
 Deafness 
 Death 
 
Risk of taking other medication with study drug: 
It is not known whether Abraxane interacts with other drugs, so all medications the subject is 
taking will be recorded and reviewed while they participate in this study.  
 
10.0 Potential Benefits of Treatment: 
Potential benefits can include a decrease in disease progression, or even potentially 
improvement in health. It is also a benefit in studying potential new treatments for subjects with 
endometrial cancer based on the information gathered in this study. 
11.0  Subject discontinuation from treatment 
Subjects who meet the following criteria should be discontinued from study treatment: 
 Recurrent treatment limiting toxicity status post reduction to dose level -2 (see 
section 4.1) 
 Unwillingness or inability of subject to comply with study requirements 
 Withdrawal of consent 
 Determination by the investigator that it is no longer safe for the subject to 
continue therapy 
 Hypersensitivity to Abraxane  
 Disease progression during treatment 
12.0  Study discontinuation 
• 
Death from any cause 
• 
Loss to follow-up 
• 
Receipt of other anticancer therapy 
If a subject is thought to be lost to follow-up, discontinues study treatment, or 
discontinues the study, attempts should be made to contact the subject to determine the 
reason for discontinuation. For subjects who are thought to be lost to follow-up, at least 
3 documented attempts, including 1 via certified mail, should be made to contact the 
subject before the subject is deemed lost to follow-up.  
13.0  Statistical Methods 
The proportion of subjects who can remain on study for 6 cycles with 2 or fewer dose 
reductions will be estimated with exact 95% confidence intervals. All subjects who 
receive any drug will be included in this intent to treat (ITT) analysis.  
 


Version 10; October 09, 2017 
 
Page 29 of 44 
 
Characteristics of subjects at baseline will be summarized using descriptive statistics 
and graphical displays. Responses evaluated by RECIST 1.1 criteria will be 
summarized using frequency distributions. Survival and percent progression free 
survival will be displayed using Kaplan-Meier curves and progression free survival rates, 
respectively.  
13.1  Determination of sample size 
Based on a single stage design, we can test the null hypothesis that the proportion of 
subjects completing 6 cycles as defined above is ≤ 0.5 versus the alternative that the 
proportion completing 6 cycles is ≥ 0.75 with an alpha of 0.05 (actual 0.047) and power 
of 80% with 23 subjects. If we observe 16 or more regimen completions in the 23 
subjects, we reject the null hypothesis. Calculations from PASS, NCSS 2008. J Hintze, 
Kaysville, Ut. 
 
14.0  Safety Reporting Of Adverse Events 
14.1  Adverse Events Reporting and Definitions 
Toxicity will be scored using CTCAE version 4.0 for toxicity and adverse event 
reporting.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
homepage –see also Appendix 8. 
(http://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_40).  
All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  All adverse clinical experiences, whether observed by the investigator or reported 
by the patient, must be recorded, with details about the onset date, duration and 
intensity of each episode, the action taken with respect to the test drug, and the 
patient’s outcome.  The investigator must evaluate each adverse experience for its 
relationship to the test drug and for its seriousness. 
 
All AEs will be collected and recorded in the for each patient from the day of signed 
informed consent until 30 days after the last dose of study treatment or until the patient 
begins participation in a new clinical trial or initiates a new chemotherapy regimen. 
In general, CTCAE (v 4.03) severity grades are: 
  
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated  
  
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL). (Instrumental ADL 
refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc)  
  
Grade 3: Severe or medically significant but not immediately life-threatening;   
hospitalization or prolongation of hospitalization indicated; disabling; limiting self- 


Version 10; October 09, 2017 
 
Page 30 of 44 
 
care ADL. (Self-care ADL refer to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden.)  
  
Grade 4: Life-threatening consequences; urgent intervention indicated  
         Grade 5: Death related to AE  
The investigator must appraise all abnormal laboratory results for their clinical 
significance.  If any abnormal laboratory result is considered clinically significant, the 
investigator must provide details on attribution to study treatment (i.e., unrelated, 
possibly, probably, definitely related and on any actions taken with respect to the test 
drug and about the patient’s outcome. 
 
In deciding on causality/attribution to treatment, one the following categories should be 
selected: 
Related: A clinical event, including laboratory test abnormality, occurs in a plausible 
time relationship to treatment administration, and which concurrent disease or other 
drugs or chemicals cannot explain. The response to withdrawal of the treatment should 
be clinically plausible. 
Possibly related: A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the treatment, unlikely to be attributed to 
concurrent disease or other drugs or chemicals. 
Unlikely related: A clinical event, including laboratory test abnormality, with a temporal 
relationship to treatment administration which makes a causal relationship improbable, 
or in which other drugs, chemicals or underlying disease provide likely explanations. 
Unrelated: A clinical event, including laboratory test abnormality, with little or no 
temporal relationship with treatment administration. Typically explained by extraneous 
factors (eg, concomitant disease, environmental factors, or other drugs or chemicals). 
14.2  NYU Data Safety Monitoring Committee. 
According to the NCI approved DSMB plan. The Data Safety Monitoring Committee 
(DSMC) of the NYU Cancer Center will monitor this study upon approval by its Protocol 
Research Monitoring Committee (PRMC).  The DSMC operates based on the 2014 
National Cancer Institute approved Charter.  The DSMC is responsible for monitoring 
safety, conduct and compliance with protocol data and safety monitoring plans for 
cancer clinical trials that are not monitored by any other institution or agency. 
 
This study will be monitored according to the monitoring plan detailed below.  The 
Investigator will also ensure that the monitor or other compliance or quality assurance 
reviewer is given access to all the above noted study-related documents and study 
related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space to 
conduct the monitoring visit.  A risk-based, data-driven monitoring approach will also 


Version 10; October 09, 2017 
 
Page 31 of 44 
 
include a centralized review of data for quality, trends, consistency and general safety 
review. 
 
During scheduled monitoring visits, the investigator and the investigational site staff 
must be available to meet with the quality assurance specialist in order to discuss the 
progress of the trial, make necessary corrections to case report form entries, respond to 
data clarification requests and respond to any other trial-related inquiries of the monitor.  
In addition to on-site monitoring visits, the Sponsor and/or representatives will also be 
routinely reviewing data.  Inquiries related to study conduct, which require further 
information or action will be discussed within the study team for appropriate and 
documented escalation plans. It is expected that response to data clarification requests 
and other trial-related inquiries will occur throughout the course of the study through 
regular communication with the site monitor, the Sponsor or representatives, and 
review/entry of data into the electronic study database. 
 
In accordance with HIPAA and associated privacy regulations, a patient’s authorization 
to use personal identifiable health information may be required from each patient before 
commencement of research activities. This authorization document must clearly specify 
what parties will have access to a patient’s personal health information, for what 
purpose and for what duration. 
 
 
At the NYU Perlmutter Cancer Center, all investigator-initiated protocols are subject to a 
standardized data and safety monitoring, which includes scientific peer review, IRB 
review and DSMC review as well as internal auditing. 
 
The review of AEs and trial conduct for this trial occurs at several levels: 
 
(1)  Principal Investigator:  Adverse events are evaluated monthly by the 
principal investigator in conjunction with the research team. 
 
(2) DSMC, twice annually 
 
(3) Institutional Review Board (IRB):  An annual report to the IRB is submitted by 
the trial PI for continuation of the protocol.  It includes a summary of all AEs, 
total enrollment with demographics, protocol violations, and status of 
subjects as well as available research data. 
 
(4) In addition, the quality assurance unit will monitor this trial every 6-8 weeks, 
to verify adherence to the protocol; the completeness, accuracy and 
consistency of the data; and adherence to ICH Good Clinical Practice 
guidelines. 
 


Version 10; October 09, 2017 
 
Page 32 of 44 
 
 
In the event of an adverse event, the first concern will be for the safety of the subject. 
Investigators are required to report to Celgene ANY serious treatment emergent 
adverse event (STEAE) within 24 hours of being aware of the event. 
 
A STEAE is any sign, symptom or medical condition that emerges during treatment or 
during a post-treatment follow-up period that (1) was not present at the start of 
treatment and 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 
14.3  Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
86 Morris Avenue 
Summit, NJ 07901 
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
 
     Telephone: 1-908-673-9667 
 
     Toll Free: 1-800-640-7854 
14.4  Safety Reporting Requirements 
Expedited Reporting by Investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform 
Celgene in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE 
within 24 hours of being aware of the event.  The written report must be completed and 
supplied to Celgene by facsimile within 24 hours/1 business day.  The initial report must 
be as complete as possible, including an assessment of the causal relationship between 
the event and the investigational product(s). Information not available at the time of the 
initial report (e.g., an end date for the adverse event or laboratory values received after 
the report) must be documented on a follow-up report.  A final report to document 
resolution of the SAE is required.  The Celgene tracking number (AX-CL-OTHER-PI-
005275) and the institutional protocol number should be included on SAE reports (or on 
the fax cover letter) sent to Celgene.  A copy of the fax transmission confirmation of the 


Version 10; October 09, 2017 
 
Page 33 of 44 
 
SAE report to Celgene should be attached to the SAE and retained with the patient 
records. 
 
Report of Adverse Events to the Institutional Review Board 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) of 
a serious adverse event according to institutional policy.   
 
Investigator Reporting to the FDA 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly 
associated to the drug, and that have not previously been reported in the Investigators 
brochure, or reference safety information document should be reported promptly to the 
Food and Drug Administration (FDA) by telephone or by fax.  Fatal or life threatening 
SAEs that meet the criteria for reporting to the FDA must be reported to the FDA within 
7 calendar days after awareness of the event.  All other SAEs that meet the criteria for 
reporting to the FDA must be reported to the FDA within 15 calendar days after 
awareness of the event.  A clear description of the suspected reaction should be 
provided along with an assessment as to whether the event is drug or disease related.    
If this is a multicenter trial, suggest including language indicating that participating study 
sites should NOT report SAEs to the FDA.  Rather, participating sites should report 
SAEs to Celgene and the primary study site, and the primary site will be responsible for 
reporting to FDA. 
Adverse event updates/IND safety reports 
Celgene shall notify the Investigator via an IND Safety Report of the following 
information: 
 
 Any AE associated with the use of drug in this study or in other studies that is 
both serious and unexpected. 
 Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and 
unexpected AE(s) or significant risks to subjects. 
 
The Investigator must keep copies of all AE information, including correspondence with 
Celgene and the IRB/EC, on file. 
 
15.0 Retention of Records 
 
All documentation of adverse events, records of study drug receipt and dispensation, 
and all IRB correspondence for at least 2 years after the investigation is completed.  
15.1  Confidentiality 
The research team will maintain clinical and laboratory data in a manner that ensures 
patient confidentiality.  All study personnel have passed human subject protection 


Version 10; October 09, 2017 
 
Page 34 of 44 
 
courses.  Systems used for electronic data capture are compliant with HIPAA and 
applicable local regulatory agency guidelines.  All documents are kept in strictly 
confidential files and are only made accessible for specific study personnel, CTO quality 
assurance specialists, and authorized representatives of regulatory agencies as 
described in the informed consent document.   
 
15.2  Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents.  Source documentation refers to 
original records of observations, clinical findings, and evaluations that are subsequently 
recorded as data.  Source documentation should be consistent with data entered into 
Velos.  Relevant source documentation to be reviewed by the DSMC throughout the 
study includes: 
 
1.  Baseline measures to assess pre-protocol status 
2.  Concurrent medications 
3.  Treatment records 
4.  Adverse events 
 
 
15.3  Data and Source Documentation 
Velos, an electronic database capture system will be created to record the data for this 
trial.  Research coordinators will input clinical trial data into the database.  This 
database is password protected and only the PI, assigned research coordinator, and 
CTO quality assurance specialists will have access to the database.  Velos is the 
primary data collection instrument for the study.  All data requested in Velos must be 
reported.  All missing data must be explained.  The quality assurance specialists will 
monitor this trial every 6-8 weeks for data entry accuracy. 
 
 
DATA MANAGEMENT 
A clinical research associate (CRA) will be assigned to the study and his/her 
responsibilities will include protocol compliance, data collection, abstraction and data 
entry, data reporting, regulatory monitoring, problem resolution and prioritization, and 
coordination of activities of the protocol study team.  
 


Version 10; October 09, 2017 
 
Page 35 of 44 
 
 
16.0 Costs Incurred to Patients on Study 
Standard of care procedures will be billed to the patient’s insurance company. If the 
patient does not have insurance costs will be billed directly to them. The following 
procedures are considered standard of care: 
 Vital Signs (blood pressure, pulse, temperature) 
 Physical Examination 
 Blood Samples  
 CT Scans 
 Administration costs for carboplatin and abraxane 
 Carboplatin (the drug) 
 
Since Abraxane is not FDA approved for the treatment of endometrial cancer, the 
drug will be provided to the patients free-of-charge from the Sponsor, Celgene INC. 
Administration procedures for Abraxane, however, will be billed to insurance (or the 
patient in the event the patient does not have insurance). 
 
Subjects will not be paid for their participation in this study. 
 
 
 


Version 10; October 09, 2017 
 
Page 36 of 44 
 
17.0 References: 
1. American Cancer Society, Facts and Figures, 2016 
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-
statistics/annual-cancer-facts-and-figures/2016/estimated-number-of-new-cancer-
cases-and-deaths-by-sex-us-2016.pdf 
 
2. Goldfinger, M., Diaz, I , Muggia F. Systemic treatment of endometrial cancer:  what is 
doxorubicin’s role?  J Clin Oncol.  2014 32(20):2181-2. 
 
3. Randall ME, Filiaci VL, Muss H, 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 24:36-44, 2006 
 
4. Cancer Genome Atlas Research Network KC, Schultz N, Cherniack AD, et al: 
Integrated genomic characterization of endometrial carcinoma. Nature 2:67-73, 2013 
 
5. Muggia FM. Introduction: why a supplement on taxanes? Anticancer Drugs. 2014 
May;25(5):481. 
 
6. Katsumata N, Yasuda M, Isonishi S, et al.  Long-term results of dose-dense paclitaxel 
and carboplatin versus conventional paclitaxel and carboplatin for treatment of 
advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): 
a randomized, controlled, open-label trial. Lancet Oncology 2013;14:10:1020-6 
7.  Vandenput I, Vergote I, et al. Leuven dose-dense paclitaxel/carboplatin regimen in 
patients with primary advanced or recurrent endometrial carcinoma. Int J Gynec Cancer 
2009 106 (2):1147-51  
8. Brochure, I.s., ABRAXANE® (Paclitaxel Albumin Nanoparticle for Injectable 
Suspension) (ABI-007). American BioScience, Inc.  
 
9. Ibrahim, N.K., et al., Phase I and pharmacokinetic study of ABI-007, a Cremophor-
free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res, 2002. 
8(5): p. 1038-44. 
 
10. Ibrahim, N.K., et al., Multicenter phase II trial of ABI-007, an albumin-bound 
paclitaxel, in women with metastatic breast cancer. J Clin Oncol, 2005. 23(25): p. 6019-
26. 
 
11. Gradishar, W.J., et al., Phase III trial of nanoparticle albumin-bound paclitaxel 
compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J 
Clin Oncol, 2005. 23(31): p. 7794-803. 
 


Version 10; October 09, 2017 
 
Page 37 of 44 
 
12. Nyman, D.W., et al., Phase I and pharmacokinetics trial of ABI-007, a novel 
nanoparticle formulation of paclitaxel in patients with advanced nonhematologic 
malignancies. J Clin Oncol, 2005. 23(31): p. 7785-93. 
13. Blum, J.L., et al., Phase II study of weekly albumin-bound paclitaxel for patients with 
metastatic breast cancer heavily pretreated with taxanes. Clin Breast Cancer, 2007. 
7(11): p. 850-6. 
 
14. Gradishar, W.J., et al., Significantly longer progression-free survival with nab-
paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J 
Clin Oncol, 2009. 27(22): p. 3611-9. 
 
15. Robidoux, A., et al., A phase II neoadjuvant trial of sequential nanoparticle albumin-
bound paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide in locally 
advanced breast cancer. Clin Breast Cancer, 2010. 10(1): p. 81-6. 
 
16, Thigpen, J.T., et al., A randomized comparison of doxorubicin alone versus 
doxorubicin plus cyclophosphamide in the management of advanced or recurrent 
endometrial carcinoma: A Gynecologic Oncology Group study. J Clin Oncol, 1994. 
12(7): p. 1408-14. 
 
17. Thigpen, J.T., et al., Phase III trial of doxorubicin with or without cisplatin in 
advanced endometrial carcinoma: a gynecologic oncology group study. J Clin Oncol, 
2004. 22(19): p. 3902-8. 
 
18. Gallion, H.H., et al., Randomized phase III trial of standard timed doxorubicin plus 
cisplatin versus circadian timed doxorubicin plus cisplatin in stage III and IV or recurrent 
endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol, 2003. 
21(20): p. 3808-13. 
 
19. Fleming, G.F., et al., Phase III randomized trial of doxorubicin + cisplatin versus 
doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Gynecologic 
Oncology Group study. Ann Oncol, 2004. 15(8): p. 1173-8. 
 
20. Fleming, G.F., 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. 22(11): p. 2159-66. 
 
21. Miller, D., Fillaci V et al., Randomized phase III noninferiority trial of first line 
chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic 
Oncology Group study, in GynecolOncol. 2012. p. 771-3. 
 
22. Tiersten, A.D., et al., A phase I trial of dose-dense (biweekly) carboplatin combined 
with paclitaxel and pegfilgrastim: a feasibility study in patients with untreated Stage III 
and IV ovarian, tubal or primary peritoneal cancer: a Gynecologic Oncology Group 
study. Gynecol Oncol, 2010. 118(3): p. 303-7. 
 


Version 10; October 09, 2017 
 
Page 38 of 44 
 
23. Socinski, M.A., et al., Weekly nab-paclitaxel in combination with carboplatin versus 
solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced 
non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol, 2012. 30(17): p. 
2055-62. 
 
24. Desai, N., et al., Increased antitumor activity, intratumor paclitaxel concentrations, 
and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, 
compared with cremophor-based paclitaxel. Clin Cancer Res, 2006. 12(4): p. 1317-24. 
 
25. Desai, N.P., et al., Improved effectiveness of nanoparticle albumin-bound (nab) 
paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of 
HER2 and SPARC status. Anticancer Drugs, 2008. 19(9): p. 899-909. 
 


Version 10; October 09, 2017 
 
Page 39 of 44 
 
Appendix 1:  Study Schema  
 
 
Test/Procedures 
Pre-
Study 
Cycle 1 
Day 1   
Cycle 1 
Day 8 
Cycles 2-6  
days 1 
Cycles 2-
6 days 8 
End of 
Treatment 
Follow-up 
(aprx 30 
days after 
treatment) 
Follow Up 
every 3 mo 
for 2 years 
unless 
specified 
H&P, Vitals 
X 
X 
X 
X 
 
X 
X 
Weight, 
Performance Status 
X 
X 
 
X 
X 
 
X 
X 
CT Scan of chest, 
abdomen, and pelvis 
X 
 
 
 
 
  
Xa (6, 12, 
18, 24 mo (± 
2 weeks) 
after start 
CA 125b 
X 
 
 
 
 
 
 
X 
Toxicity Notationc 
X 
X 
X 
X 
 
X 
Xd 
Medication Review 
X 
X 
X 
X 
 
X 
X 
CBC with diff 
X 
X 
X 
X 
X 
X 
X 
Basic Metabolic 
Panel 
Xe 
X 
X 
X 
X 
X 
X 
LFTs 
X 
X 
X 
X 
 
X 
X 
a.  Scans will take place at 6, 12, 18, 24 months (± 2 weeks) after onset of treatment, as per standard of care, unless 
medically indicated to obtain imaging sooner. Scans will not be a part of the clinical follow-up every 3 months. 
b. Measurement routinely used to follow treatment but not mandatory in this trial 
c. Monitoring for toxicity is mandatory prior to each cycle; any intervening side effect will also be recorded before the 
next cycle 
d. After treatment, monitoring primarily for any non-hematologic persistent treatment-related adverse events for 30 
days after treatment discontinuation. 
e Basic metabolic panel with magnesium 


Version 10; October 09, 2017 
 
Page 40 of 44 
 
Appendix 2:  Treatment Schema 
 
 
 
 
 


Version 10; October 09, 2017 
 
Page 41 of 44 
 
Appendix 3:  Common NCI Toxicity Criteria 
 
Common NCI Toxicity Criteria:  CTCAE version 4  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 


Version 10; October 09, 2017 
 
Page 42 of 44 
 
Appendix 4:  FDA Medwatch 
 
FDA Medwatch 3500a Form 
 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM04 
8334.pdf 


Version 10; October 09, 2017 
 
Page 43 of 44 
 
Appendix 5:  NYHA Guidelines 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 10; October 09, 2017 
 
Page 44 of 44 
 
Appendix 6:  Dose Reduction Levels 
 
Dose Reduction Levels  
Initial Treatment Dose 
Dose Level -1 
Dose Level -2 
Abraxane 100mg/m2 IV D1, 8 
Abraxane 75mg/m2 IV D1, 8 
Abraxane 60mg/m2 IV D1, 8 
Carboplatin AUC 6 IV D1  
Carboplatin AUC 5 IV D1 
Carboplatin AUC 4 IV D1 
 
 
Dose Reduction Levels for Patients with Prior Whole Pelvic Radiation 
Initial Treatment Dose 
Dose Level -1 
Dose Level -2 
Abraxane 75mg/m2 IV D1, 8 
Abraxane 60mg/m2 IV D1, 8 
Abraxane 50mg/m2 IV D1, 8 
Carboplatin AUC 5 IV D1  
Carboplatin AUC 4 IV D1 
Carboplatin AUC 3 IV D1