Conditions: Advanced, Persistent, or Recurrent Endometrial Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 74
Healthy volunteers: no

Brief summary:
The main purpose of this study is to evaluate the effectiveness of the combination of the drugs Everolimus and Letrozole compared to Tamoxifen and Medroxyprogesterone acetate in treating endometrial cancer and to determine the types and severity of side effects caused by treatment with these drug combinations.

Detailed description:

Arms:
arm 1: Everolimus 10 mg daily and Letrozole 2.5 mg PO daily arm 2: Tamoxifen 20 mg PO BID; on alternating weeks (even numbered) weeks, Medroxyprogesterone Acetate 200 mg PO daily with Tamoxifen 20 mg PO BID

Interventions: intervention 1: Everolimus intervention 2: Tamoxifen intervention 3: Letrozole intervention 4: Medroxyprogesterone Acetate
Intervention descriptions: intervention 1: 10mg daily by mouth intervention 2: 20 mg daily by mouth on alternating weeks (even numbered) weeks intervention 3: 2.5mg once a day by mouth intervention 4: 200 mg daily by mouth

Protocol document:
Prot_SAP_000.pdf: 
Philip J. DiSaia, M.D. 
Group Chair 
 
Administrative Office 
Four Penn Center 
1600 John F. Kennedy Boulevard, Suite 1020 
Philadelphia, Pennsylvania 19103 
Phone: 215-854-0770 Fax: 215-854-0716 
 
Laura L. Reese 
Executive Director of Operations 
 
Larry J. Copeland, M.D. 
Group Vice Chair 
 
Finance/Development Office 
2127 Espey Court 
Suite 100 
Crofton, Maryland 21114 
Phone: 410-721-7126 Fax: 301-261-3972 
 
Mary C. Sharp 
Chief Financial Officer 
 
 
 
PROTOCOL GOG-3007 
(ClinicalTrials.gov NCT02228681) 
 
A RANDOMIZED PHASE II TRIAL OF EVEROLIMUS AND LETROZOLE OR HORMONAL THERAPY 
(TAMOXIFEN/MEDROXYPROGESTERONE ACETATE) IN WOMEN WITH ADVANCED, PERSISTENT, OR 
RECURRENT ENDOMETRIAL CARCINOMA 
SPONSOR: GOG FOUNDATION, INC. 
IND EXEMPT  
Version Date: June 25, 2015 
 
STUDY CHAIR 
 
NURSE CONTACT 
BRIAN M. SLOMOVITZ, M.D.                                        
NANCY FUSCO, CCRP 
 
SYLVESTER COMPREHENSIVE CANCER CTR  
UNIVERSITY HOSPITALS 
 
 
U MIAMI MILLER SCHOOL OF MED 
 
CASE MEDICAL CENTER 
1475 NW 12 AVE, SUITE 3500 
 
DEPT GYN/ONC 
MIAMI, FL  33136                                           
 
11100 EUCLID AVE 
(305) 243-2233 
 
CLEVELAND OH 44106 
 
 
216 844 1661 
 
FAX: (305) 243-4938 
 
FAX: 216-844- 8596 
E-MAIL: bxs255@med.miami.edu 
 
E-MAIL: nancy.fusco@uhhospitals.org 
 
 
 
 
STUDY CO-CHAIR 
 
 
 
 
ROBERT L. COLEMAN, M.D. 
 
 
 
 
 
 
 
 
See GOG Website directory 
 
TRANSLATIONAL RESEARCH CO-CHAIR 
 
PATHOLOGIST 
KAREN H. LU, M.D. 
 
 ELIZABETH D. EUSCHER, MD 
See GOG Website Directory 
 
See GOG Website Directory 
 
TRANSLATONAL RESEARCH SCIENTIST 
 
STATISTICIAN  
 
 
 
HEATHER A LANKES, PhD, MPH 
 
VIRGINIA FILIACI, PhD 
See GOG Website Directory 
 
See GOG Website Directory 
 
 
 
 
 
 
 
 
 
 
 
 
OPEN TO PATIENT ENTRY FEBRUARY 19, 2015 REVISED MARCH 10, 2015 REVISED JUNE 25, 2015, CLOSED 
TO PATIENT ENTRY APRIL 18, 2016 
 
 
 
 
 
 
 
This protocol was designed and developed by the GOG and Novartis. It is intended to be used only in conjunction with 
institution-specific IRB approval for study entry. No other use or reproduction is authorized by GOG nor does GOG 
assume any responsibility for unauthorized use of this protocol. 
SCHEMA (6/25/15) 
Arm 1:  Everolimus 10 mg daily and Letrozole 2.5 mg PO daily 
 
Arm 2:  Tamoxifen 20 mg PO BID (days 1-28); Medroxyprogesterone Acetate 200mg PO (once a day days 8-14 and 
22-28) 
 
Continue until disease progression or adverse events prohibit further therapy 
Cycle Length = 28 days 
 


 
 
 
 
 
GOG-3007 
PARTICIPATING INSTITUTIONS (03/10/2015, 6/25/15) 
 
601-01  
Abington Memorial Hospital 
602-01  
Barbara Ann Karmanos Cancer Institute 
603-01  
St. Dominic-Jackson Memorial Hospital 
604-01  
University of Colorado 
605-01  
Huntsman Cancer Institute 
606-01  
Johns Hopkins 
607-01  
UNC Chapel Hill 
608-01  
Magee Women's Hospital of UPMC 
609-01  
SUNY Downstate Medical Center 
610-01  
New Mexico Cancer Alliance 
611-01  
Women's Cancer Care Associates, LLC 
612-01  
St. Vincent Hospital and Health Care Center, Inc. 
 
614-01  
The Ohio State University Wexner Medical Center 
615-01  
University of Texas MD Anderson Cancer Center 
616-01  
University of Massachusetts Memorial Medical Center 
617-01  
Women's Cancer Center of Nevada 
618-01  
University of Oklahoma 
619-01  
Sylvester Comprehensive Cancer Center, University of Miami 
620-01  
University of Chicago 
621-01  
University Hospital Case Medical Center 
622-01  
Women & Infants Hospital of Rhode Island 
623-01  
Maine Medical Center 
624-01  
Memorial Health University Medical Center 
625-01  
John B. Amos Cancer Center 
626-01  
St. Joseph's Hospital & Medical Center 
629-01  
Metro MN CCOP 
630-01  
Sanford Medical Center – Sioux Falls 
631-01  
Shivers Cancer Center at University Medical Center Brackenridge 
632-01  
University of Mississippi Medical Center 
638-01  
The University of Pennsylvania 
639-01  
Memorial Center – Las Cruces 
640-01  
Southwest Gynecologic Oncology Associates 
 
 
 
 
 
 
 
 
 


 
 
 
 
TABLE OF CONTENTS 
   
 
PAGE 
 
 
 
1.0 
OBJECTIVES 
 
 
1 
 
2.0 
BACKGROUND AND RATIONALE  
 2 
 
3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS 
 9 
 
4.0 
STUDY MODALITIES 
 
 
14 
 
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 
19 
 
6.0 
TREATMENT MODIFICATIONS 
 
 22 
 
7.0 
STUDY PARAMETERS 
 
 
33 
 
8.0 
EVALUATION CRITERIA 
 
 
39 
 
9.0 
DURATION OF STUDY 
 
 
46 
 
10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
47 
 
11.0 
STATISTICAL CONSIDERATIONS  
 51 
 
12.0 
BIBLIOGRAPHY 
 
 
55 
 
 
 
 
SUGGESTED PATIENT INFORMATION/INFORMED CONSENT 
 
APPENDIX I – FIGO Surgical Staging  
 
APPENDIX II – General Chemotherapy Guidelines 
 
APPENDIX III – Patient Pill Calendar 
 
APPENDIX IV – Translational Research Specimen Procedures (03/10/2015)
APPENDIX V – CT scan Date Calculator 
 


 
GOG-3007 
 
 
-1- 
1.0 
OBJECTIVES  
 
1.1 
Objectives 
 
 
Primary Objectives: (6/25/15) 
1.1.1 
To determine the objective response rate of patients with advanced, persistent or 
recurrent endometrial cancer when treated with each of the arms of the trial. The 
proposed arms are: 
 
• 
Arm #1 everolimus 10 mg daily and Letrozole 2.5 mg PO daily 
 
• 
Arm #2 Tamoxifen 20 mg PO BID; on alternating weeks (even numbered) weeks, 
Medroxyprogesterone Acetate 200 mg PO once daily with Tamoxifen 20 mg PO 
BID 
 
Secondary Objectives: 
1.1.2   To estimate the time to disease progression for each arm  
 
1.1.3 
To describe the toxicities of each of the arms of the trial when used for patients with 
advanced/metastatic endometrial cancer. 
 
 
1.2 
Translational Research Objectives: 
 
1.2.1  To determine if relevant biomarkers correlate with response to treatment in each of the 
two arms. Three panels of biomarkers are proposed. 
• 
immunohistochemical expression of hormone receptors (estrogen 
receptor-alpha, estrogen receptor-beta, progesterone receptor-A, 
progesterone receptor B and the G protein-coupled estrogen receptor, 
GPR-30), 
• 
immunohistochemical evaluation of components of the mTOR pathway 
and related proteins, including phosphorylated  S6 ribosomal protein, 
PTEN, total and phosphorylated AKT, total and phosphorylated 
mTOR, and phospho-ERK1/2  
• 
mutational analysis including PTEN, PIK3CA, KRAS, and CTNNB1 
(beta-catenin) performed using a sequencing panel assay.  
   
 
 
 
   
 
 
 


 
GOG-3007 
 
 
-2- 
2.0 
BACKGROUND AND RATIONALE 
 
The identification of novel targets in malignant tumors has led to the development of inhibitors 
for the treatment of a wide range of cancers. The rationale for targeting dysregulated pathways 
has led to the development and testing of several targeted agents. The challenges of developing 
rational targets for therapeutic intervention in specific solid tumors remain an area of intense 
research. The current study will evaluate the impact targeting two dominant pathways, 
hormonal regulation and mTOR, has on endometrial cancer growth in women with recurrent 
and progressive disease. 
 
 
2.1 
Endometrial Cancer 
 
Endometrial cancer is the most common gynecologic malignancy in the United States with 
53,630 new cases and 8,590 deaths estimated for 2014 (Siegel, 2014). The standard treatment 
for primary endometrial cancer consists of a total hysterectomy with bilateral salpingo-
oophorectomy and possible lymph node dissection. This may be followed by radiation therapy 
depending on tumor factors and stage. Treatment failure in low-risk patients is rare. Tumor 
recurrence is most common in women with advanced-stage disease or those with high risk 
features. Women with isolated pelvic recurrences can potentially be salvaged with radiation 
therapy or surgery. However, in women with distant recurrent disease, treatment is largely 
systemic. 
 
 
2.2 
Treatment of Recurrent or Advanced Endometrial Cancer 
 
Several chemotherapeutic agents or combinations of agents have been studied in the treatment 
of women with advanced or recurrent endometrial cancer. Paclitaxel and carboplatin has been 
established as the usual initial chemotherapy for endometrial cancer (Miller, 2012).  Initial 
chemotherapy with paclitaxel and carboplatin is given either in the adjuvant or 
advanced/recurrent disease setting. 
 
In addition, some endometrial cancers are hormonally sensitive. Treatment of recurrent and 
progressive tumors with progestins and progestins in combination with tamoxifen (a selective 
estrogen receptor modulator) has been evaluated (Lentz, 1996; Thigpen, 1999; Whitney, 2004; 
Fiorica, 2004).  In GOG 81, medroxyprogesterone acetate at 200 mg daily resulted in an 
objective response rate of 25% (36/145 patients) (Thigpen, 1999).  Median duration of response 
was short (3.2 months).   In GOG 119, single arm phase II trial of medroxyprogesterone acetate 
plus tamoxifen (tamoxifen 20 mg BID with medroxyprogesterone acetate 100 mg BID given on 
alternating weeks) showed a 33% (19/58 patients) objective response rate (Whitney, 2004).  
Again, median progression free survival was short (3 months).  In a phase II study by the 
Gynecologic Oncology Group, an aromatase inhibitor (anastrozole) had limited activity as a 
single agent against recurrent and progressive endometrial cancer (Rose, 2000). In this study, of 
the 23 patients enrolled, two had partial responses (9%) and two had short-term stable disease. 
 
More effective systemic agents with longer durations of response are needed. Prognosis remains 
poor for patients who recur following first-line chemotherapy (generally paclitaxel/carboplatin) 
given in either the adjuvant or advanced/recurrent disease setting. 
 
 
 
2.3 
PTEN/AKT/mTOR Pathway 
 
 
 
PTEN, a tumor suppressor gene, has been shown to play several roles in tumor suppression, 
including cell cycle arrest and promotion of apoptosis. Inactivating mutations in PTEN occur 
frequently in many human cancers. In particular, mutations in PTEN are frequent in endometrial 
carcinomas (TCGA, 2013). 
 


 
GOG-3007 
 
 
-3- 
Tumor cells lacking PTEN contain high levels of activated AKT. This suggests that PTEN is 
necessary for the appropriate regulation of the phosphatidylinositol 3-kinase/AKT pathway. 
Recent studies have identified the AKT kinase as a potential mediator of tumorigenesis in 
endometrial cancer cell lines. The finding of PTEN mutations in the majority of endometrial 
cancer suggests that the loss of PTEN function may be one mechanism by which AKT activity 
is increased in this disease. Because PTEN-deficient cancer cells may have upregulated activity 
of the mammalian target of rapamycin (mTOR), which is downstream of AKT, these cells may 
be sensitive to mTOR inhibition.  
 
 
 
2.4 
Everolimus 
Everolimus is a novel derivative of rapamycin. It has been in clinical development since 1996 as 
an immunosuppressant in solid organ transplantation. Everolimus is approved in Europe and 
other global markets (trade name: Certican®) for cardiac and renal transplantation, and in the 
United States (trade name: Zortress®) for the prevention of organ rejection in kidney transplant 
patients. Afinitor® was approved for adults with advanced renal cell carcinoma (RCC) after 
failure of treatment with sunitinib or sorafenib in 2009. In 2010, Afinitor® received United 
States (US) approval for patients with subependymal giant cell astrocytoma (SEGA) associated 
with tuberous sclerosis complex (TSC). Everolimus is also available as Votubia® in the 
European Union (EU) for patients with SEGA associated with TSC who require therapeutic 
intervention but are not candidates for curative surgical resection. Afinitor® was approved for 
“progressive pancreatic neuroendocrine tumor (PNET) in patients with unresectable, locally 
advanced, or metastatic disease” in 2011 in various countries, including the US and Europe. In 
2012 Afinitor® received approval for the treatment of postmenopausal women with advanced 
hormone receptor-positive, HER2- negative breast cancer (advanced HR+ BC) in combination 
with exemestane, after failure of treatment with letrozole or anastrozole. Furthermore in 2012, 
Afinitor® received approval for the treatment of patients with TSC who have renal 
angiomyolipoma not requiring immediate surgery. 
 
Approximately 30,582 cancer patients have been treated with everolimus as of 30-Sep-2013 
• 
16,671 patients in Novartis-sponsored clinical trials 
• 
1,911 patients in the individual patient supply program 
• 
More than 12,000 patients in investigator-sponsored studies. 
• 
In addition, healthy volunteer subjects and non-oncology hepatically impaired subjects 
have participated in the clinical pharmacology studies. 
 
The following is a brief summary of the main characteristics of everolimus. More complete 
information can be obtained from the everolimus Investigator’s Brochure (IB).  
 
2.41 
Overview of Everolimus 
Everolimus is a derivative of rapamycin which acts as a signal transduction inhibitor. 
Everolimus selectively inhibits mTOR (mammalian target of rapamycin), specifically 
targeting the mTOR-raptor signal transduction complex. mTOR is a key serine-
threonine kinase in the PI3K/AKT signaling cascade, which is known to be 
dysregulated in a wide spectrum of human cancers (Boulay, 2007). 
Everolimus is being investigated as an anticancer agent based on its potential to act 
• 
Directly on the tumor cells by inhibiting tumor cell growth and proliferation; 
• 
Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via 
potent inhibition of tumor cell VEGF (vascular endothelial growth factor) 
production and VEGF-induced proliferation of endothelial cells). 
 
 
2.42 
mTOR pathway and cancer 


 
GOG-3007 
 
 
-4- 
At the cellular and molecular level, everolimus acts as a signal transduction inhibitor. It 
selectively inhibits mTOR (mammalian target of rapamycin), a key protein kinase 
which regulates cell growth, proliferation and survival. The mTOR kinase is mainly 
activated via the phosphatidylinositol 3-kinase (PI3-Kinase) pathway through 
AKT/PKB and the tuberous sclerosis complex (TSC1/2). Mutations in these 
components or in PTEN, a negative regulator of PI3-kinase, may result in their 
dysregulation. Abnormal functioning of various components of the signaling pathways 
contributes to the pathophysiology of numerous human cancers. Various preclinical 
models have confirmed the role of this pathway in tumor development (Cohen, 2005). 
The main known functions of mTOR include the following (Bjornsti, 2004): 
• 
mTOR functions as a sensor of mitogens, growth factors and energy and 
nutrient levels; 
• 
Facilitating cell-cycle progression from G1-S phase in appropriate growth 
conditions; 
• 
The PI3K/mTOR pathway itself is frequently dysregulated in many human 
cancers, and oncogenic transformation may sensitize tumor cells to mTOR 
inhibitors; 
• 
PI3-kinase mutations have been reported in the primary tumor in 10-20% of 
human colorectal cancers (Frattini 2005, Velho 2005); 
• 
The loss of PTEN protein, either through gene deletion or functional 
silencing (promoter hypermethylation), is reported in approximately 60% 
of primary human colorectal cancers (Goel, 2004); 
• 
The mTOR pathway is involved in the production of pro-angiogenic factors 
(i.e., VEGF) and inhibition of endothelial cell growth and proliferation; 
• 
Through inactivating eukaryotic initiation factor 4E binding proteins and 
activating the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates 
protein translation, including the HIF-1 proteins. Inhibition of mTOR is 
expected to lead to decreased expression of HIF-1. 
 
2.43   
Non-clinical experience 
Everolimus inhibits the proliferation of a range of human tumor cell lines in vitro 
including lines originating from lung, breast, prostate, colon, melanoma and 
glioblastoma. IC50s range from sub/low nM to µM. Everolimus also inhibits the 
proliferation of human umbilical vein endothelial cells (HUVECS) in vitro, with 
particular potency against VEGF-induced proliferation suggesting that everolimus may 
also act as an anti-angiogenic agent. The anti-angiogenic activity of everolimus was 
confirmed in vivo. Everolimus selectively inhibited VEGF-dependent angiogenic 
response at well tolerated doses. Mice with primary and metastatic tumors treated with 
Everolimus showed a significant reduction in blood vessel density when compared to 
controls. 
The potential of everolimus as an anti-cancer agent was shown in rodent models. 
Everolimus is orally bioavailable, residing longer in tumor tissue than in plasma in a 
subcutaneous mouse xenograft model, and demonstrating high tumor penetration in a 
rat pancreatic tumor model. The pharmacokinetic profile of everolimus indicates 
sufficient tumor penetration, above that needed to inhibit the proliferation of endothelial 
cells and tumor cell lines deemed sensitive to everolimus in vitro. 
Everolimus administered orally daily was a potent inhibitor of tumor growth, at well 
tolerated doses, in 11 different mouse xenograft models (including pancreatic, colon, 
epidermoid, lung and melanoma) and two syngeneic models (rat pancreatic, mouse 
orthotopic melanoma). These models included tumor lines considered sensitive and 


 
GOG-3007 
 
 
-5- 
“relatively resistant” in vitro. In general, everolimus was better tolerated in mouse 
xenograft models than standard cytotoxic agents (i.e., doxorubicin and 5-fluorouracil), 
while possessing similar anti-tumor activity. Additionally, activity in a VEGF-
impregnated subcutaneous implant model of angiogenesis and reduced vascularity 
(vessel density) of everolimus-treated tumors (murine melanoma) provided evidence of 
in vivo effects of angiogenesis. 
It is not clear which molecular determinants predict responsiveness of tumor cells to 
everolimus. Molecular analysis has revealed that relative sensitivity to everolimus in 
vitro correlates with the degree of phosphorylation (activation) of the AKT/PKB protein 
kinase and the S6 ribosomal protein; in some cases (i.e., glioblastoma) there is also a 
correlation with PTEN status. 
In vivo studies investigating the anti-tumor activity of everolimus in experimental 
animal tumor models showed that everolimus monotherapy typically reduced tumor cell 
growth rates rather than produced regressions. These effects occurred within the dose 
range of 2.5 mg to 10 mg/kg, orally once a day. 
In preclinical models, the administration of everolimus is associated with reduction of 
protein phosphorylation in target proteins downstream of mTOR, notably 
phosphorylated S6 ribosomal protein (p-S6rp) and p-4E-BP1, and occasionally with an 
increase in phosphorylated AKT, a protein upstream of mTOR signaling pathway. 
All significant adverse events observed in toxicology studies with everolimus in mice, 
rats, monkeys and mini-pigs were consistent with its anticipated pharmacological action 
as an anti-proliferative and immunosuppressant and at least in part reversible after a 2 
or 4-week recovery period with the exception of the changes in male reproductive 
organs, most notably testes. 
In vitro genotoxicity studies covering relevant genotoxicity end-points showed no 
evidence of clastogenic or mutagenic activity. 
In male fertility studies in rats, testicular morphology was affected at 0.5 mg/kg and 
above, and sperm motility, sperm head count and plasma testosterone levels were 
diminished at 5 mg/kg which corresponded to 0.7 times the estimated clinical exposure 
at 10 mg/day, and caused a decrease in male fertility. There was evidence of reversibility. 
Female fertility was not affected, but everolimus caused an increase of pre-implantation 
loss in female rats at doses > 0.1 mg/kg, suggesting it could also potentially impact 
fertility in females.  Everolimus crossed the placenta and was toxic to the conceptus. In 
rats, everolimus caused embryo/fetotoxicity at systemic exposure below the planned 
therapeutic level comprising mortality and reduced fetal weight. The incidence of skeletal 
variations and malformations at 0.3 and 0.9 mg/kg (e.g. sternal cleft) was increased. In 
rabbits, embryo toxicity was evident by an increase in late resorptions. Effects of 
everolimus on the pre- and postnatal development of rats were limited to slightly affected 
body weight and survival in the F1-generation at ≥0.1 mg/kg, and did not indicate a 
specific toxic potential.  
The potential reproductive risk for humans is unknown. However, due to the observed 
malformations in rats, everolimus should be considered potentially teratogenic. 
Everolimus should not be given to pregnant women unless the potential benefit outweighs 
the potential risk for the fetus. Women of childbearing potential should be advised to use 
highly effective contraception methods while they are receiving everolimus and up to 8 
weeks after treatment has been stopped. It is not known whether everolimus is excreted 
in human milk. In animal studies, everolimus and/or its metabolites were readily 
transferred into the milk of lactating rats. Therefore women who are taking everolimus 
should not breastfeed. 
Further details can be found in the everolimus Investigator’s Brochure. 


 
GOG-3007 
 
 
-6- 
 
 
2.5 
mTOR inhibition and endometrial cancer 
 
Recent molecular profiling has shown that increased PI3K/AKT/mTOR signaling is associated 
with aggressive disease and poor prognosis, irrespective of endometrial cancer histology.   
 
Clinically available mTOR inhibitors target either mTORC1 alone, or mTORC1/2. Others in 
development target multiple nodes of the PI3K pathway including PI3K.  mTORC1 inhibitor 
currently in clinical development include everolimus, temsirolimus and ridaforolimus.  
 
Recently, everolimus and temsirolimus showed antitumor activity in endometrial cancer cell 
lines, with greatest sensitivity in cells with PIK3CA and/or PTEN mutations. Furthermore, 
everolimus reduced progression of endometrial hyperplasia in a PTEN heterozygous mouse 
model, and repressed tumor growth in mouse xenograft models harboring endometrial cancer 
cells with loss of PTEN and/or PIK3CA mutations. Consistent with these findings, 
ridaforolimus also showed antitumor activity in endometrial cancer cells and a mouse xenograft 
model, with greatest sensitivity observed in cells with loss of PTEN or increased 
phosphorylated or total AKT.  
 
In patients with recurrent and/or metastatic endometrial cancer, single-agent treatment with 
everolimus, temsirolimus, and ridaforolimus has led to clinical benefit rates of 21%, 52% to 
83%, and 33% to 66%, respectively (Slomovitz, 2010; Oza, 2011; Colombo, 2013). For both 
temsirolimus and ridaforolimus, the best responses were seen in patients with no prior 
chemotherapy. Furthermore, ridaforolimus was also shown to significantly improve 
progression-free survival (PFS) in patients with no further approved treatment options. 
Common adverse events in these studies included fatigue, nausea, mucositis, diarrhea, and rash. 
Hypertriglyceridemia was also reported in 2 studies, and pneumonitis was common in 1 study 
(37%). In addition, hyperglycemia, a possible “on target” effect of PI3K/AKT/mTOR pathway 
inhibition, was observed in 2 studies (27% and 19%, respectively). 
 
2.6 
Hormonal Therapy and endometrial cancer 
The Gynecologic Oncology Group (GOG) has a long history of studying hormonal therapy in 
women with advanced/recurrent endometrial carcinoma.  Although such regimens are generally 
well tolerated, and may produce responses of long duration in selected patients, the overall 
response rates and progression free survival (PFS) have been disappointing.  Among the more 
active hormonal regimens tested by the GOG has been  the sequential use of Megestrol Acetate 
(MA) at 80 mg bid for 3 weeks alternating with Tamoxifen (T) 20 mg bid for 3 weeks (Fiorica, 
2004).  This regimen produced a response rate of 27% in 56 eligible women with no prior 
chemotherapy or hormonal therapy.  Median PFS was 2.7 months and median overall survival 
was 14.0 months. This trial was closed to patient entry in November 1995. Another study 
(GOG-0119), evaluated the efficacy of tamoxifen citrate plus intermittent administration of 
medroxyprogesterone acetate in patients with recurrent or metastatic endometrial carcinoma 
(Whitney, 2004).  This regimen produced a response rate of 33% in 58 eligible patients with no 
prior chemotherapy or hormonal therapy. Median PFS was 3 months and the median overall 
survival as 13.0 months. This study will evaluate this hormonal therapy in a contemporary 
cohort including patients who have received prior adjuvant chemotherapy. 
 
 
 
2.7 
Rationale for the combination of hormones and everolimus 
 
Given the importance of ER signaling in type I endometrial cancer, and the cross-regulation 
between the ER and PI3K/AKT/mTOR pathways, combining agents that disrupt ER signaling 


 
GOG-3007 
 
 
-7- 
with PI3K/AKT/mTOR pathway inhibitors may also result in synergistic antitumor responses. 
The combination of everolimus with the aromatase inhibitor exemestane significantly improved 
PFS in patients with aromatase inhibitor-refractory breast cancer, thus demonstrating proof-of-
concept that PI3K/AKT/mTOR pathway inhibitors may reverse resistance to aromatase 
inhibitors. 
 
The GOG-0248 evaluated the combination of temsirolimus and megestrol acetate compared to 
temsirolimus alone (Fleming, 2014). In this study, the temsirolimus/hormonal arm was closed 
secondary to a high rate of thromboembolic events.  
 
In patients with advanced breast cancer, the combination of everolimus 10 mg/day and letrozole 
2.5 mg/day was tolerable.  Efficacy data in patients with advanced breast cancer have 
demonstrated some activity in some patients that do not respond to letrozole alone.  
 
Our group recently completed a single arm phase II activity trial of everolimus in combination 
with letrozole for patients with recurrent endometrial cancer (Slomovitz, 2011). Of the 35 
evaluable patients, the response rate was 31% (11/35). There were 8 patients who achieved a 
complete remission and 3 patients with a partial remission. 
 
The safety profile of everolimus was acceptable in the context of heavily pretreated patients 
with endometrial cancer. Compared to a previous phase 2 single agent everolimus trial showing 
no objective responses, the addition of letrozole likely blocks the bypass of PI3K/AKT/mTOR 
pathway and thus resulted in better treatment response. 
 
2.8 
Translational Research 
The translational research component for this study will be performed in collaboration with the 
MD Anderson Uterine Cancer SPORE. This group has been studying biomarkers to predict 
responsiveness to mTOR inhibitors alone and in combination with aromatase inhibitors. These 
biomarker studies have developed from two SPORE-sponsored completed clinical trials: the 
first was a single agent everolimus study (Slomovitz, 2010) and the second was a dual 
everolimus and letrozole study (Slomovitz, 2011). 
 
Biomarkers to predict responsiveness to mTOR inhibitors have been examined in a number of 
different cancers, including renal cell carcinoma, neuroendocrine cancers, sarcoma, 
glioblastoma and endometrial cancer. To date, no single biomarker predictive of response to an 
mTOR inhibitor has been identified and validated. In a Phase II study of temsirolimus in renal 
cell carcinoma, high phospho-S6rp levels were correlated to response, with phospho-AKT 
levels demonstrating a trend toward positive response. In endometrial cancer, neither we, nor 
the Canadian NCIC group found an obvious correlation between PTEN status, phospho-AKT, 
phospho-S6rp or phospho-mTOR levels and response to temsirolimus or everolimus (Oza, 
2011).  Although our numbers were small, our study showed that the combination of high 
phospho-S6rp levels with an activating KRAS mutation was predictive of non-response to these 
agents in endometrial tumors. Therefore, identifying biomarkers that predict non-response to 
mTOR inhibitors may be a more clinically achievable goal, and will contribute to the 
development of personalized treatment regimens for endometrial cancer. 
 
With the positive report of BOLERO 2 demonstrating the efficacy of the combination of 
everolimus with the aromatase inhibitor exemestane in metastatic breast cancer (BOLERO 2 
study; Baselga 2012), there is increasing clinical and pre-clinical evidence of the close 
interaction between the PI3K/AKT/mTOR pathway and ER ligand-independent signaling. More 
specifically, studies have demonstrated that S6 kinase is involved in phosphorylation of 
estrogen receptor for ligand-independent receptor activation (phospho-ERalpha-S167 and 
phospho-ERalpha-S118) (Yamnik, 2010; Yamnik, 2009, de Leeuw, 2011).  With the 


 
GOG-3007 
 
 
-8- 
availability of phosphorylation site specific antibodies, we are currently evaluating these 
markers in pre-and post-treatment samples.   
 
i)  Tissue Analysis 
For the GOG trial, biomarkers will be performed from formalin-fixed paraffin embedded 
samples.   Three panels of biomarkers are proposed.  
- 
First, immunohistochemical expression of hormone receptors (estrogen receptor-alpha, 
phospho-ERalpha-S167, phospho-ERalpha-S118, estrogen receptor-beta, progesterone 
receptor-A, progesterone receptor B and the G protein-coupled estrogen receptor, GPR-30) 
will be quantified.  
- 
Second, immunohistochemical evaluation of components of the mTOR-signaling pathway 
and related proteins, including phospho- S6rp, PTEN, total and phospho-AKT, and 
phospho-ERK1/2 will be performed.  
- 
Third, mutational analysis including PTEN, PIK3CA, KRAS, and CTNNB1 will be 
performed. Mutations in PIK3CA have been demonstrated to be a marker for response to 
everolimus and letrozole. Mutations in KRAS have been implicated in non-response to 
everolimus.  Using endometrial cancer TCGA data, we have recently identified beta-catenin 
(CTNNB1) as a predictor of poor outcome for patients with endometrioid endometrial 
cancer (unpublished data).   Hotspot mutations for these genes will be analyzed using a 
CLIA-certified next-generation sequencing panel including 42 additional cancer-related 
genes (Singh, 2013).  This assay has been validated for use with FFPE samples.  In 
addition, because of the low somatic mutation rate of KRAS we observed in previous phase 
II trials, it is possible that rather than the KRAS mutation, the KRAS expression level may 
play a role in response to everolimus. Quantitive PCR analysis of mRNA extracted from 
patient tissue will be used an alternative method to study KRAS as a biomarker. 
 
ii) Blood collection 
We plan to collect pre-treatment blood from patients enrolled in this study. DNA extracted from 
peripheral blood mononuclear cells (PBMC) can be used as control to identify somatic 
mutations in tumor tissue samples. Approximately 10ml of blood should be collected at the time 
of study entry.   
 
2.9 
Inclusion of Women and Minorities 
 
The GOG Partners institutions will not exclude potential subjects from participating in this or 
any study solely on the basis of ethnic origin or socioeconomic status.  Every attempt will be 
made to enter all eligible patients into this protocol and therefore address the study objectives in 
a patient population representative of the entire endometrial cancer population treated by 
participating institutions. 
 
 


 
GOG-3007 
 
 
-9- 
3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS  
 
3.1 
Eligible Patients  
 
3.11 
Patients must have histologically confirmed advanced (FIGO Stage III or IV), 
persistent, or recurrent endometrial carcinoma, which is not likely to be curable by 
surgery or radiotherapy. Histologic documentation of the recurrence is not required.  
 
3.12 
All patients must have measurable disease. Measurable disease is defined by RECIST 
version 1.1). Measurable disease is defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded). Each lesion must 
be greater than or equal to 10 mm when measured by CT, MRI or caliper measurement 
by clinical exam; or greater than or equal to 20 mm when measured by chest x-ray. 
Lymph nodes must be greater than or equal to 15 mm in short axis when measured by 
CT or MRI (See section 8). 
 
Patients must have at least one “target lesion” to be used to assess response on this 
protocol as defined by RECIST 1.1 (Section 8.1). Tumors within a previously irradiated 
field will be designated as “non-target” lesions unless progression is documented or a 
biopsy is obtained to confirm persistence at least 90 days following completion of 
radiation therapy. 
. 
3.13 
Prior chemoradiotherapy for a pelvic recurrence is permitted.  Prior chemotherapy in 
the adjuvant setting for Stage I, II or III disease is permitted. 
 
 
Note:  No prior chemotherapy in the setting of Stage IV disease is permitted unless the 
patient was without evidence of disease at the completion of chemotherapy and had at 
least six months of progression-free survival since the completion of chemotherapy. 
 
 
 
Regardless of circumstances, no more than one prior chemotherapy regimen (including 
chemo-radiotherapy) is permitted.   
 
3.14 
Patient must be able to take p.o. medications. 
 
3.15 
Performance status must be 0-1. 
 
 
 
3.16 
Patients must have adequate organ and marrow function as defined below: 
NOTE: Institutional/laboratory upper limit of normal = ULN  
 
Institutional/laboratory lower limit of normal = LLN  
 
3.161 Bone marrow function:  
• 
Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl 
• 
Platelets greater than or equal to 100,000 cells/mcl 
• 
Hemoglobin greater than or equal to 9 g/dL 
 
 
3.162 Renal function:   
• 
Creatinine less than or equal to 1.5 x ULN 
 
3.163 Hepatic function:  
• 
Bilirubin less than or equal to 1.5 x ULN 
• 
ALT and AST less than or equal to 3 x ULN 
• 
Alkaline phosphatase less than or equal to 2.5 x ULN 


 
GOG-3007 
 
 
-10-
• 
Albumin greater than or equal to 2.8 g/dL 
 
3.164 Lipid panel:  
• 
Fasting serum cholesterol less than or equal to 300 mg/dL 
• 
Fasting triglycerides less than or equal to 300 mg/dL 
 
3.17 
At least 4 weeks must have elapsed since the patient underwent any major surgery (e.g., 
major: hysterectomy, resection of a lung nodule; minor: central venous access catheter 
placement). 
 
3.18 
At least 4 weeks must have elapsed since the patient received any radiation therapy. 
 
3.19 
Patients who have met the pre-entry requirements specified in Section 7.0. 
 
3.20 
Patients must have signed an approved informed consent and authorization permitting 
release of personal health information. 
 
3.21  
All patients must be at least 18 years of age 
 
3.22 
Patients of childbearing potential must have a negative serum pregnancy test prior to 
the study entry and be practicing a highly effective form of contraception. 
 
 
 
During the study treatment and for 8 weeks after stopping the treatment.  Highly 
effective contraception methods include combination of any two of the following: 
a. Use of oral, injected or implanted hormonal methods of contraception or; 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
c. Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository; 
d. Total abstinence or; 
e. Male/female sterilization. 
Women are considered post-menopausal and not of child-bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at 
least six weeks prior to randomization. In the case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment is she considered not of child-bearing potential. 
 
3.2 
Ineligible Patients  
 
3.21 
Patients who have previously received everolimus, any another mTOR inhibitor or any 
agent targeting the PI3K/AKT/mTOR pathway.  
 
3.22 
Known intolerance or hypersensitivity to Everolimus or other rapamycin analogs (e.g. 
sirolimus, temsirolimus) 
 
3.23 
Patients who have previously received hormonal therapy for endometrial cancer. 
 
3.24 
Patients with concomitant invasive malignancy or a history of other invasive 
malignancies, with the exception of non-melanoma skin cancer, are excluded if there is 
any evidence of other malignancy being present within the past five years.  Patients are 
also excluded if their previous cancer treatment contraindicates this protocol. 
 


 
GOG-3007 
 
 
-11-
 
3.25 
Patients receiving chronic treatment with systemic steroids or another 
immunosuppressive agent. 
 
  
 
3.26 
Patients with active or uncontrolled systemic infection.  
 
3.27 
Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. 
 
 
Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) 
 
 
may be included, however blood glucose and anti-diabetic treatment must be monitored 
 
 
closely throughout the trial and adjusted as necessary. 
 
3.28 
Known severely impaired lung function, including: 
• 
CTCAE grade 2 (or greater) hypoxia (decreased oxygen saturation with exercise 
[e.g., pulse oximeter <88%]; intermittent supplemental oxygen)  
 
3.29 
Patients with a known history of cardiac disease.  This includes: 
3.291 Uncontrolled hypertension, defined as systolic greater than 150  
mm Hg or diastolic greater than 90 mm Hg despite antihypertensive 
medications. 
 
3.292 Myocardial infarction or unstable angina within 6 months prior to registration. 
 
3.293 New York Heart Association (NYHA) Class II or greater congestive heart 
failure. 
 
3.294 History of serious ventricular arrhythmia (i.e., ventricular tachycardia or 
ventricular fibrillation) or serious cardiac arrhythmia requiring medication. This 
does not include asymptomatic atrial fibrillation with controlled ventricular 
rate. 
 
3.295 Cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) within 
6 months prior to the first date of study therapy. 
 
3.210 
Patients who are pregnant or breast-feeding. 
 
3.211 
Patients with known central nervous system metastases. 
 
 
 
 
3.212 Patients with known human immunodeficiency virus (HIV) infection. 
 
3.213 Patients with an impairment of gastrointestinal function or gastrointestinal disease that 
may significantly alter the absorption of everolimus (e.g., ulcerative disease; 
uncontrolled nausea, vomiting and/or diarrhea; malabsorption syndrome; clinical signs 
and symptoms of gastrointestinal obstruction; and/or patients who require parenteral 
hydration and/or nutrition). 
 
3.214 Patients who plan to receive live attenuated vaccines within 1 week of start of 
everolimus and during the study. Patient should also avoid close contact with others 
who have received live attenuated vaccines. Examples of live attenuated vaccines 
include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, 
varicella and TY21a typhoid vaccines. 
 
3.215    Patients with active bleeding or pathologic conditions that carry high risk of bleeding, 
such as known bleeding disorder or coagulopathy. 


 
GOG-3007 
 
 
-12-
 
3.216 Patients with history of unprovoked venous thrombosis unless taking anticoagulation 
treatment for duration of trial. 
 
3.217 Patients who are currently part of or have participated in any clinical investigation with 
an investigational drug within 30 days prior to dosing. 
 
3.218 Patients must be able to follow concomitant medication restrictions: 
• 
Avoid the use of strong CYP3A/PgP inhibitors (e.g., ketoconazole, itraconazole, 
clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, 
indinavir, nelfinavir, voriconazole). 
• 
Use caution when co-administered with moderate CYP3A4/PgP inhibitors (e.g., 
amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, 
diltiazem). 
• 
Grapefruit, grapefruit juice, and other foods known to inhibit cytochrome P450 and 
PgP activity may increase everolimus exposures and should be avoided during 
treatment. 
• 
Avoid the use of concomitant strong CYP3A4/PgP inducers (e.g., phenytoin, 
carbamazepine, rifampin, rifabutin, rifapentine, and phenobarbital). 
• 
St. John’s Wort may decrease everolimus exposure unpredictably and should be 
avoided. 
 
3.219 Patients with active hepatitis B or C. 
Screening for hepatitis B 
Prior to randomization/start of everolimus, the following three categories of patients 
should be tested for hepatitis B viral load and serologic markers, that is, HBsAg, HBcAb, 
HBsAb and quantitative hepatitis B DNA PCR (HBV-DNA):   
• 
All patients who currently live in (or have lived in) Asia, Africa, Central and South 
America, Eastern Europe, Spain, Portugal and Greece. 
[http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-
related-to-travel/hepatitis-b.htm] 
• 
Patients with any of the following risk factors: 
• 
known or suspected past hepatitis B infection, 
• 
blood transfusion(s) prior to 1990, 
• 
current or prior IV drug users, 
• 
current or prior dialysis, 
• 
household contact with hepatitis B infected patient(s), 
• 
current or prior high-risk sexual activity, 
• 
body piercing or tattoos, 
• 
mother known to have hepatitis B 
• 
history suggestive of hepatitis B infection, e.g., dark urine, jaundice, right 
upper quadrant pain. 
• 
Additional patients at the discretion of the investigator 
The management guidelines, in Section 6, are provided according to the results of the 
baseline assessment of viral load and serological markers for hepatitis B. 


 
GOG-3007 
 
 
-13-
Screening for hepatitis C 
Patients with any of the following risk factors for hepatitis C should be tested using 
quantitative RNA-PCR: 
• 
known or suspected past hepatitis C infection (including patients with past 
interferon ‘curative’ treatment), 
• 
blood transfusions prior to 1990, 
• 
current or prior IV drug users, 
• 
current or prior dialysis, 
• 
household contact of hepatitis C infected patient(s), 
• 
current or prior high-risk sexual activity, 
• 
body piercing or tattoos. 
At the discretion of the investigator, additional patients may also be tested for hepatitis 
C. 
The management guidelines, in Section 6 are provided according to the results of the 
baseline assessment of hepatitis C viral load. 
 
 


 
GOG-3007 
 
 
-14-
4.0 
STUDY MODALITIES   
 
4.1  
Medroxyprogesterone Acetate (Provera®) (06/25/15) 
 
 
 
 
 
4.1.1 
Formulation: Tablets of 10 mg medroxyprogesterone acetate  
 
 
 
 
 
 
4.1.2 
Storage: Room temperature protected from heat and light. 
 
4.1.3 
Adverse Effects: Weight gain, thromboembolic phenomena, nausea and vomiting, 
edema, break through bleeding, dyspnea, tumor flare, hyperglycemia, carpal tunnel 
syndrome, and rash. 
 
4.1.4 
Supplier: Commercially available.  See package insert for further information. 
 
 
4.2  
Tamoxifen Citrate (Nolvadex®) 
 
4.21  
Formulation: Tablets of 10 and 20 mg of tamoxifen. 
 
4.22  
Storage: Room temperature protected from heat and light. 
 
4.23  
Adverse Effects: Transient thrombocytopenia and leukopenia, menopause-like reactions 
(hot flushes, nausea), skin rashes/changes, pruritus vulvae, dizziness, headaches, 
depression, lassitude, muscle pain, fluid retention, anorexia, menstrual irregularities, 
vaginal bleeding, vaginal discharge, food distaste and thromboembolic events. Of note 
also is a report of a few cases of severe retinopathy associated with decreased visual 
acuity in patients on high doses (>200 mg/day) for prolonged periods over a year. Dose 
modifications or cessation of drug because of adverse effects are seldom necessary. See 
package insert for complete list of adverse effects. 
 
4.24  
Supplier: Commercially available. See package insert for further information. 
 
4.3 
Everolimus (Afinitor®) (6/25/15) 
 
4.31 
Other Names:  RAD001  
 
4.32 
Description: Everolimus is a novel oral derivative of rapamycin. 
 
4.33 
Investigator Brochure (IB): All participating institutions must obtain an IB. Each site 
must have an executed CDA (Confidential Disclosure Agreement) or CTSA (Clinical 
Trial Site Agreement) before the IB can be distributed.  Upon execution of a CDA or 
CTSA, an IB may be requested.   
 
 
 
Please submit a request to GOG3007ib@gog.org and include: 
• 
Institution Name 
• 
Institution Number 
• 
Institution Principal Investigator 
 
4.34 
Supplier: Everolimus will be supplied by Novartis. 
 
4.35 
How Supplied: Everolimus is formulated as tablets for oral administration.  For 
everolimus, each patient is started with 10 mg tablets. Patients who require dose de-
escalation will be given 5mg and 2.5mg tablets as needed.  Tablets are blister- packed 


 
GOG-3007 
 
 
-15-
under aluminum foil in units of 7 tablets, which should be opened only at the time of 
administration as drug is both hygroscopic and light-sensitive. Refer to label for 
expiration date and storage conditions.  
 
The extent of absorption of everolimus through topical exposure is not known.  
Therefore, caregivers are advised to avoid contact with suspensions of Afinitor Tablets.  
Wash hands thoroughly before and after preparation of either suspension. 
 
Medication labels will comply with US legal requirements and will be printed in 
English. They will supply no information about the patient. The storage conditions for 
study drug will be described on the medication label. 
 
4.36 
Stability/Storage: Everolimus must be stored below 30◦ C in the original double-side 
aluminum blister packaging and protected from light and moisture. The expiration date 
of the supply will be provided with the drug shipment. 
 
4.37 
Drug Distribution: Everolimus will be supplied by Novartis Pharmaceuticals and 
distributed by Fisher Clinical Services. 
 
Novartis must do an initial regulatory review before an initial shipment of everolimus 
can be shipped to the institution. The GOG Regulatory Department will e-mail the 
institution-specific 1572, IRB approval, informed consent form (ICF – must match the 
draft that was reviewed by Novartis prior to IRB submission (see Section 5.0)), PI CV, 
PI medical license and Pharmacy Information Form to Novartis for review. Please be 
sure to include the pharmacy shipping address in box 3 of the 1572.  Novartis will do a 
review for accuracy and completeness.   Please allow 10-14 days for this review 
process before screening your first patient. 
 
For all subsequent shipments, Novartis will ensure that the institutions’ regulatory 
documents are not expired.  If any documents are expired, updated documents must be 
submitted to GOG and Novartis prior to drug shipment.  Please allow 5 days for this 
review when requesting a subsequent shipment of drug. 
 
4.371 Initial Supply (02/19/2015) 
To request an initial supply of everolimus, please complete the “Everolimus-
RAD001 Drug Order Form” and email to: john.sabo@novartis.com 
 
Novartis requires a 10-day window for initial drug delivery to the 
institution.  
 
Novartis will notify Fisher Clinical Services of when to ship drug. Drug is only 
shipped Monday through Thursday and any orders received on Fridays will be 
shipped on Monday. Fisher Clinical Services does not deliver during major 
holidays.   
  
4.372  Subsequent Supply Requests (02/19/2015) 
To receive subsequent drug, please complete the “Everolimus-RAD001 Drug 
Order Form” and email to: john.sabo@novartis.com 
  
Novartis requires a 5-day window for subsequent drug delivery to the 
institution.  
 
Novartis will notify Fisher Clinical Services of when to ship drug. Drug is only 
shipped Monday through Thursday and any orders received on Fridays will be 


 
GOG-3007 
 
 
-16-
shipped on Monday. Fisher Clinical Services does not deliver during major 
holidays.   
 
4.38 
Drug Accountability: All study drug supplies must be kept in a locked room with 
limited access. The study drug must not be used outside the context of this protocol. 
Under no circumstances should the investigator or other site personnel supply study 
drug to other investigators, patients, or clinic, or allow supplies to be used other than 
directed by this protocol without prior authorization from Novartis. 
 
The pharmacist will maintain a complete drug accountability record on the GOG 
Investigational Agent Drug Accountability Record Form (on GOG-3007 web site) for 
each capsule strength with lot numbers of each drug received, including the number of 
bottles dispensed to each patient, the date’s drug was dispensed, and the daily dose of 
everolimus or placebo the patient received. The prescribed dose should also be recorded 
in the patient’s medical records. 
 
4.39 
Drug Disposition: All used, unused or expired drug should be destroyed according to 
the institution’s standard operating procedures, and their disposition should be recorded 
on a GOG Investigational Agent Drug Accountability Record Form. 
 
4.40 
Adverse Effects: Adverse events most frequently observed with everolimus are rash, 
stomatitis/oral mucositis, fatigue, headache, anorexia, nausea, vomiting, and diarrhea. 
Infections have not been notably frequent or severe. Non-infectious pneumonitis has 
also been observed. The majority of these AEs have been of mild to moderate severity 
(CTC grade 1-2). Overall, the most frequently observed laboratory abnormalities 
include reduced blood counts, hyperlipidemia mostly reported as hypercholesterolemia 
and/or hypertriglyceridemia. 
 
Stomatitis (grade 3) was the principal DLT in Phase 1 trials. 
 
Hyperlipidemia was reported as a serious adverse reaction. It is a recognized side-effect 
of rapamycins. Use of lipid-lowering drugs should be associated with dietary 
recommendations. Monitoring of blood lipid levels requires patients to be fasting so 
that this aspect must be verified when interpreting results. 
Hyperglycemia was reported as a serious adverse reaction. Similarly, the fasting state of 
patients should be verified when interpreting results. 
 
Pneumonitis is a recognized adverse effect of rapamycins (sirolimus, temsirolimus, and 
everolimus). Numerous case reports in the literature suggest that rapamycin-associated 
pneumonitis is relatively unaggressive, limited in extent, and reversible upon drug 
discontinuation. The term ‘pneumonitis’ is used here to describe non-infectious, non-
malignant infiltration in the lungs which is evident radiologically. More precise 
diagnosis should follow histocytological examination following lung biopsy, generally 
during bronchoscopy which may or may not be symptomatic. 
 
In oncology studies with everolimus, severe pneumonitis suspected as drug- related has 
been reported as a serious adverse event on 13 occasions and additionally in the 
following associated preferred terms including acute respiratory distress syndrome 
(n=2), alveolitis (n=1) and allergic alveolitis (n=1), interstitial lung disease (n=10), lung 
infiltration (n=23), cryptogenic organizing pneumonia, lung consolidation, pulmonary 
alveoloar hemorrhage, pulmonary toxicity and pulmonary fibrosis (n=1, each). One 
fatal case of drug- related pneumonitis was reported for a patient with metastatic 
infiltrating ductal carcinoma of the breast treated with 10 mg/day, which developed 
approximately two months after starting everolimus. Cytology for both the pleural and 


 
GOG-3007 
 
 
-17-
pericardial fluids were positive for malignancy. The death was considered possibly 
related to the underlying late stage tumor and study drug. Additionally, one patient 
treated with 10 mg/day died due to severe acute respiratory distress syndrome and 
septic shock. Thoracic CT scan demonstrated condensation in the majority of the left 
lower lobe and frosted glass appearance in the left upper lobe, lingula, and right lung. 
 
Serious opportunistic infections have also been reported in cancer patients treated with 
RAD001: mycobacterium, Aspergillus, and fatal candidal sepsis, and fatal 
pneumocystis carinii in particular. Because everolimus, as other rapamycins, inhibits 
proliferation of activated lymphocytes and reduces neutrophil counts, treatment with 
everolimus must be considered as predisposing patients to the risk of infection. This 
risk will be higher in patients severely immunocompromised because of their 
underlying disease and/or co- medications. Outcome may be fatal in case of serious 
infections. 
 
Cytopenias. A reduction in blood cell counts is frequent when everolimus therapy is 
initiated. Without clinical significance and infrequently, anemia and thrombocytopenia 
have been reported. In heavily pretreated patients with aggressive lymphoma, the 
incidence of grade 3 anemia, neutropenia, and thrombocytopenia was reported to be 
11%, 16%, and 30%, respectively. Serious, suspected drug-related hemorrhages have 
been exceptional. Nevertheless, everolimus should be considered as predisposing 
patients to hemorrhage, potentially fatal, should they develop severe drug-related 
thrombocytopenia. 
 
Liver Transaminase Elevation. Discrete, reversible changes in liver enzymes have been 
found to occur in numerous patients during treatment with everolimus in oncology 
clinical studies, and in a study in rheumatoid arthritis. In oncology studies, these 
changes may be evident only in patients without severe underlying morbidity. The 
increase in transaminases (AST and ALT) generally appears after four weeks of 
treatment. In all but a few cases it does not exceed Grade 1 (≤ 2.5 x ULN). Similarly, 
mild increases in alkaline phosphatases can coexist. Spontaneous corrections or 
intermittent correction with continued treatment can occur. Serum bilirubin is not 
increased. In studies of patients with advanced cancers, clinically relevant changes in 
liver enzymes have been invariably associated with the presence of liver metastases 
and/or progression of the underlying cancer. Fatal reactivation of hepatitis B and C have 
been reported. 
 
Renal failure has been reported in five suspected cases to date. One patient with no 
alternative explanation made a complete recovery following study drug adjustment and 
no treatment/therapy for the event. The rest of the patients had concurrent morbidities, 
which might have contributed to the reported events. 
 
Electrolyte Abnormalities. Hypophosphatemia, hypomagnesemia, hyponatremia and 
hypocalcemia have been reported as serious adverse reactions. Electrolytes should be 
monitored in patients treated with everolimus. 
 
Consult the package insert for the most current and complete information. 
 
 
Please reference the everolimus Investigator Brochures for complete information 
regarding adverse effects for everolimus. 
 
4.4    
Letrozole (Femara®) 
 
4.41  
Description: Letrozole is a highly potent, orally active non-steroidal competitive 
inhibitor of the aromatase enzyme system.   


 
GOG-3007 
 
 
-18-
 
4.42 
Formulation: Tablets of 2.5 mg of letrozole 
 
4.43  
Storage: Room temperature protected from heat and light. 
 
4.44  
Adverse Effects: The most common side effects are sweating, hot flashes, arthralgia 
(joint pain), and fatigue. Generally, side effects include signs and symptoms of 
hypoestrogenism. Dose modifications or cessation of drug because of adverse effects 
are seldom necessary. See package insert for complete list of adverse effects. 
 
4.45  
Supplier: Commercially available. See package insert for further information. 
  
4.5 
Pathology Requirements 
 
 
4.51 
Eligible disease characteristics: Patients must have histologically confirmed, advanced 
(FIGO stage III or IV), persistent, or recurrent endometrial carcinoma. All histologic 
cell types and grades of endometrial carcinoma of the uterine corpus are allowed. 
 
4.52 
Ineligible disease characteristics: Patients with a sarcoma, carcinosarcoma (MMMT), or 
leiomyosarcoma of the uterine corpus are not eligible. 
 
4.53 
Requirements:  Pathology report for histologic confirmation of primary tumor.  
Pathology report for histologic confirmation of recurrent or persistent disease is not 
required for this protocol.  Stained slides to confirm eligibility by Central Pathology 
Committee Review are not required for this protocol. 
 
4.54 
See Section 7.2 and Appendix IV for information and instructions regarding the 
specimen requirements for Translational Research.  
 
 


 
GOG-3007 
 
 
-19-
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE     
 
Before a patient can be screened and enrolled, each institution must have an executed CTSA and 
approval of the required regulatory documents.   
To obtain regulatory approval, please submit the following regulatory documents to the GOG 
Administrative Office via e-mail to GOG3007Regulatory@gog.org.  
Sites must submit the draft informed consent (initial and amendments) for review by GOG and 
Novartis prior to IRB submission.   
• 
IRB approval* 
• 
IRB-approved informed consent 
• 
IRB approved site-specific HIPAA consent 
• 
IRB Membership list or FWA assurance letter 
• 
Study-specific signed FDA Form 1572 for institution PI**  
• 
Current CV (signed and dated within two-years) for institution PI  
• 
Medical license for institution PI  
• 
Signed GOG Investigator Signature Page for PI** 
• 
Signed GOG Financial Disclosure Form for all investigators listed on FDA Form 1572** 
• 
Pharmacy Information Form** 
Please allow 10-14 days for processing of regulatory documents before screening the first patient. 
All copies of the above should be filed into a study-specific regulatory binder at your institution. 
*All initial, continuing and amendment reviews must be sent to the GOG Administrative Office. 
** Please see GOG-3007 protocol documentation page to download forms by clicking on the 
“Regulatory Forms” link. 
The GOG Administrative Office will forward these documents to Novartis for review and approval. 
Novartis will notify the GOG Administrative Office when the documents have been approved (see 
Section 4.37).  
When an institution has an executed CTSA and has received regulatory approval, an institution will be 
notified, via e-mail, from GOG, that patients may be screened and enrollment can begin.   
5.1 Patient Entry and Registration  
This trial is open to U.S. GOG Member Institutions. The GOG Statistical and Data Center 
(SDC) utilizes a web-based patient registration system (available at the GOG web menu page). 
When a suitable candidate has been identified for protocol entry, the following steps should be 
taken: 
5.11 
An IRB-approved informed consent form and authorization permitting the release of 
personal health information must be signed by the patient or guardian. Current FDA, 
and institutional regulations concerning informed consent will be followed. 
5.12 
All eligibility requirements indicated in Section 3.0 must be satisfied. 
5.13 
The Fast Fact Sheet data must be gathered. 


 
GOG-3007 
 
 
-20-
5.14 
The institution must register the patient using the web-based registration application or 
by phone if necessary (800-523-2917). Instructions for web-based registration and 
randomization can be found by going to the GOG Web Menu page, selecting 
"Start/finish a patient registration," and then selecting "Directions" found on the left 
side of the page.  
5.15 
The institution will enter the patient's name, GOG patient identification number, and 
date of registration in the appropriate place in their Log Book to document the patient's 
entry. 
 
5.2 
Treatment Plan 
 
Treatment randomization will be stratified into two levels based on previous treatment for 
endometrial cancer: Level 1. Patients who have received adjuvant chemotherapy or 
chemoradiation either at time of initial diagnosis or for a pelvic recurrence; Level 2. Patients 
who have never received adjuvant chemotherapy or chemoradiation.  
 
Prior radiotherapy in the absence of chemotherapy is not considered in this stratification. 
 
Study therapy will be randomized between: 
Arm 1: Everolimus 10 mg PO daily and Letrozole 2.5 mg PO daily  
Arm 2: Tamoxifen 20 mg PO BID; on alternating weeks (even numbered) weeks, 
medroxyprogesterone acetate 200 mg PO daily with Tamoxifen 20 mg PO BID. 
 
Therapy is to be continued until tumor progression or undue toxicity. Tumor assessments will be 
performed per Appendix V (excel tool for calculating dates).  
 
See Appendix II for General Chemotherapy Guidelines. 
 
5.3 
Everolimus and letrozole administration 
 
5.31 
Everolimus will be provided and dispensed by the pharmacy. Letrozole is commercially 
available and will be prescribed.  Study medication will be supplied in an open label 
fashion. Patients will self-administer the both medications at home. 
 
5.32 
Patients will be instructed to take the study medication at an approximately consistent 
time each day.  
 
5.33 
Everolimus is formulated as tablets of 2.5, 5 and 10 mg strength and supplied in blister 
packs under aluminum foil, which should be opened only at the time of administration as 
drug is both hygroscopic and light-sensitive.  Tablets should be taken orally once daily 
in a fasting state or after no more than a light, fat-free meal. Avoid grapefruit-containing 
products during the treatment period. 
 
The tablets should be swallowed whole with a glass of water and should not be chewed or 
crushed. For patients unable to swallow tablets, the tablet(s) should be dispersed 
completely in a glass of water (containing approximately 30 mL) by gently stirring until 
the tablet(s) is fully disintegrated (approximately 7 minutes), immediately prior to 
drinking. The glass should be rinsed with the same volume of water and the rinse 
completely swallowed to ensure the entire dose is administered.  
 
If vomiting occurs, no attempt should be made to replace the vomited dose. Patients should 
be instructed that if they miss a dose on one day, they must not take any extra dose the 
next day.  


 
GOG-3007 
 
 
-21-
 
5.34 
Letrozole is formulated as tablets of 2.5 mg and supplied in bottles. The dose of 
letrozole is one 2.5 mg tablet administered orally once daily. The oral single dose of 
everolimus should be taken together with the daily dose of letrozole 2.5 mg.  
 
5.35 
The use of a patient pill calendar (See Appendix III) during study therapy will be 
utilized by the patient and the treating clinic to help promote and monitor compliance 
with everolimus and letrozole. 
 
5.4  
Tamoxifen and medroxyprogesterone acetate administration 
5.41 
Tamoxifen and medroxyprogesterone acetate are commercially available and will be 
prescribed. Patients will self-administer both medications at home. 
 
5.42 
Patients will be instructed to take the study medication at an approximately consistent 
time each day.  
 
5.43 
Tamoxifen is formulated as tablets of 20 mg strength and supplied in bottles.   
  
5.44 
Medroxyprogesterone acetate is formulated in tablets of 10 mg strength and supplied in 
bottles. The dose of medroxyprogesterone acetate is 20, 10 mg tablets (200mg total) 
administered orally once daily. (6/25/15) 
 
5.45 
The use of a patient pill calendar (See Appendix III) during study therapy will be 
utilized by the patient and the treating clinic to help promote and monitor compliance 
with medroxyprogesterone acetate and Tamoxifen.  
 
 


 
GOG-3007 
 
 
-22-
6.0 
TREATMENT MODIFICATIONS    
 
Toxicity will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE), 
version 4.0. 
 
6.1   
Tamoxifen/ medroxyprogesterone acetate 
 
There are no dose modifications for the tamoxifen/ medroxyprogesterone acetate.  However, 
because of the risk of DVT, subjects not already on anticoagulation who require major 
abdominal or pelvic surgery or fracture a femur or pelvis should have drug held from one week 
prior to the procedure (if it is a planned procedure) until they are ambulatory again. Suspected 
severe and unusual toxicities from either agent (e.g. hives from tamoxifen) should be discussed 
with the study chair. 
 
6.2   
Everolimus/Letrozole 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. Details of study treatment 
schedule adjustments and dose levels are provided in Table 6-1. 
 
Table 6-1. Dose Levels 
 
 
6.21 
Algorithm for interpretation and dose modification due to suspected treatment 
related toxicity: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose level  
-2 
-1 
0 
Everolimus  
2.5 mg daily 
5 mg daily  
10 mg daily  
Letrozole  
Not applicable 
Not applicable 
2.5 mg daily  


 
GOG-3007 
 
 
-23-
 
Table 6-2. Dosing guidelines for everolimus-related non-hematologic toxicities 
Toxicity 
Action 
Non-Infectious Pneumonitis 
Please refer to 6-4 
Reactivation of HBV or HCV flare 
Please refer to Table 6-6 and Table 6-7 
AST or ALT elevation 
Grade 1 (> ULN - 3.0 x ULN) 
Grade 2 (> 3.0 - 5.0 x ULN) 
Maintain current dose level 
AST or ALT elevation 
Grade 3 (> 5.0 - 20.0 ULN)* 
Interrupt everolimus administration until resolution to ≤ grade 1 
(or ≤ grade 2 if baseline values were within the range of grade 
2). If resolution occurs ≤ 7 days, everolimus should be re-started 
at the dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, 
hold everolimus until recovery to ≤ grade 1 or baseline grade / 
value and reintroduce everolimus at one dose level lower, if 
available. 
AST or ALT elevation 
Grade 4 (> 20 x ULN)* 
 
 
 
Recurrence of grade 4 after dose 
reduction or toxicity requiring 
everolimus interruption for > 28 
days 
Interrupt everolimus administration until resolution to ≤ grade 1 
(or ≤ grade 2 if baseline values were within the range of grade 
2). If resolution occurs ≤ 7 days, everolimus should be re-started 
at one dose level lower. If resolution takes > 7 days, discontinue 
everolimus. 
Discontinue everolimus. 
Intolerable grade 2 mucositis, or 
grade 3 AE, except hyperglycemia 
or hypertriglyceridemia or 
hypercholesterolemia (see Section 
6.2.2.5) 
Interrupt everolimus administration until resolution to ≤ grade 1 
or baseline grade / value. 
If resolution occurs within ≤ 7 days, everolimus should be re-
started at the dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, 
hold everolimus until recovery to ≤ grade 1 or baseline grade / 
value and reintroduce everolimus at one dose level lower, if 
available. 
Patients will be withdrawn from the study treatment if they fail 
to recover to ≤ grade 1 or baseline grade / value within 28 days. 
Any other grade 4 
Hold everolimus until recovery to grade ≤ 1 or baseline value 
Reintroduce everolimus at one dose level lower, if available. 
Grade 3 or 4 clinical liver failure 
(asterixis or encephalopathy/coma) 
Discontinue everolimus 
Recurrence of intolerable grade 2 
mucositis or grade 3 event after 
dose reduction 
Reduce dose to the next lower dose level, if available. The 
lowest possible dose level of everolimus is 2.5 mg daily. Below 
this level, everolimus must be discontinued. 
If toxicity recurs at Grade 3, consider discontinuation. 
Recurrence of grade 4 after dose 
reduction 
Discontinue everolimus 
Any non-hematologic toxicity 
requiring everolimus interruption 
for > 28 days 
Discontinue everolimus 
* Should HCV flare be confirmed, the guidelines for flare must take precedence(Table 6-7) 


 
GOG-3007 
 
 
-24-
 
Table 6-3. Dosing guidelines for Everolimus-related hematologic toxicities 
Toxicity 
Action 
Grade 2 thrombocytopenia (platelets 
<75, ≥ 50x109/L) 
No action 
 
Grade 3 thrombocytopenia (platelets 
<50, ≥ 25 x109/L) 
Interrupt everolimus until resolution to grade ≤1  
If resolution occurs ≤ 7 days, reintroduce everolimus at the 
dose level prior to interruption. 
If resolution occurs > 7 days, or event occurs within 28 days, 
reintroduce everolimus at one dose level lower, if available. 
Grade 4 thrombocytopenia (platelets < 
25 x109/L) 
Interrupt everolimus until recovery to grade ≤ 1. Then 
reintroduce everolimus at one dose level lower, if available. 
Grade 3 neutropenia or anemia 
(neutrophil <1, ≥0.5 x109/L) 
Interrupt everolimus until resolution to grade ≤1 or baseline 
value 
If AE resolution occurs ≤ 7 days, reintroduce everolimus at 
the same dose level. 
If AE resolution occurs > 7 days, or event occurs within 28 
days, reintroduce everolimus at one dose level lower, if 
available. 
Grade 4 neutropenia or anemia 
Interrupt everolimus until recovery to grade ≤ 1 or baseline 
value. Reintroduce everolimus at one dose level lower, if 
available.* 
Febrile neutropenia (grade>2) 
Interrupt everolimus until resolution to grade ≤ 1 (or baseline 
value) and no fever. Reintroduce everolimus at one dose level 
lower, if available.* 
Recurrence of grade 3 toxicity after 
dose reduction 
Reduce dose to the next lower dose level, if available. The 
lowest possible dose level of everolimus is 5 mg every other 
day (2.5 mg daily). Below this level, everolimus must be 
discontinued. 
*Recurrence of grade 4 toxicity 
(including febrile neutropenia) after 
dose reduction 
Discontinue everolimus 
*Any hematologic toxicity requiring 
everolimus interruption for > 28 
days 
Discontinue everolimus 
If discontinuation of everolimus is required, patients should continue on single agent letrozole 
until progression or unacceptable toxicity.  
 
6.22 
Management of specific toxicities 
Overall, safety data available from completed, controlled and uncontrolled studies 
indicate that everolimus is generally well tolerated at weekly or daily dose schedules. 
The safety profile is characterized by manageable adverse events (AEs). These AEs are 
generally reversible and non-cumulative. 
Adverse events most frequently observed with everolimus are stomatitis, rash, diarrhea, 
fatigue, infections, asthenia, nausea, peripheral edema, decreased appetite, headache, 
dysgeusia, epistaxis, mucosal inflammation, pneumonitis, weight decreased, vomiting, 
pruritus, cough, dyspnea, dry skin, nail disorder, and pyrexia. . Overall, the most 
frequently observed laboratory abnormalities include decreased hematology parameters 


 
GOG-3007 
 
 
-25-
including hemoglobin, lymphocytes, platelets, and neutrophils (or collectively as 
pancytopenia).; increased clinical chemistry parameters including cholesterol, 
triglycerides, glucose, aspartate transaminases, creatinine, alanine transaminases, and 
bilirubin; and decreased clinical chemistry parameters including phosphate and 
potassium.. The majority of these AEs have been of mild to moderate severity (CTCAE 
grade 1-2). 
6.221  Management of infections 
Everolimus has immunosuppressive properties and may predispose patients to 
bacterial, fungal, viral or protozoal infections, including infections with 
opportunistic pathogens. Localized and systemic infections, including 
pneumonia, other bacterial infections, invasive fungal infections, such as 
aspergillosis or candidiasis and viral infections including reactivation of 
hepatitis B virus, have been described in patients taking everolimus Some of 
these infections have been severe (e.g., leading to sepsis, respiratory or hepatic 
failure) and occasionally have had a fatal outcome. 
Physicians and patients should be aware of the increased risk of infection with 
everolimus Treat pre-existing infections prior to starting treatment with 
everolimus. While taking everolimus, be vigilant for symptoms and signs of 
infection; if a diagnosis of infection is made, institute appropriate treatment 
promptly and consider interruption or discontinuation of everolimus. 
If a diagnosis of invasive systemic fungal infection is made, discontinue 
everolimus and treat with appropriate antifungal therapy. 
Cases of pneumocystis jiroveci pneumonia (PJP), some with a fatal outcome, 
have been reported in patients who received everolimus. PJP may be associated 
with concomitant use of corticosteroids or other immunosuppressive agents.  
Prophylaxis for PJP should be considered when concomitant use of 
corticosteroids or other immunosuppressive agents are required. 
6.222 Management of skin toxicity 
For patients with grade 1 toxicity, no specific supportive care is usually needed 
or indicated. Rash must be reported as an AE. Patients with grade 2 or higher 
toxicity may be treated with the following suggested supportive measures at the 
discretion of the investigator: oral minocycline, topical tetracycline, topical 
clindamycin, topical silver sulfadiazine, diphenhydramine, oral prednisolone 
(short course), topical corticosteroids, or pimecrolimus. 
6.223 Management of Hypersensitivity reactions 
Hypersensitivity reactions manifested by symptoms including, but not limited 
to, anaphylaxis, dyspnea, flushing, chest pain or angioedema (e.g. swelling of 
the airways or tongue, with or without respiratory impairment) have been 
observed with everolimus. 
6.224 Angioedema with concomitant use of angiotensin-converting enzyme (ACE) 
inhibitors 
Patients taking concomitant ACE inhibitor therapy may be at increased risk for 
angioedema (e.g. swelling of the airways or tongue, with or without respiratory 
impairment). 
6.224 Renal Failure Events 
Cases of renal failure (including acute renal failure), some with fatal outcome, 
occurred in patients treated with everolimus. Renal function of patients should 


 
GOG-3007 
 
 
-26-
be monitored particularly where patients have additional risk factors that may 
further impair renal function. 
Elevations of serum creatinine, usually mild, and proteinuria have been reported 
in patients taking everolimus. Monitoring of renal function, including 
measurement of blood urea nitrogen (BUN), urinary protein, or serum 
creatinine, is recommended prior to the start of everolimus therapy and 
periodically thereafter. 
6.225 Management of stomatitis / oral mucositis / mouth ulcers 
Adverse Drug Reaction 
Severity 
Everolimus Dose Adjustment and Management 
Recommendations 
Stomatitis 
Grade 1 
(Minimal 
symptoms, 
normal diet) 
 
No dose adjustment required.  
Manage with non-alcoholic or salt water (0.9%) 
mouth wash several times a day until resolution. 
 
Grade 2 
(Symptomatic 
but can eat and 
swallow 
modified diet) 
Temporary dose interruption until recovery to grade 
≤1.  
Re-initiate everolimus at same dose. 
If stomatitis recurs at grade 2, interrupt dose until 
recovery to grade ≤1. Re-initiate everolimus at lower 
dose. 
Manage with topical analgesic mouth treatments (e.g. 
benzocaine, butyl aminobenzoate, tetracaine 
hydrochloride, menthol or phenol) with or without 
topical corticosteroids (i.e. triamcinolone oral paste)*. 
 
Grade 3 
(Symptomatic 
and unable to 
adequately eat 
or hydrate 
orally) 
 
Temporary dose interruption until recovery to grade 
≤1.  
Re-initiate everolimus at lower dose. 
Manage with topical analgesic mouth treatments (i.e. 
benzocaine, butyl aminobenzoate, tetracaine 
hydrochloride, menthol or phenol) with or without 
topical corticosteroids (i.e. triamcinolone oral paste)* 
 
Grade 4 
(Symptoms 
associated with 
life-threatening 
consequences) 
Discontinue everolimus and treat with appropriate 
medical therapy. 
* using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in management of 
stomatitis is discouraged as they may worsen mouth ulcers. 
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with gastrointestinal 
morbidity associated with mouth/dental infections, irritation of esophageal mucosa e.g. gastro esophageal 
reflux disease (GERD) and pre-existing stomatitis/mucositis must be monitored even more closely. 
Patients should be instructed to report the first onset of buccal mucosa irritation/reddening to their study 
physician immediately. 
Stomatitis/oral mucositis/mouth ulcers due to everolimus should be treated using local supportive care. 
Please note that investigators in earlier trials have described the oral toxicities associated with everolimus 
as mouth ulcers, rather than mucositis or stomatitis. If your examination reveals mouth ulcers rather than 
a more general inflammation of the mouth, please classify the adverse event as such. Agents containing 
alcohol, hydrogen peroxide, iodine, and thyme derivatives may tend to worsen mouth ulcers.  These agents 
should be avoided. Antifungal agents should be avoided unless a fungal infection is diagnosed. In 


 
GOG-3007 
 
 
-27-
particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) should be 
avoided in all patients due to their strong inhibition of everolimus metabolism, therefore leading to higher 
everolimus exposures. Therefore, topical antifungal agents are preferred if an infection is diagnosed.  
6.226 Management of diarrhea 
Appearance of grade 1-2 diarrhea attributed to study drug toxicity may be treated with 
supportive care such as loperamide, initiated at the earliest onset (for example 4 mg orally 
followed by 2 mg orally every 2 hours until resolution of diarrhea). 
6.227 Management of hyperlipidemia and hyperglycemia 
 
Adverse Drug 
Reaction 
Severity 
Everolimus Dose Adjustment and Management 
Recommendations 
Metabolic events 
(e.g., hyperglycemia, 
dyslipidemia) 
Grade 1 
No dose adjustment required. 
Initiate appropriate medical therapy and monitor. 
 
Grade 2 
No dose adjustment required. 
Manage with appropriate medical therapy and 
monitor. 
 
Grade 3 
Temporary dose interruption. 
Re-initiate everolimus at lower dose. 
Manage with appropriate medical therapy and 
monitor. 
 
Grade 4 
Discontinue everolimus and treat with appropriate 
medical therapy. 
 
Treatment of hyperlipidemia should take into account the pre-treatment status and 
dietary habits of the patient. Grade 2 or higher hypercholesterolemia (>300 mg/dL or 
7.75 mmol/L) or grade 2 hypertriglyceridemia or higher (>300 mg/dl or 3.42 mmol/L 
should be treated with a 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor 
(e.g. atorvastatin, pravastatin, fluvastatin) or appropriate triglyceride-lowering 
medication, in addition to diet. 
Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been 
reported in patients taking everolimus.  Monitoring of blood cholesterol and triglycerides 
prior to the start of everolimus therapy and periodically thereafter as well as 
management with appropriate medical therapy is recommended. 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is 
associated with an increased risk of a rare but serious skeletal muscle toxicity manifested 
by rhabdomyolysis, markedly elevated creatinine phosphokinase (CPK) levels and 
myoglobinuria, acute renal failure and sometimes death. The risk versus benefit of using 
this therapy should be determined for individual patients based on their risk of 
cardiovascular complications of hyperlipidemia. 
Hyperglycemia has been reported in patients taking everolimus. Monitoring of fasting 
serum glucose is recommended prior to the start of everolimus and periodically 
thereafter. More frequent monitoring is recommended when everolimus is co-
administered with other drugs that may induce hyperglycemia. Optimal glycemic control 
should be achieved before starting a patient on everolimus. 
 
6.228 Management of non-infectious pneumonitis` 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-
infectious pneumonitis (including interstitial lung disease) have also been described in 


 
GOG-3007 
 
 
-28-
patients taking everolimus. Some of these have been severe and on rare occasions, a fatal 
outcome was observed. 
• 
A diagnosis of non-infectious pneumonitis should be considered in patients 
presenting with non-specific respiratory signs and symptoms such as hypoxia, 
pleural effusion, cough or dyspnea, and in whom infectious, neoplastic and other 
non-medicinal causes have been excluded by means of appropriate 
investigations. Opportunistic infections such as PJP should be ruled out in the 
differential diagnosis of non-infectious pneumonitis. Patients should be advised 
to report promptly any new or worsening respiratory symptoms. 
 
Patients who develop radiological changes suggestive of non-infectious pneumonitis and 
have few or no symptoms may continue Afinitor therapy without dose alteration. 
If symptoms are moderate (grade 2), consideration should be given to interruption of 
therapy until symptoms improve.  The use of corticosteroids may be indicated.  Afinitor 
may be reintroduced at a daily dose approximately 50% lower than the dose previously 
administered. 
 
For cases of grade 3 non-infectious pneumonitis, interrupt Afinitor until resolution to less 
than or equal to grade 1.  Afinitor may be re-initiated at a daily dose approximately 50% 
lower than the dose previously administered depending on the individual clinical 
circumstances.  If toxicity recurs at grade 3, consider discontinuation of Afinitor.  For 
cases of grade 4 non-infectious pneumonitis, Afinitor therapy should be discontinued.  
Corticosteroids may be indicated until clinical symptoms resolve. 
 
For patients who require use of corticosteroids for treatment of non-infectious 
pneumonitis, prophylaxis for pneumocystis jiroveci pneumonia (PJP) may be 
considered. The two compounds studied most extensively for prophylaxis against PJP 
have been trimethoprim-sulfamethoxazole, given orally, and pentamidine, given as an 
aerosol. 
 
If non-infectious pneumonitis develops, the guidelines in Table 6-4 should be followed. 
Consultation with a pulmonologist is recommended for any case of pneumonitis that 
develops during the study. 


 
GOG-3007 
 
 
-29-
Table 6-4. Management of non-infectious pneumonitis 
Worst grade 
pneumonitis 
Suggested investigations 
Management of 
pneumonitis 
Everolimus dose adjustment 
Grade 1  
(Asymptoma
tic, 
radiologic 
findings 
only) 
CT scans with lung windows. 
No specific 
therapy is 
required 
No dose adjustment required.  
Initiate appropriate monitoring. 
Grade 2 
(Symptomati
c, not 
interfering 
with 
Activities of 
Daily 
Living) 
CT scan with lung windows. 
Consider pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest. Consider a 
bronchoscopy with biopsy 
and/or BAL. Monitoring at each 
visit until return to ≤ grade 1. 
Return to initial monitoring 
frequency if no recurrence. 
Symptomatic 
only. Consider 
corticosteroids 
and/or other 
supportive 
therapy if 
symptoms are 
troublesome. 
Rule out infection and consider 
interruption of everolimus until 
symptoms improve to Grade ≤ 
1. 
Re-initiate Everolimus at one 
dose level lower.  
Discontinue Everolimus if 
failure to recover within ≤ 28 
days. 
Grade 3 
(Symptomati
c, interfering 
with 
Activities of 
Daily Living, 
O2 
indicated) 
CT scan with lung windows and 
pulmonary 
function 
testing 
includes: spirometry, DLCO, and 
room air O2 saturation at rest. 
Monitoring at each visit until 
return to ≤ grade 1. Return to 
initial monitoring frequency if no 
recurrence. Bronchoscopy with 
biopsy 
and/or 
BAL 
is 
recommended. 
Consider 
corticosteroids if 
infective origin 
is 
ruled 
out. 
Taper 
as 
medically 
indicated. 
Rule out infection and interrupt 
Everolimus until symptoms 
improve to Grade ≤ 1. 
Consider re-initiating 
Everolimus at one dose level 
lower (approximately 50% 
lower than the dose previously 
administered depending on 
individual clinical 
circumstances) 
Discontinue Everolimus if 
failure to recover within ≤ 28 
days.  If toxicity recurs at 
Grade 3, consider 
discontinuation 
Grade 4 
(Life 
threatening, 
ventilatory 
support 
indicated) 
CT scan with lung windows and 
required 
pulmonary 
function 
testing, if possible, includes: 
spirometry, DLCO, and room air 
O2 saturation at rest. Monitoring 
at each visit until return to ≤ 
grade 
1. 
Return 
to 
initial 
monitoring 
frequency 
if 
no 
recurrence. Bronchoscopy with 
biopsy 
and/or 
BAL 
is 
recommended if possible. 
Consider 
corticosteroids if 
infective origin 
is 
ruled 
out. 
Taper 
as 
medically 
indicated. 
Rule 
out 
infection 
and 
discontinue everolimus. 
 
 
6.229 Management of hepatitis reactivation / flare 
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving 
chemotherapy (Yeo 2004). Sporadic cases of Hepatitis B reactivation have also been 


 
GOG-3007 
 
 
-30-
seen in this setting with everolimus. Use of antivirals during anti-cancer therapy has 
been shown to reduce the risk of Hepatitis B virus reactivation and associated morbidity 
and mortality (Loomba 2008). A detailed assessment of Hepatitis B/C medical history 
and risk factors must be done for all patients at screening, with testing performed prior to 
the first dose of everolimus.  
 
Monitoring and prophylactic treatment for hepatitis B reactivation 
Table 6-5 provides detail of monitoring and prophylactic therapy according to the 
screening results of viral load and serologic markers testing. 
 
Table 6-5. Action to be taken based on screening hepatitis B results 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBsAb 
+ or - 
+ or - 
+ 
and no prior 
HBV 
vaccination 
+ or - 
- 
or + with prior 
HBV vaccination 
HBcAb 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendation 
Prophylaxis treatment 
should be started 1-2 weeks 
prior to first dose of 
everolimus 
 
Monitor HBV-DNA 
approximately every 4-8 
weeks 
No prophylaxis 
 
Monitor HBV-DNA 
approximately every 3-4 weeks  
No specific 
action 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of everolimus. 
For HBV reactivation definition and management guidelines, see Table 6-6. 


 
GOG-3007 
 
 
-31-
Table 6-6 
Guidelines for the management of hepatitis B reactivation 
HBV reactivation (with or without clinical signs and symptoms)* 
For patients with baseline 
results:  
Positive HBV-DNA 
OR 
positive HBsAg 
---------------------------------- 
reactivation is defined as: 
[Increase of 1 log in HBV-
DNA relative to baseline 
HBV-DNA value OR new 
appearance of measurable 
HBV-DNA] 
Treat: Start a second antiviral medication 
AND 
Interrupt everolimus administration until resolution:  
• 
≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days, everolimus should be re-started 
at one dose lower, if available.  If the patient is already receiving the 
lowest dose of everolimus according to the protocol, the patient should 
restart at the same dose after resolution. Both antiviral therapies should 
continue at least 4 weeks after last dose of everolimus.  
If resolution occurs > 28 days Patients should discontinue everolimus 
but continue both antiviral therapies at least 4 weeks after last dose of 
everolimus. 
For patients with baseline 
results: 
Negative HBV-DNA and 
HBsAg 
AND 
[Positive HBsAb (with no 
prior history of vaccination 
against HBV), OR positive 
HBcAb] 
---------------------------------- 
Reactivation is defined as: 
New appearance of 
measurable HBV-DNA 
Treat : Start first antiviral medication 
AND 
Interrupt everolimus administration until resolution: 
• 
≤ undetectable (negative) HBV-DNA levels 
If resolution occurs within ≤ 28 days, everolimus should be re-started 
at one dose lower, if available (see 6-1 for dose levels available). If the 
patient is already receiving the lowest dose of everolimus according to 
the protocol, the patient should restart at the same dose after resolution. 
Antiviral therapy should continue at least 4 weeks after last dose of 
everolimus. 
If resolution occurs > 28 days Patients should discontinue everolimus 
but continue antiviral therapy at least 4 weeks after last dose of 
everolimus. 
* All reactivations of HBV are to be recorded as grade 3 (e.g. CTCAE Version 4.0 - 
Investigations/Other: Viral Reactivation), unless considered life threatening by the investigator, in 
which case they should be recorded as grade 4. Date of viral reactivation is the date on which the rise 
or reappearance of HBV-DNA was recorded. 
Monitoring for hepatitis C flare 
The following two categories of patients should be monitored every 4–8 weeks for HCV flare: 
• 
Patients with detectable HCV RNA-PCR test at screening. 
• 
Patients known to have a history of HCV infection, despite a negative viral load test at screening 
(including those that were treated and are considered ‘cured’) 
• 
For definitions of HCV flare and actions to be taken in the event of a flare, please refer to Table 6-7. 


 
GOG-3007 
 
 
-32-
 
Table 6-7 
Guidelines for the management of hepatitis C flare 
Baseline results 
HCV flare definition* 
HCV flare 
management 
Detectable HCV-RNA 
 
> 2 log10 IU/mL increase in HCV-RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher. 
Discontinue everolimus 
Knowledge of past hepatitis C 
infection with no detectable 
HCV-RNA 
New appearance of detectable HCV-
RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher. 
Discontinue everolimus 
* All flares of HCV are to be recorded as grade 3 (e.g. CTCAE Version 4.0 - Investigations - Other: 
Viral Flare), unless considered life threatening by the investigator; in which case they should be 
recorded as grade 4. Date of viral flare is the date on which both the clinical criteria described above 
were met. (e.g., for a patient whose HCV-RNA increased by 2 logs on 01 JAN 2011 and whose ALT 
reached > 5 x ULN on 22 JAN 2011, the date of viral flare is 22 JAN 2011). 
 
6.230 Hepatic impairment dose modifications 
• 
Mild hepatic impairment (Child-Pugh A) – the recommended dose is 7.5 mg daily. 
• 
Moderate hepatic impairment (Child-Pugh B) – the recommended dose is 5 mg 
daily. 
• 
Severe hepatic impairment (Child-Pugh C) – not recommended. If the desired 
benefit outweighs the risk, a dose of 2.5 mg daily must not be exceeded. 
• 
Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes 
during treatment. 
• 
Afinitor is not recommended for patients with hepatic impairment who require doses 
below 2 mg every other day or 2.5 every other day. Everolimus exposure was 
increased in patients with mild (Child-Pugh A), moderate (Child-Pugh B), and 
severe (Child-Pugh C) hepatic impairment (see Section 5.2.3). Everolimus is not 
recommended for use in postmenopausal women with hormone receptor positive 
advanced breast cancer, or in patients with advanced neuroendocrine tumors of 
gastrointestinal, lung, or pancreatic origin or advanced renal cell carcinoma with 
severe hepatic impairment (Child-Pugh C) unless the potential benefit outweighs the 
risk. 
 
6.231 Special Populations 
Geriatrics (≥ 65 years):  
No dosage adjustment is required. 
Renal impairment: 
No dosage adjustment is required. 
Ethnicity: 
Pharmacokinetic characteristics are similar for Caucasian and Japanese subjects. 
Pharmacokinetic studies in Black transplant patients have shown an average 
20% higher clearance. 
 
 


 
GOG-3007 
 
 
-33-
6.232 Concomitant therapy 
Patients must be instructed not to take any medications (over-the-counter or other products) 
during the protocol treatment period without prior consultation with the investigator. The 
investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of study drug. All medications (other than study drug) and 
significant non-drug therapies (including physical therapy and blood transfusions) taken 
within 28 days of starting study treatment through the 30-day safety follow up visit should be 
recorded. 
 
Cytochrome P450 and P-glycoprotein inhibitors/inducers/substrates 
Co-administration with strong inhibitors of CYP3A4 or PgP should be avoided; and may 
cause increased everolimus concentrations. For a current table of Substrates, Inhibitors and 
Inducers please access the following website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/ucm093664.htm 
 
Everolimus is metabolized by CYP3A4 in the liver and to some extent in the intestinal wall. 
Therefore, the following are recommended: 
• 
Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
ritonavir) or P-glycoprotein (PgP) inhibitor should be avoided. 
• 
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) 
or PgP inhibitors should be used with caution. If a patient requires co-administration of 
moderate CYP3A4 inhibitors or PgP inhibitors, reduce the dose of everolimus by 
approximately 50%. . Additional dose reductions to every other day may be required to 
manage toxicities. If the inhibitor is discontinued, the everolimus dose should be 
returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor after 
a washout period of 2 to 3 days. 
• 
Grapefruit, Seville oranges and star fruit juices effect P450 and PgP activity. 
Concomitant use should be avoided. 
• 
If patients require co-administration of a strong CYP3A4 inducer, consider doubling the 
daily dose of everolimus (based on pharmacokinetic data), using increments of 5 mg or 
less. This dose of everolimus is predicted to adjust the AUC to the range observed 
without inducers. However, there are no clinical data with this dose adjustment in 
patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued, 
consider a washout period of at least 3 to 5 days (reasonable time for significant enzyme 
de-induction), before the Afinitor dose is returned to the dose used prior to initiation of 
the strong CYP3A4 inducer. 
• 
This dose adjustment of everolimus is intended to achieve similar AUC to the range 
observed without inducers. However, there are no clinical data with this dose adjustment 
in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the 
everolimus dose should be returned to the dose used prior to initiation of the strong 
CYP3A4/PgP inducer. 
 
Please refer to Table 6-8 listing relevant inducers and inhibitors of CYP3A and Table 6-9 for 
a list of relevant substrates, inducers, and inhibitors of PgP.   
 
Everolimus and drugs influencing CYP3A4 enzyme 
Everolimus is a substrate of CYP3A4, and a substrate and moderate inhibitor of the 
multidrug efflux pump, PgP (PgP, MDR1, and ABCB1). Therefore, extent of absorption and 
subsequent elimination of systemically absorbed everolimus may be influenced by products 
that are substrates, inhibitors, or inducers of CYP3A4 and/or PgP. Concurrent treatment with 
strong CYP3A4-inhibitors should be avoided. Refer to Table 6-2 in section 6 for a 
comprehensive list of inducers and inhibitors of CYP3A4 and Table 6-3 ]for a list of relevant 


 
GOG-3007 
 
 
-34-
substrates, inducers and inhibitors of PgP. Inhibitors of PgP may decrease the efflux of 
everolimus from brain or tumor and therefore increase everolimus concentrations in these 
tissues. In vitro studies showed that everolimus is a competitive inhibitor of CYP3A4 and of 
CYP2D6, potentially increasing the concentrations of products eliminated by these enzymes. 
Thus, caution should be exercised when co-administering everolimus with CYP3A4 and 
CYP2D6 substrates with a narrow therapeutic index. Clinical studies have been conducted in 
healthy subjects to assess pharmacokinetic drug interactions between everolimus and 
potential CYP3A modifiers (ketoconazole, verapamil, erythromycin, rifampin, midazolam, 
and HMGCoA reductase inhibitors (statins).  
 
Table 6-8. Clinically relevant drug interactions: inducers, and inhibitors of isoenzyme CYP3A 
Inducers 
Strong inducers: 
avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St. John's wort 
(hypericum perforatum) 
Moderate inducers: 
bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, ritonavir, [talviraline], thioridazine, tipranavir 
Weak inducers: 
amprenavir, aprepitant, armodafinil (R-modafinil), bexarotene, clobazam, danshen, dexamethasone, Echinacea, 
garlic (allium sativum), gingko (ginkgo biloba), glycyrrhizin, methylprednisolone, nevirapine, oxcarbazepine, 
pioglitazone, prednisone, [pleconaril], primidone, raltegravir, rufinamide, sorafenib, telaprevir, terbinafine, 
topiramate, [troglitazone] , vinblastine 
Inhibitors 
Strong inhibitors: 
boceprevir, clarithromycin, cobicistat, conivaptan, elvitegravir, indinavir, itraconazole, ketoconazole, lopinavir, 
mibefradil, nefazodone, nelfinavir, posaconazole (Krishna et al 2009), ritonavir, saquinavir, telaprevir, 
telithromycin, tipranavir, troleandamycin, voriconazole 
Moderate inhibitors: 
Amprenavir, aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, cyclosporine, darunavir, diltiazem, 
dronedarone, erythromycin, fluconazole, fosamprenavir, grapefruit juice (citrus parasidi fruit juice), imatinib, 
schisandra sphenanthera, tofisopam, verapamil 
 
Table 6-9. Clinically relevant drug interactions: substrates, inducers, inhibitors of PgP and 
PgP/CYP3A dual inhibitors 
 
Substrates 
colchicine, digoxin, fexofenadine, indinavir, paclitaxel, talinolol, topotecan, vincristine, everolimus 
Inducers 
rifampin, St John’s wort 
PgP Inhibitors and PgP/CYP3A Dual Inhibitors 
amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, elacridar, 
erythromycin, felodipine, fexofenadine, fluvoxamine, ginkgo (ginkgo biloba), indinavir, itraconazole, lopinavir, 
mibefradil, milk thistle (silybum marianum), nelfinavir, nifedipine, nitrendipine, paroxetine, quercetin, quinidine, 
ranolazine, rifampin, ritonavir, saquinavir, Schisandra chinensis, St John’s wort (hypericum perforatum), talinolol, 
Telaprevir, telmisartan, ticagrelor, tipranavir, tolvaptan, valspodar, verapamil 
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Oct. 2, 2011,29-Oct-2012 
which summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug Interaction 
Studies”, the University of Washington’s Drug Interaction Database, and Indiana University School of Medicine's 
Drug Interaction Table. 


 
GOG-3007 
 
 
-35-
 
Vaccinations 
Immunosuppressants may affect the response to vaccination and vaccination during 
treatment with everolimus may therefore be less effective. The use of live vaccines 
should be avoided during treatment with everolimus Examples of live vaccines are: 
intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, 
and TY21a typhoid vaccines. 
 


 
GOG-3007 
 
 
-36-
7.0 
 
STUDY PARAMETERS 
 
Assessments 
Pre-
Therapy 
Prior to 
Each Cycle 
Every 
other Cycle 
Every 8 weeks x 2, 
then every 12 weeks 
Off All Study 
Therapy 
Medical history & Physical 
1 
X 
 
 
 
Review of Medications ** 
1 
X 
 
 
 
Vital Status 
 
 
 
 
2 
Vital signs 
1 
X 
 
 
 
Pulse oximeter 
1 
 
 
 
 
Weight 
1 
X 
 
 
 
Performance Status 
1 
X 
 
 
 
Toxicity Assessment 
1 
X 
 
 
2, 4 
CBC with differential and 
platelets 
3 
5 
 
 
 
 
 
 
 
 
 
Electrolytes, glucose, BUN,  
Creatinine 
3 
5 
 
 
 
Bilirubin, AST, ALT, Alkaline 
Phosphatase, Albumin 
3 
5 
 
 
 
Fasting Lipid panel 
1 
 
5 
 
 
HbA1C 
1 
 
 
 
 
HBV-DNA 
8 
 
 
 
 
HBsAg 
8 
 
 
 
 
HBcAb 
8 
 
 
 
 
HBsAb 
8 
 
 
 
 
HCV RNA-PCR 
9 
 
 
 
 
Pregnancy Test (if 
childbearing potential exists) 
3 
 
 
 
 
Chest imaging (x-ray or CT 
of chest) 
1 
 
 
6 
6 
CT of abdomen and pelvis 
1 
 
 
 
 
Radiographic tumor 
measurement 
1 
 
 
7 
7 
ECG 
1 
 
 
 
 
ONE CYCLE = 28 days 
 
Notes: 
1. Must be obtained within 28 days prior to initiating protocol therapy. 
2. Follow-up every 3 months from the last dose of study drug (+/- 2 weeks) for 2 years and then every 6 months 
(+/- 2 weeks) for 3 years.  Follow-up forms (Form Q) are collected for the 5-year follow-up period or until 
study termination. 
3. Must be obtained within 14 days prior to initiating protocol therapy.  
4. Report all adverse events that occur within 30 days of last protocol treatment on the T form for the last cycle 
of therapy administered.  For reporting of delayed toxicity, see Section 10.1. 
5. Labs must be obtained within 4 days of re-treatment with protocol therapy.   
6. Repeat chest imaging every 8 weeks (+/- 7 days) from cycle 1, day 1 (regardless of delays and/or changes in 
treatment schedule) x 2; then every 12 weeks (+/- 7 days) thereafter, if required to monitor tumor response; 
also repeat at any other time if clinically indicated based on symptoms or physical signs suggestive of 
progressive disease.  A tool is provided to calculate dates of re-imaging (Appendix V).  
7. CT scan or MRI of the abdomen and pelvis if used to follow lesion for measurable disease every 8 weeks 
(+/- 7 days) from cycle 1, day 1 (regardless of delays and/or changes in treatment schedule) x 2; then every 
12 weeks (+/- 7 days) thereafter until disease progression is confirmed; also repeat at any other time if 


 
GOG-3007 
 
 
-37-
clinically indicated based on symptoms or physical signs suggestive of progressive disease.  A tool is 
provided to calculate dates of re-imaging (Appendix V).  
8. Hepatitis B Virus testing: Prior to randomization, the categories of patients listed in Section 3.215 should be 
tested for hepatitis B serologic markers and viral load: HBV-DNA, HBsAg, HBcAb, and HBsAb. HBV DNA 
monitoring should be done depending on results from serologic markers and viral load as listed in Tables 6-5 
and 6-6. 
9. Hepatitis C Virus testing: Patients with hepatitis C risk factors and additional patients at the discretion of the 
investigator should be tested for HCV RNA-PCR test at baseline. For a list of hepatitis C risk factors, refer to 
Section 3.215. Patients with detectable HCV RNA-PCR (determined at baseline) and patients known to have 
a history of HCV infection, despite a negative viral load test at baseline (including those that were treated 
and are considered “cured”) should be monitored every 4 weeks for HCV reactivation.  See Table 6-7. 
**  Whether or not patient is taking metformin should be noted and if she starts to take it while on protocol that 
should be noted as well. 
 
7.2 
Pathology Requirements 
 
 
7.21 Pathology report for histologic confirmation of primary tumor. 
 
 
7.22 
 Pathology report for histologic confirmation of recurrent or persistent disease is not required for 
this protocol. 
 
 
 
7.3 
Translational Research 
 
 
7.31 
Specimen Requirements 
 
If the patient gives permission for her specimens to be collected and used for this optional 
translational research component, then participating institutions are required to submit the 
patient’s translational research specimens as outlined below (unless otherwise specified). 
 
A detailed description of the translational research specimen procedures can be found in 
Appendix IV. 
 
Required Specimen 
(Specimen Code) 
Collection Time Point 
Ship To 
FFPE Primary Tumor (FP01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to all treatment (Preferred FFPE) 
Biopathology Center within 8 
weeks of registration1 
FFPE Metastatic Tumor (FM01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to all treatment (Optional if FP01, 
FRP01, FRM01, FPP01, or FPM01 is 
submitted) 
FFPE Recurrent Primary Tumor 
(FRP01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to study treatment (Optional if 
FP01, FM01, FRM01, FPP01, or FPM01 
is submitted) 
FFPE Recurrent Metastatic Tumor 
(FRM01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to study treatment (Optional if 
FP01, FM01, FRP01, FPP01, or FPM01 
is submitted) 


 
GOG-3007 
 
 
-38-
FFPE Persistent Primary Tumor 
(FPP01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to study treatment (Optional if 
FP01, FM01, FRP01,  FRM01, or 
FPM01 is submitted) 
FFPE Persistent Metastatic Tumor 
(FPM01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to study treatment (Optional if 
FP01, FM01, FRP01, FRM01, or FPP01 
is submitted) 
Whole Blood (WB01) 
7-10mL drawn into purple top 
(EDTA) tube(s) 
Prior to or after starting study treatment 
Biopathology Center the day 
the specimen is collected1 
* 
A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the Biopathology Center. 
1 
Biopathology Center / Protocol GOG-3007, Nationwide Children’s Hospital, 700 Children’s Drive, WA1340, Columbus, OH 43205, 
Phone: (614) 722-2865, FAX: (614) 722-2897, Email: BPCBank@nationwidechildrens.org 
 
 
7.32 
Laboratory Testing 
 
7.321  Hormone Receptor Immunohistochemistry  
 
 
Unstained sections of formalin-fixed, paraffin-embedded (FFPE) tumor will be used for 
hormone receptor (e.g., estrogen receptor [ER]-alpha, ER-beta, progesterone receptor 
[PR]-alpha, PR-beta, G protein-coupled ER [GPR-30]) immunohistochemistry (IHC). 
 
7.322  mTOR Pathway Immunohistochemistry 
 
 
Unstained sections of FFPE tumor will be used for mTOR pathway (e.g., phosphorylated 
S6 ribosomal protein, PTEN, total and phosphorylated AKT, total and phosphorylated 
mTOR, phosphor-ERK1/2) IHC. 
 
7.323 Mutation Analysis 
 
 
Unstained sections and DNA extracted from whole blood will be used for mutational 
analysis (e.g., PTEN, PIK3CA, KRAS, CTNNB1 [beta-catenin]). 
 
 
7.33 
Future Research 
 
Details regarding the banking and use of translational research specimens for future 
research can be found in Appendix IV. 


 
GOG-3007 
 
 
-39-
8.0 
EVALUATION CRITERIA   
 
 
8.1 
Antitumor Effect – Solid Tumors 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eisenhauer, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
 
8.11 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >10 mm with 
CT scan, as >20 mm by chest x-ray, or >10 mm with calipers by clinical exam.  All 
tumor measurements must be recorded in decimal fractions of centimeters. 
 
Note:  Tumor lesions that are situated in a previously irradiated area will not be 
considered measurable unless progression is documented or a biopsy is obtained to 
confirm persistence at least 90 days following completion of radiation therapy. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease.  Leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal/pelvic masses (identified by physical exam and not CT or MRI), are 
considered as non-measurable. 
 
Notes: 
Bone lesions:  Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, that can be evaluated by CT or MRI can be considered as measurable 
lesions if the soft tissue component meets the definition of measurability described 
above.  Blastic bone lesions are non-measurable. 
 
Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.  ‘Cystic lesions’ thought to represent cystic metastases 
can be considered as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, and in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.  A sum of the diameters (longest for 
non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 


 
GOG-3007 
 
 
-40-
and reported as the baseline sum diameters.  If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum.  The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions 
and should also be recorded at baseline.  Measurements of these lesions are not required, 
but the presence, absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
 
8.12 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans), but NOT lung.   
 
  Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline, and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, subsequent image acquisitions should use the same type of 
scanner and follow the baseline imaging protocol as closely as possible.  If possible, 
body scans should be performed with breath-hold scanning techniques. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  PET-CT scans are not always done with oral and IV contrast.  In 


 
GOG-3007 
 
 
-41-
addition, the PET portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed.  For these reasons, the GOG 
will not allow PET-CT use for RECIST 1.1 response criteria. 
 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT 
scanning in assessment of progression (particularly possible “new” disease).  New 
lesions on the basis of FDG-PET imaging can be identified according to the following 
algorithm:  
a. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign 
of PD based on a new lesion. 
b. 
No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, 
this is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site 
of disease on CT, additional follow-up CT  scans are needed to determine if 
there is truly progression occurring at that site (if so, the date of PD will be the 
date of the initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-
up corresponds to a pre-existing site of disease on CT that is not progressing on 
the basis of the anatomic images, this is not PD. 
 
 
Note:  A “positive” FDG-PET scan lesion means one that is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, 
it cannot be guaranteed that the same technique and measurements will be taken from 
one assessment to the next.  If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
 
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases, e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain. 
 
It is mandatory to obtain cytological confirmation of the neoplastic origin of any 
effusion that appears or worsens during treatment when measurable disease has met 
criteria for response or stable disease.  This confirmation is necessary to differentiate 
response or stable disease versus progressive disease, as an effusion may be a side effect 
of the treatment. 
 
 
 
8.13 
Response Criteria 
 
  
Determination of response should take into consideration all target (See 8.131) and non-
target lesions (See 8.132) and, if appropriate, biomarkers (See 8.133). 
 
 
 
 
8.131  
Evaluation of Target Lesions 
 


 
GOG-3007 
 
 
-42-
Complete Response (CR): Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm.  
 
 
 
 
 
 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new 
lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
 
 
 
 
8.132  
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions. All 
lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It must be 
representative of overall disease status change, not a single lesion increase. 
 
Not evaluable (NE):  When at least one non-target lesion is not evaluated at 
a particular time point. 
 
Although a clear progression of only “non-target” lesions is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and 
the progression status should be confirmed at a later time by the review 
panel (or Principal Investigator). 
 
8.133 
Evaluation of Biomarkers 
 
Biomarker measurements are not used to determine response or progression 
on this study. 
  
 
 
 
8.134  
Evaluation of Best Overall (unconfirmed) Response 
 
The best overall response is the best time point response recorded from the 
start of the treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest sum recorded since baseline).  
The patient's best response assignment will depend on the achievement of 
both measurement and confirmation criteria in some circumstances. 
 
Time Point Response for Patients with Measurable Disease at baseline (i.e., Target 
Disease) 


 
GOG-3007 
 
 
-43-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time Point Response for Patients with only Non-Measurable Disease at baseline 
(i.e., Non-Target Disease) 
 
Non-Target 
Lesions 
 
New 
Lesions* 
Time Point 
Response 
CR 
 
No 
CR 
CR 
 
No 
Non-CR/non-PD* 
Non-CR/non-PD 
 
No 
Non-CR/non-PD* 
NE 
 
No 
NE 
Unequivocal PD 
 
Yes or No 
PD 
Any 
 
Yes 
PD 
*See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion  
**  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
8.135 Best Overall Confirmed Response  
 
Confirmation of CR and PR for determination of best overall response is required 
for studies with a primary endpoint that includes response. 
 
 
Confirmed CR and PR for best overall confirmed response 
 
Time Point 
Response 
First time point 
Time Point Response 
Subsequent time 
point 
BEST overall confirmed 
response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR* 
Target 
Lesions 
Non-Target 
Lesions 
 
New 
Lesions* 
Time Point  
Response 
CR 
CR 
 
No 
CR 
CR 
Non-CR/Non-PD 
 
No 
PR 
CR 
NE 
 
No 
PR 
PR 
Non-PD or NE 
 
No 
PR 
SD 
Non-PD or NE 
 
No 
SD 
NE 
Non-PD 
 
No 
NE 
PD 
Any 
 
Yes or 
No 
PD 
Any 
PD** 
 
Yes or 
No 
PD 
Any 
Any 
 
Yes 
PD 
 
*See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion  
 
** In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 


 
GOG-3007 
 
 
-44-
CR 
SD 
SD provided minimum 
criteria for SD duration 
met, otherwise, PD 
CR 
PD 
SD provided minimum 
criteria for SD duration 
met, otherwise, PD 
CR 
NE 
SD provided minimum 
criteria for SD duration 
met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD  
PR 
PD 
SD provided minimum 
criteria for SD duration 
met, otherwise, PD 
PR 
NE 
SD provided minimum 
criteria for SD duration 
met, otherwise, NE 
NE 
NE 
NE 
 
*If a CR is truly met at first time point, then any disease seen at a subsequent 
time point, even disease meeting PR criteria relative to baseline, makes the 
disease PD at that point (since disease must have reappeared after CR).  
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small 
lesions were likely still present and in fact the patient had PR or SD, not CR at 
the first time point. Under these circumstances, the original CR should be 
changed to PR or SD and the best response is PR or SD.  
 
In non-randomized trials where response is part of the primary endpoint, 
confirmation of CR or PR is needed to deem either one the “best overall 
response.”   Responses (CR and PR) require confirmation at greater than or 
equal to 4 weeks from initial documentation. 
 
For this study, the minimum criteria for SD duration is 8 weeks. 
 
Patients with a global deterioration of health status requiring discontinuation of 
treatment or die without objective evidence of disease progression at that time 
should be reported to be off study treatment due to “symptomatic deterioration.”  
Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
  
 
 
8.14 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 


 
GOG-3007 
 
 
-45-
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since date of study entry, including the baseline measurements.  
 
8.15 
Progression-Free Survival 
 
Progression-Free Survival (PFS) is defined as the duration of time from study entry to 
time of progression or death, whichever occurs first. 
 
 
8.16 
Survival 
 
Survival is defined as the duration of time from study entry to time of death or the date 
of last contact. 
 
 
 


 
GOG-3007 
 
 
-46-
9.0 
DURATION OF STUDY    
 
 
9.1 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the 
following criteria applies: 
 
• Disease progression, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s), 
• Patient withdraws consent for the study, 
• Patient non-compliance with the protocol, or 
• General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
9.2 
If patient comes off study treatment prior to progression, continue tumor measurements and 
radiologic evaluations on schedule until progression or initiation of a subsequent cancer 
therapy. Toxicity assessments will be continued until resolution or return to baseline. Patients 
will be followed after last drug dose until toxicity resolution or return to baseline, until 
progression if patient withdraws before progressive disease, or until study withdrawal if it 
occurs before this time. 
 
9.3 
All patients will be treated (with completion of all required case report forms) until disease 
progression or study withdrawal. Patients will then be followed every three months for the first 
two years and then every six months for the next three years. Patients will be monitored for 
delayed toxicity and survival for this 5-year period with Follow-Up Forms submitted to the 
GOG Statistical and Data Center, unless consent is withdrawn. Follow-Up Forms will no longer 
be required if the study is terminated prior to the completion of the 5-year follow-up period.  
 
9.4 
A patient is considered off study therapy when the patient has progressed or died, a non-
protocol drug or therapy (directed at the disease) is initiated or all study therapy is totally 
discontinued. Report all treatment received on Cycle Drug Information Forms and adverse 
events on Adverse Event Forms up until the patient qualifies as being off study therapy.  
 
 
 
   
 
 
 
 
 


 
GOG-3007 
 
 
-47-
10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
 
 
 
Sponsor:  GOG 
10.1 
ADVERSE EVENT REPORTING  
   
 
10.11 Definitions 
 
 
 
 
10.111 Adverse Event (AE):  Any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related. 
 
 
 
 
10.112 Suspected Adverse Reaction (SAR):  Adverse event for which there is a 
reasonable possibility that the investigational drug caused the adverse event 
(i.e., attribution to study drug of possible, probable, or definite).   
 
 
 
10.113 Serious Adverse Event (SAE):  An adverse event or suspected adverse reaction 
is considered “serious” if in the view of either the Investigator or sponsor, it 
results in any of the following outcomes: 
 
1) Death, 
2) A life-threatening adverse event, 
3) Inpatient hospitalization or prolongation or existing hospitalization, 
4) A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions,  
5) A congenital anomaly/birth defect. 
6) Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
 
10.114 Unexpected Adverse Event:  An adverse event is considered “unexpected” if it 
is not listed in the investigator brochure or is not listed at the specificity or 
severity that has been observed. 
 
10.12 Reporting Requirements:  All investigators and ultimately the protocol Principal 
Investigator (PI) have the primary responsibility for AE identification, documentation, 
grading, and assignment of attribution to the study drug.  It is the responsibility of the 
investigator to supply the medical documentation needed to support expedited AE 
reports in a timely manner.  Investigators MUST immediately report to the sponsor any 
serious adverse event, whether or not considered drug related, including those listed in 
the protocol or investigator brochure and must include an assessment of whether there 
is reasonable possibility that the drug caused the event (21 CFR 312.64(b)).  Please 
refer to Section 10.15 for reporting procedures. 
 
Information regarding AEs and SAEs will be collected from the time of the first dose of 
study drug until 30 days from the last dose administered.   
   
When possible, adverse events should be described in terms of a change in the baseline 
status or with a diagnosis or summary term rather than as individual symptoms. 
 


 
GOG-3007 
 
 
-48-
The Investigator is responsible for reporting SAEs to the appropriate Institutional 
Review Board (IRB) or other committees in accordance with local institutional and IRB 
policies.   
 
10.13 Criteria for Determining Adverse Event Severity:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 will be utilized for AE reporting.  
 
10.14 Criteria for Determining Adverse Event Causality:  The following attribution categories 
will be used in assessing the relationship between the AE and the study drug: 
 
 
 
 
 
 
 
 
 
 
10.15 Procedures for SAE Reporting:  The investigator must report to GOG any serious 
adverse event, including pregnancy, whether or not considered drug-related, within 24 
hours of any site personnel becoming aware of the event.   
 
All SAE reports (both initial and follow-up) are to be submitted using the GOG SAE 
Portal within SEDES.  Instructions for using the GOG SAE Portal can be found at 
(GOG username and password is required):   
https://gogmember.gog.org/gog/sae_portal/using%20the%20sae%20portal%20-
%20site%20user.pdf 
 
The GOG Regulatory Compliance Department will forward all SAE reports to 
usdrugsafety.operations@novartis.com within 24 hours of first awareness.   
      
10.2  
GOG DATA MANAGEMENT FORMS 
 
The following forms must be completed for all patients registered and submitted to the GOG 
Statistical and Data Center (SDC) in accordance with the schedule below.  Use the SDC 
Electronic Data Entry System (SEDES) online application found at the GOG Web Menu page, 
to view and print a copy of each form along with instructions, and to submit forms 
electronically.  All amendments to forms submitted through SEDES must also be submitted 
through SEDES.  The original form and required copies for forms NOT submitted online must 
be mailed to the GOG SDC.  Note:  Pathology report should be submitted via postal mail.  
The Upload feature in SEDES is an alternate method for submitting Pathology reports. 
 
 
RELATIONSHIP  
ATTRIBUTION DESCRIPTION 
Unrelated to 
investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention 
Unlikely 
The AE is doubtfully related to the intervention 
Related to investigational 
agent/intervention 
Possible 
The AE may be related to the intervention 
Probable 
The AE is likely related to the intervention 
Definite 
 
The AE is clearly related to the intervention 


 
GOG-3007 
 
 
-49-
 
Form± 
Due within 
Copies* 
Comments 
Weeks 
Event 
Form R (Registration 
Form) 
2 
 
Registration 
 
N/A  
Mandatory Submission via SEDES 
Specimen Consent 
1 
Registration 
N/A 
Mandatory Submission via SEDES 
 
Form OSR (Recurrent 
Gynecologic Cancer On-
Study Form) 
2 
 
Registration 
 
N/A  
Mandatory Submission via SEDES 
 
Form DR (Pre-Treatment 
Summary Form) 
2 
Registration 
N/A 
Mandatory Submission via SEDES 
 
Form CONM 
(Concomitant Medication 
Form) - baseline 
2 
Registration 
N/A 
Mandatory Submission via SEDES 
 
Form D2M (Solid Tumor 
Evaluation Form) - 
baseline 
2 
Registration 
N/A 
Mandatory Submission via SEDES 
Primary/Advanced 
Disease: 
Pathology Report** 
Persistent or Recurrent 
Disease: 
 
Pathology Report 
(only if histologically 
documented) 
 
 
6 
 
 
 
6 
 
 
 
 
Registration 
 
 
Registration 
 
 
 
1 
 
 
 
 
1 
 
 
 
Submit pathology reports via postal 
mail to SDC in Buffalo, New York or 
via report uploader 
Form D2R_TREAT (Cycle 
Dose Drug Form) 
2 
Completion of each cycle 
of therapy 
N/A 
Mandatory Submission via SEDES 
Form LABSPG1 (Labs 
and Chemistries Form 
Page 1) 
2 
Completion of each cycle 
of therapy 
N/A 
Mandatory Submission via SEDES 
Form LABSPG2 (Labs 
and Chemistries Form 
Page 2) 
2 
Completion of each cycle 
of therapy 
N/A 
Mandatory Submission via SEDES 
Form VITALSV2 (Vital 
Signs Form) 
2 
Completion of each cycle 
of therapy 
N/A 
Mandatory Submission via SEDES 
Form D2M (Solid Tumor 
Evaluation Form) 
2 
Tumor response or 
progression assessment 
 N/A 
Mandatory Submission via SEDES 
Form TR-FP01-3007*** 
FFPE primary tumor  
8 
Registration 
N/A 
Mandatory submission via SEDESƒ 
Form TR-FM01-3007*** 
FFPE metastatic tumor 
(optional) 
8 
Registration 
N/A 
Mandatory submission via SEDESƒ 
Form TR-FRP01-3007*** 
FFPE recurrent primary 
tumor (optional) 
8 
Registration 
N/A 
Mandatory submission via SEDESƒ 
Form TR-FRM01-3007*** 
FFPE recurrent metastatic 
tumor (optional) 
8 
Registration 
N/A 
Mandatory submission via SEDESƒ 
Form TR-FPP01-3007*** 
FFPE persistent primary 
tumor (optional) 
8 
Registration 
N/A 
Mandatory submission via SEDESƒ 


 
GOG-3007 
 
 
-50-
Form TR-FPM01-3007*** 
FFPE persistent metastatic 
tumor (optional) 
8 
Registration 
N/A 
Mandatory submission via SEDESƒ 
Form TR-WB01-3007 
whole blood 
26 
Registration 
N/A 
Mandatory submission via SEDESƒ 
Form T (Common 
Toxicity Reporting Form) 
2 
Beginning of each 
subsequent cycle 
N/A 
Mandatory Submission via SEDES 
Form Q0 (Treatment 
Completion Form) 
2 
Completion of study Rx 
and change in Rx 
N/A 
Mandatory Submission via SEDES 
Form Q (Follow-Up Form) 
2 
Disease progression; 
death; normal follow-up; 
change in treatment 
N/A 
Submit via SEDES  
quarterly for 2 years, semi-annually 
for 3 more years, annually thereafter 
 
* 
The number of required copies including the original form which must be sent to the Statistical and Data 
Center. 
** 
Pathology slides for central Pathology Committee review are not required on this study.  
*** A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the 
Biopathology Center. 
ƒ Form TR must be submitted regardless of whether the specimen is submitted for research. 
 
This study utilizes the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) for 
defining and grading adverse events to be reported on GOG case report forms.


 
GOG-3007 
 
 
-51-
11.0 
STATISTICAL CONSIDERATIONS (06/25/15)  
 
Overview, Study Registration and Randomization:  This study is a single stage, open-label 
randomized phase II clinical trial.  The intent of this study is to screen regimens for activity.  The two 
regimens will be assessed separately to estimate the probability of response.  All patients on this study 
will be registered and receive a random treatment assignment centrally at the GOG Statistical and Data 
Center.  Prior to registration, eligibility will be reviewed via Fast Fact Sheet verification.  The sequence 
of treatment assignments will be concealed from institutions and patients until registration with 
verification of eligibility.  A procedure will be used that tends to allocate the two regimens in the ratio 
of 1:1 within the strata defined by 1) Patients who have received adjuvant chemotherapy or any 
chemoradiation for treatment of endometrial cancer and 2) Patients who have never received adjuvant 
chemotherapy or chemoradiation for treatment of endometrial cancer.  Study reports will include a 
complete accounting of all patients registered to this protocol. 
 
11.1 
Data Collection:  The principal parameters to be collected, analyzed and reported to evaluate 
the activity level of these treatment regimens are: 
 
11.11 Outcome Variables: the primary outcome variable is the frequency of complete and 
partial clinical response among all eligible patients; survival time and progression-free 
survival time distributions will also be estimated. 
11.12 Tumor Characteristics: FIGO stage, recurrence status, sites and sizes/status of target 
and non-target lesions, tumor grade, histological cell type and estrogen receptor status.  
11.13 Patient Characteristics: age at entry, performance status, race, and prior therapy.   
11.14 Adverse Effects: frequency and severity of adverse effects, regardless of attribution, in 
patients who received any amount of study drug categorized and graded according to 
CTCAE v4.0.  
11.15 Treatment:  the total dose of each study drug administered, the number of cycles of 
study therapy administered, the reason for discontinuing study therapy. 
11.16 Laboratory Testing Results:  immunohistochemical expression of estrogen receptor-
alpha, estrogen receptor-beta, progesterone receptor-A, progesterone receptor B and the 
G protein-coupled estrogen receptor, GPR-30, phosphorylated S6rp, PTEN, total and 
phosphorylated AKT, total and phosphorylated mTOR, mutational analysis for PTEN, 
PIK3CA and K-ras, and mutational analysis of K-ras in circulating tumor cells  
 
11.2 
Accrual Rate: 5 per month based on accrual to GOG-0248   
 
11.3 
Study Design and Sample Size: This study will implement a single stage stratified statistical 
design. There is no planned statistical test to compare the regimens with respect to response. 
 
Hormonal agents studied by the GOG have yielded response rates ranging from 11% to 33% in 
chemo-naïve patients.  Within estrogen receptor positive subgroups, response rates of hormonal 
agents studied varied from 0% to 50%.  The response rate for a standard hormonal therapy 
studied by the GOG (Protocol 81 MPA:  200 mg PO daily) is 25% overall.   
 
Response rates are expected to differ based on a history of previous chemotherapy (alone or in 
combination with radiation) for endometrial carcinoma.  Patients with or without a history of 
chemotherapy or chemoradiation are eligible for this study.   
 
Fifty-five percent of patients enrolled on GOG-0248 in 2010-2011 had received adjuvant 
chemotherapy.  The increasing use of adjuvant chemotherapy for endometrial carcinoma 
suggests that the proportion of patients receiving prior chemotherapy is increasing over time.  A 
simple (i.e. single) binomial distribution approximating the marginal number of responses over 
both populations may not be adequate.  Furthermore, splitting the patient population by prior 
chemotherapy to create two separate trials is not feasible due to the length of time it would take 


 
GOG-3007 
 
 
-52-
to get sufficient patients in each trial.  Therefore, a conditional stratified phase II trial as 
proposed by London and Chang will be used which utilizes the marginal number of responses 
across all populations while factoring differing probabilities of response within each population.  
Conditioned on the realized sample size in each stratum, the probability mass function for R1 
can be found with: 
 
(
)
(
)
1
2
1
1
,
1,2.
ij
ij
ij
j
kj
j
n
r
ij
r
j
j
i
i
ij
r
r
r
i
n
P R
r
p
p
j
r
−
+
+
=
=


=
=
−
=




∑
∏

 
 
Where i indexes the number of important stratification levels under consideration and j indexes 
the stage of accrual, in this case there is only one stage.  The distribution of Rj depends on the 
probabilities of response, pi, within each stratum.  Stratum 1 will correspond with those patients 
who have been treated with chemotherapy whereas stratum 2 will correspond with those 
patients who have never had prior chemotherapy.  A response rate of 20% or less in those 
patients who have not had previous chemotherapy and a response rate of 10% or less in those 
patients who have received previous chemotherapy would be considered not worthy of further 
study.   The null hypothesis of no treatment effect is H0: p1 = 0.10 and p2 = 0.20.  Under the 
alternative hypothesis of H1: p1 = 0.30 and p2 = 0.40, the following design will limit the 
probability of type I error to 0.06 and type II to 0.10.  According to London and ChangA, the 
rejection boundary, a1, is found with the following equation: 
 
(
)
1
1
0
|
i
i
i
P R
a
p
p
γβ
<
=
+ ∆
≈
 
 
where p10 = 0.20, Δ1 = 0.20, p20 = 0.10, Δ2 = 0.20, and γβ is the probability of a type II error.  
Since it is important to maintain the original design parameters for this study, a1 is found with  
 
(
)
1
1
0
|
0.5 0.10
0.05
i
i
i
P R
a
p
p
<
=
+ ∆
≈
×
=
 
 
The cumulative targeted accrual will be set at 36 patients for each treatment arm or a 
total of 72 patients.  Each regimen will be assessed separately.  Because the rejection boundary 
depends on the realized sample size and the proportion of patients from each stratum, it is 
difficult to present an exhaustive list of rejection boundaries that could be used to determine the 
worthiness of the agent to undergo further investigation, however, Table 11.1 is provided here 
to give examples of the properties of the design where α is the probability of a type I error, and 
β is the probability of a type II error: 
 
Table 11.1 Rejection boundaries for various scenarios for an individual treatment arm 
Proportion 
in stratum 1 
Proportion 
in stratum 
2 
Number 
in stratum  
1 
Number 
in stratum  
2 
Sample 
Size 
Rejection 
boundary 
a1 
α 
1- β 
0.4 
0.6 
15 
22 
37 
9 
.058 
.907 
0.5 
0.5 
19 
19 
38 
9 
.048 
.906 
0.6 
0.4 
22 
14 
36 
8 
.052 
.908 
0.7 
0.3 
26 
11 
37 
8 
.042 
.906 
0.8 
0.2 
28 
7 
35 
7 
.050 
.914 


 
GOG-3007 
 
 
-53-
Proportion 
in stratum 1 
Proportion 
in stratum 
2 
Number 
in stratum  
1 
Number 
in stratum  
2 
Sample 
Size 
Rejection 
boundary 
a1 
α 
1- β 
0.9 
0.1 
29 
3 
32 
6 
.053 
.907 
 
If the number of responses reported for an individual regimen is less than the value in the 
column labeled as “Rejection Boundary a1” then the regimen will be deemed unworthy of 
further investigation. 
 
Table 11.2 displays the operating characteristics for the boldfaced design and decision rule in 
Table 11.1 under different alternative hypotheses. 
 
Table 11.2 Operating characteristics 
πA 
πB 
Pr(neither A 
nor B are 
deemed active 
|πA,  πB) 
Pr(both A and 
B are deemed 
active |πA,  πB) 
Pr(A is 
deemed active 
and B is not 
deemed 
active|πA,  πB) 
Pr(B is 
deemed 
active and A 
is not deemed 
active|πA,  πB) 
0.1,0.2 
0.1,0.2 
0.899 
0.003 
0.049 
0.049 
0.1,0.2 
0.3,0.4 
0.087 
0.047 
0.005 
0.861 
0.1,0.2 
0.4,0.5 
0.006 
0.052 
<0.001 
0.942 
0.3,0.4 
0.1,0.2 
0.087 
0.047 
0.861 
0.005 
0.3,0.4 
0.3,0.4 
0.008 
0.824 
0.084 
0.084 
0.3,0.4 
0.4,0.5 
<0.001 
0.903 
0.005 
0.091 
0.4,0.5 
0.1,0.2 
0.006 
0.052 
0.942 
<0.001 
0.4,0.5 
0.3,0.4 
<0.001 
0.903 
0.091 
0.005 
0.4,0.5 
0.4,0.5 
<0.001 
0.988 
0.006 
0.006 
πA =probabilities of response on regimen A (stratum 2, stratum 1); 
πB =probabilities of response on regimen B (stratum 2, stratum 1) 
Sum the last three columns in each row to get the probability of declaring at least one of the regimens 
active. 
 
95% Confidence intervals for proportion responding to each regimen will be calculated. 
 
11.4 
Study Monitoring:  In general, data sheets from patients on this protocol will be reviewed 
semi-annually and will also be reviewed by the Study Chair annually or at the discretion of the 
Statistical and Data Center.  In some instances because of unexpectedly severe toxicity, the 
Statistical and Data Center may elect to suspend accrual and, after consultation with the Study 
Chair and the committee responsible for monitoring the safety data for phase II trials, 
recommend early closure of a study. 
 
The frequency and severity of all toxicities will be tabulated from submitted case report forms 
and summarized for review by the study chairperson and GOG Safety Review Committee 
(SRC) in conjunction with each semi-annual Group meeting.  
 


 
GOG-3007 
 
 
-54-
All reports of serious and/or unexpected adverse events are communicated to the Study Chair, 
sponsor, and regulatory agencies as mandated in the protocol. These reports are reviewed by the 
Study Chair (or designated co-chair) for consideration of investigator notification, amendment, 
or immediate study suspension. When immediate suspension is warranted, all participating 
institutions will then receive notification of the toxicities and reason for study suspension. 
Under these circumstances, accrual cannot be re-activated until the study is reviewed by the 
committee responsible for monitoring the safety data for phase II trials. However, in some 
instances patients currently receiving treatment may continue to receive treatment in accordance 
with protocol guidelines at the discretion of their physicians, unless directed otherwise.   
 
11.5 
Study Duration:  The anticipated duration of accrual is 17 months.  An additional 6-18 months 
may be necessary for data maturity, laboratory and statistical analysis. 
 
11.6 
Secondary Objectives:  Progression-free survival (PFS) will be estimated using the Kaplan-
Meier product limit estimator and graphed by treatment arm.  Median PFS will be reported with 
a 95% confidence interval for each treatment arm.  The frequency and severity of adverse 
events will be tabulated without regard to attribution by treatment arm using adverse event 
terms and grades defined in CTCAE version 4.   
 
11.7 
Translational Research Analysis: 
The expression of candidate markers will be determined by standard semi-quantitative methods 
for IHC evaluation of hormone receptors (estrogen receptor-alpha, estrogen receptor-beta, 
progesterone receptor-A, progesterone receptor B and the G protein-coupled estrogen receptor, 
GPR-30) and components of the mTOR signaling pathway (phosphorylated S6rp, as well as 
PTEN, total and phosphorylated AKT, phospho-ERK1/2). Additionally, mutational analysis, 
including PTEN, PIK3CA, KRAS, and CTNNB1 will be performed. These data will be 
transmitted to the GOG Statistical Office, Buffalo, NY.  The levels of expression of the 
candidate markers measured prior to study treatment will be tabulated and described. 
Associations between markers, other baseline data and clinical outcome will be assessed in an 
exploratory manner. Methods such as logistic or proportional hazards regression will likely be 
used for these analyses when response, PFS or survival is the dependent variable when 
necessary model assumptions are appropriate. Exploratory analyses utilizing methods 
appropriate to the type of data will be conducted to examine the associations between markers 
and between markers and clinical characteristics.  
 
 
 


 
GOG-3007 
 
 
-55-
 
12.0 
BIBLIOGRAPHY   
 
Atkinson, EN, Brown BW.  Confidence limits for probability of response in multistage phase II clinical trials. 
Biometrics 1985; 41(3): 741-4. 
 
Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal 
hormone-receptor-positive advanced breast cancer. N Engl J Med 2012; 366:520–9. 
 
Bjornsti MA, Houghton PJ. The TOR Pathway: A target for Cancer therapy. Nat Rev Cancer 2004; 4(5):335-48. 
 
Boulay A, Lane HA.  The mammalian target of rapamycin kinase and tumor growth inhibition. Recent Results 
Cancer Res 2007; 172:99-124. 
 
Cohen HT, McGovern FJ.  Renal Cell Carcinoma. N Engl J Med 2005; 353(23):2477-90. 
 
Colombo N, McMeekin DS, Schwartz PE, Sessa C, Gehrig PA, and Holloway R et al. Ridaforolimus as a single 
agent in advanced endometrial cancer: results of a single-arm, phase 2 trial. Br J Cancer 2013; 108(5):1021-6.  
 
de Leeuw R, Neefjes J, Michalides R. A role for estrogen receptor phosphorylation in the resistance to 
Tamoxifen. Int J Breast Cancer 2011; 2011:232435. 
 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Ca 2009; 45:228-247. 
 
Fiorica JV, Brunetto VL, Hanjani P, Lentz SS, Mannel R, Andersen W et al. Phase II trial of alternating courses 
of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. 
Gynecol Oncol 2004;92(1):10-4. 
 
Fleming GF, Filiaci VL, Marzullo B, et al.  Temsirolimus with or without megestrol acetate and tamoxifen for 
endometrial cancer:  A gynecologic oncology group study.  Gynecol Oncol 2014; 132(3):585-92. 
 
Frattini M, Signoroni S, Pilotti S.  Phosphatase protein homologue to tensin expression and 
phosphatidylinositol-3 phosphate kinase mutations in colorectal cancer. Cancer Res 2005; 65(23):11227. 
 
Goel A, Arnold CN, Niedzwiecki D, et al.  Frequent inactivation of PTEN by promoter hypermethylation in 
microsatellite instability-high sporadic colorectal cancers. Cancer Res 2004; 64(9):3014-21. 
 
Gu C, Zhang Z, Yu Y, Liu Y, Zhao F, Yin L, et al. Inhibiting the PI3K/AKT pathway reversed progestin 
resistance in endometrial cancer. Cancer Sci 2011; 102:557–64. 
 
Lentz S, Brady MF, Major FJ, Reid GC, Soper JT.  High Dose Megestrol Acetate in Advanced or Recurrent 
Endometrial Carcinoma: A Gynecologic Oncology Group Study. J Clin Oncol 14(2): 357-361, 1996. 
 
London WB, Chang MN. One- and two-stage designs for stratified phase II clinical trials.  Statist. Med 2005; 
24:2597-2611. 
 
Loomba R, Rowley A, Wesley R, et al. Systematic review: the effect of preventive lamivudine on hepatitis B 
reactivation during chemotherapy. Ann Intern Med 2008; 148(7): 519-28. 
 
Mendoza MC, Er EE, Blenis J. The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends 
Biochem Sci 2011; 36: 320–8. 
 


 
GOG-3007 
 
 
-56-
Milam MR, Celestino J,Wu W, Broaddus RR, Schmeler KM, Slomovitz BM, et al. Reduced progression of 
endometrial hyperplasia with oral mTOR inhibition in the Pten heterozygote murine model. Am J Obstet 
Gynecol 2007; 196:247–5. 
 
Miller D, Filiaci V, Fleming G, Mannel R, Cohn D, Matsumoto T, Tewari K, DiSilvestro P, Pearl M, Zaino R. 
Randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial 
carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 125: 771-3, 2012. (Abstract) 
 
Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J 
Clin Oncol 2011; 29: 4452–61. 
 
Oza AM, Elit L, Tsao MS, Kamel-Reid S, Biagi J, Provencher DM, et al. Phase II study of temsirolimus in 
women with recurrent or metastatic endometrial cancer: a trial of the NCIC clinical trials group. J Clin Oncol 
2011; 29: 3278–85. 
 
Rose PG, Brunetto VL, Van Le L, et al. A phase II trial of anastrozole in advanced recurrent or persistent 
endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2000;78(2):212-6. 
 
Rustin GJ, Quinn M, Thigpen T, et al. Re: New guidelines to evaluate the response to treatment in solid tumors 
(ovarian cancer). JNCI 96:487-488, 2004 
 
Siegel R, Ma J, Zou Z, et al.  Cancer Statistics, 2014.  CA Cancer J Clin 2014; 64:9-29. 
 
Singh RR, Patel KP, Routbort MJ, et al. Clinical validation of a next-generation sequencing screen for 
mutational hotspots in 46 cancer-related genes. J Mol Diagn. 2013; 15(5):6 
 
Slomovitz BM, Brown J, Johnston TA, Mura D, Levenback C, Wolf J, et al. A phase II study of everolimus and 
letrozole in patients with recurrent endometrial carcinoma [abstract]. J Clin Oncol 2011; 29: abstract 5012. 
 
Slomovitz BM, Lu KH, Johnston T, Coleman RL, Munsell M, Broaddus RR, et al. A phase 2 study of the oral 
mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma. Cancer 
2010; 116:5415–9. 
 
The Cancer Genome Atlas Research Network.  Integrated genomic characterization of endometrial carcinoma.  
Nature 2013; 487:67-73. 
 
Thigpen JT, Brady MF, Alvarez RD, Adelson MD, Homesley HD, Manetta A, Soper J, Given FT.  Oral 
Medroxyprogesterone Acetate in the Treatment of Advanced or Recurrent Endometrial Carcinoma: A Dose-
Response Study by the Gynecologic Oncology Group. J Clin Oncol 17: 1736-1744, 1999. 
 
Velho S, Oliveira C, Ferreira A, et al.  The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J 
Cancer 2005; 41(11):1649-54. 
 
Vergote I, Rustin GJ, Eisenhauer EA, et al. Re: new guidelines to evaluate the response to treatment in solid 
tumors [ovarian cancer]. Gynecologic Cancer Intergroup. JNCI 92:1534-1535, 2000. 
 
Whitney CW, Brunetto VL, Zaino RJ, Lentz SS, Sorosky J, Armstrong DK, et al., Phase II study of 
medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology 
Group study. Gynecol Oncol. 2004;92(1):4-9. 
 
Yamnik RL, Digilova A, Davis DC, et al. S6 kinase 1 regulates estrogen receptor alpha in control of breast 
cancer cell proliferation. J Biol Chem 2009; 284(10):6361-9. 
 


 
GOG-3007 
 
 
-57-
Yamnik RL, Holz MK. mTOR/S6K1 and MAPK/RSK signaling pathways coordinately regulate estrogen 
receptor alpha serine 167 phosphorylation. FEBS Lett 2010; 584:124-8. 
 
Yeo W, Lam KC, Zee B, et al.  Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing 
systemic chemotherapy. Annals of Oncology 2004; 15:1661-1666 
 


 
GOG-3007 
 
 
-58-
 
APPENDIX I - Clinical Staging (FIGO) 
  
 
CARCINOMA OF THE ENDOMETRIUM 
FIGO CLASSIFICATION 
2009 
 
Stage I* 
Tumor confined to the corpus uteri. 
IA* 
No or less than half myometrial invasion 
IB* 
Invasion equal to or more than half of the myometrium 
Stage II* 
Tumor invades cervical stroma, but does not extend beyond the uterus** 
Stage III* 
Local and/or regional spread of the tumor 
IIIA* 
Tumor invades the serosa of the corpus uteri and/or adnexae# 
IIIB* 
Vaginal and/or parametrial involvement# 
IIIC* 
Metastases to pelvic and/or para-aortic lymph nodes# 
IIIC1* 
Positive pelvic nodes 
IIIC2* 
Positive para-aortic lymph nodes with or without positive pelvic lymph         
nodes 
Stage IV* 
Tumor invades bladder and/or bowel mucosa, and/or distant metastases 
IVA* 
Tumor invasion of bladder and/or bowel mucosa 
IVB 
Distant metastases, including intra-abdominal metastases and/or inguinal 
lymph nodes 
 
*Either G1, G2, or G3. 
 
**Endocervical glandular involvement only should be considered as Stage I and no longer as Stage II. 
 
#Positive cytology has to be reported separately without changing the stage. 
 
 
 


 
GOG-3007 
 
 
-59-
APPENDIX II - General Chemotherapy Guidelines 
 
• For 21 or 28 day cycles, a patient will be permitted to have a new cycle of chemotherapy 
delayed up to 7 days (without this being considered to be a protocol violation) for major life 
events (e.g., serious illness in a family member, major holiday, vacation which is unable to be 
re-scheduled).  Documentation to justify this decision should be provided. 
• It will be acceptable for individual chemotherapy doses to be delivered within a “24-hour 
window before and after the protocol-defined date” for “Day 1” treatment of 21 or 28 day 
cycles.  If the treatment due date is a Friday, and the patient cannot be treated on that Friday, 
then the window for treatment would include the Thursday (1 day earlier than due) through the 
Monday (day 3 past due). 
• For weekly regimens, it will be acceptable for individual chemotherapy doses to be delivered 
within a “24-hour window,” for example; “Day 8 chemotherapy” can be delivered on Day 7, 
Day 8, or Day 9 and “Day 15 chemotherapy” can be given on Day 14, Day 15, or Day 16. 
• Chemotherapy doses can be “rounded” according to institutional standards without being 
considered a protocol violation (most institutions use a rule of approximately +/- 5% of the 
calculated dose). 
Chemotherapy doses are required to be recalculated if the patient has a weight change of greater 
than or equal to 10%. Patients are permitted to have chemotherapy doses recalculated for < 10% 
weight changes.  
 


 
GOG-3007 
 
 
-60-
APPENDIX III - PATIENT PILL CALENDAR: ARM I 
 
Patient Name: ________________________ Date of first dose on calendar: __________________ 
Patient Study ID: _____________________ Cycle #:____________________________________ 
 
 
 
• Complete one form for each cycle of treatment 
• You will take Letrozole and Everolimus once a day 
• Please bring this form and your bottles of Letrozole and Everolimus each time you 
return for an appointment 
Day 
Date 
Time of 
Letrozole Dose 
Dose 
taken 
Time of 
Everolimus 
Dose 
Dose  
taken 
 
Comments 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 


 
GOG-3007 
 
 
-61-
APPENDIX III - PATIENT PILL CALENDAR: ARM II 
 
Patient Name: ________________________ Date of first dose on calendar: __________________ 
Patient Study ID: _____________________ Cycle #:____________________________________ 
 
 
 
• Complete one form for each cycle of treatment 
• You will take Tamoxifen (20 mg) twice a day 
• On alternating weeks (even numbered weeks) you will take Medroxyprogesterone 
Acetate (200 mg) once daily with Tamoxifen (20 mg) twice a day 
• Please bring this form and your bottles of Tamoxifen and Medroxyprogesterone 
each time you return for an appointment 
Day 
Date 
Time of 
Tamoxifen 
Dose AM 
Time of 
Tamoxifen 
Dose PM 
Dose 
taken 
Time of 
Medroxyprogesterone 
Dose 
Dose  
taken 
 
Comments 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 


 
GOG-3007 
 
 
-62-
 
APPENDIX IV - Translational Research Specimen Procedures (03/10/2015) 
 
I. 
Summary of Specimen Requirements 
 
If the patient gives permission for her specimens to be collected and used for this optional 
translational research component, then participating institutions are required to submit the 
patient’s specimens as outlined below (unless otherwise specified). 
 
Required Specimen 
(Specimen Code) 
Collection Time Point 
Ship To 
FFPE Primary Tumor (FP01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to all treatment (Preferred FFPE) 
Biopathology Center within 8 
weeks of registration1 
FFPE Metastatic Tumor (FM01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to all treatment (Optional if FP01, 
FRP01, FRM01, FPP01, or FPM01 is 
submitted) 
FFPE Recurrent Primary Tumor 
(FRP01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to study treatment (Optional if 
FP01, FM01, FRM01, FPP01, or FPM01 
is submitted) 
FFPE Recurrent Metastatic Tumor 
(FRM01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to study treatment (Optional if 
FP01, FM01, FRP01, FPP01, or FPM01 
is submitted) 
FFPE Persistent Primary Tumor 
(FPP01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to study treatment (Optional if 
FP01, FM01, FRP01,  FRM01, or 
FPM01 is submitted) 
FFPE Persistent Metastatic Tumor 
(FPM01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
Prior to study treatment (Optional if 
FP01, FM01, FRP01, FRM01, or FPP01 
is submitted) 
Whole Blood (WB01) 
7-10mL drawn into purple top 
(EDTA) tube(s) 
Prior to or after starting study treatment 
Biopathology Center the day 
the specimen is collected1 
* 
A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the Biopathology Center. 
1 
Biopathology Center / Protocol GOG-3007, Nationwide Children’s Hospital, 700 Children’s Drive, WA1340, Columbus, OH 
43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: BPCBank@nationwidechildrens.org 
 
II. 
Obtaining a Biopathology Center Number for Translational Research Specimens  
 
Only one GOG Foundation BPC # (# # # # - # # - F # # #) is assigned per patient. Note: GOG 
Foundation BPC # includes the letter “F.”  All translational research specimens and 
accompanying paperwork must be labeled with this coded patient number. A BPC # can be 
obtained online via the Tissue Bank Portal (under Tools on the Web Menu page). 
 
Obtain the patient’s study ID before requesting a BPC # from the Tissue Bank Portal. Be sure to 
indicate if the patient has a previous study ID when registering.  


 
GOG-3007 
 
 
-63-
 
Please contact Support if you need assistance or have assigned more than one BPC # to a patient 
(Email: support@gogstats.org; Phone: 716-845-7767). 
 
III. Requesting Translational Research Specimen Kits  
 
Kits are not provided for this protocol. A pre-paid FedEx air bill is provided for the submission of 
whole blood. 
 
IV. Labeling Translational Research Specimens  
 
A waterproof permanent marker or printed label should be used to label each translational 
research specimen with: 
 
BPC # (# # # # - # # - F # # #) Note: GOG Foundation BPC # includes the letter “F.” 
GOG protocol number (GOG-3007) 
specimen code (see section I) 
collection date (mm/dd/yyyy) 
surgical pathology accession number (tissue specimens only) 
block number (tissue specimens only) 
 
Note: If labeling slides, only label on the top, front portion of the slide. Do not place a label on 
the back of the slide or over the tissue. The label must fit on the slide and should not be wrapped 
around the slide or hang over the edge. 
 
V. 
Submitting Formalin-Fixed, Paraffin-Embedded Tissue 
 
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the 
specimen type (primary, metastatic, recurrent). Primary and metastatic tumor should be 
collected prior to all treatment. Recurrent and persistent tumor should be collected prior to the 
study treatment. Recurrent or persistent tumor collected from the site of primary disease should 
be labeled recurrent primary or persistent primary, respectively. Recurrent or persistent tumor 
collected from a site other than the site of primary disease (e.g., lymph node) should be labeled 
recurrent metastatic or persistent metastatic, respectively. Only one block may be submitted 
per tissue type. 
 
Every attempt should be made to provide a FFPE block; however, if a block cannot be provided 
on a permanent basis, then 20 unstained slides (10 charged, 5µm and 10 uncharged, 10 µm) 
should be submitted. All tissue sections should be cut sequentially from the same block.  
 
The type of specimen (block or slides) should be specified on Form TR. If submitting slides, the 
slide type, thickness, and count should also be specified. 
 
All FFPE tissue should be submitted with the corresponding pathology report. 
 
VI. Submitting Whole Blood 
 
1.  Label the lavender/purple top (EDTA) collection tube(s) as described above. Multiple tubes 
may be used to collect the required amount. 


 
GOG-3007 
 
 
-64-
 
2. Draw 7-10mL of blood into the labeled lavender/purple top tube(s). A minimum of 3mL is 
needed for processing. 
 
3.  Immediately after collection, gently invert the tube 5-10 times to mix the blood and EDTA. 
   
4. Whole blood specimens should be refrigerated (4°C) until the specimens can be shipped. Ship 
whole blood to the Biopathology Center the day the specimen is collected. If the whole blood 
absolutely cannot be shipped the day it is collected, the tube(s) should be refrigerated (4°C) 
until the specimen can be shipped. 
 
VII. 
Submitting Form TR 
 
Form TR must be submitted via SEDES for each required specimen regardless of whether the 
specimen is submitted for research. 
 
A copy of the SEDES-completed Form TR must accompany each specimen shipped to the 
Biopathology Center (or alternate laboratory). Handwritten forms will not be accepted. 
 
Note: A copy does not need to be sent if the specimen is not collected. 
 
Retain a printout of the completed form for your records. 
 
Please contact Support if you need assistance (Email: support@gogstats.org; Phone: 716-845-
7767). 
 
VIII. Shipping Translational Research Specimens 
 
A SEDES-completed copy of Form TR must be included for each translational research 
specimen. 
 
A. FFPE Tissue 
 
FFPE tissue and a copy of the corresponding pathology report should be shipped using your 
own container at your own expense to: 
 
Biopathology Center / Protocol GOG-3007 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
Do not ship FFPE tissue for Saturday delivery. 
 
B. Whole Blood 
 
Whole blood specimens should be shipped to the Biopathology Center (address above). 


 
GOG-3007 
 
 
-65-
 
Whole blood specimens can be shipped to the Biopathology Center Monday through Friday 
for Tuesday through Saturday delivery. Do not ship whole blood the day before a holiday. 
Use your own shipping container to ship specimens via FedEx priority overnight. 
 
When shipping whole blood specimens, your institution must comply with IATA 
standards (www.iata.org). If you have questions regarding your shipment, contact the 
Biopathology Center at BPCBank@nationwidechildrens.org or by phoning 866-464-2262.  
 
To ship whole blood specimens you will need (1) a sturdy shipping container (e.g., a 
cardboard or styrofoam box), (2) a leak proof biohazard envelope with absorbent material*, 
(3) a puncture and pressure resistant envelope (e.g. Tyvek envelope), (4) an Exempt Human 
Specimen sticker, and (5) a pre-paid FedEx air bill. 
 
*If you will be shipping whole blood specimens from more than one patient, please put each 
specimen in a separate plastic zip-lock bag before placing the specimens in the shipping bag. 
You may include up to four different blood specimens in one biohazard envelope. 
 
If you do not have these materials available at your institution, you may order them from any 
supplier (e.g., Saf-T-Pak; Phone: 800-814-7484; Website: www.saftpak.com). 
 
Shipping Whole Blood Using Your Own Shipping Container 
 
1. Place the whole blood specimen in a biohazard envelope containing absorbent material. 
Expel as much air as possible before sealing the bag. 
  
2. Wrap the biohazard envelope in bubble wrap or another padded material. 
 
3. Place the padded tube(s) into a Tyvek envelope. Expel as much air as possible before 
sealing the envelope. 
 
4. Place the Tyvek envelope in a sturdy shipping container (e.g., cardboard FedEx box). 
 
5. Insert a copy of Form SP for each specimen.  
 
6. Attach an Exempt Human Specimen sticker to the outside of the shipping container. 
 
7. Print a pre-paid FedEx air bill using the Kit Management application (found under Data 
Entry on the Web Menu page). Attach the air bill. 
 
8. Make arrangements for FedEx pick-up through your usual institutional procedure or by 
calling 800-238-5355. 
 
IX. Distributing Translational Research Specimens 
 


 
GOG-3007 
 
 
-66-
The GOG Statistical and Data Center and Biopathology Center (or alternate laboratory) will 
coordinate the distribution of specimens to approved investigators. 
 
Investigators will not be given access to any personal identifiers. 
 
Investigators will be responsible for the direct supervision and oversight of translational research 
and for keeping accurate records. 
 
Investigators will ensure the results are linked to the appropriate specimen-specific identifiers 
and are responsible for transferring laboratory data to the statistics center. 
 
At the discretion of the Committee on Experimental Medicine Chair and Director of the 
Biopathology Center, investigators may be required to ship any specimens (or by-products) 
remaining after the completion of the translational research to the Biopathology Center. 
 
A. FFPE 
 
FFPE will be batch shipped upon trial completion to: 
 
Dr. Karen Lu 
 
ATTN: Joseph Celestino 
MD Anderson Cancer Center 
Gyn Onc & Reproductive Med-Rsch 
1515 Holcombe Blvd. 
Houston, TX 77030 
Phone: 713-745-8902 
Email: khlu@mdanderson.org 
 
B. Whole Blood 
 
The Biopathology Center will extract DNA form whole blood. Aliquots of DNA will be batch 
shipped upon trial completion to Dr. Karen Lu (address above). 
 
X. 
Banking Translational Research Specimens for Future Research 
 
Specimens will remain in the Biopathology Center and made available for approved research 
projects if the patient has provided permission for the use of her specimens for future health 
research. The patient’s choices will be recorded on the signed informed consent document and 
electronically via the specimen consent form. At the time of specimen selection for project 
distribution, the most recent consent information will be used. 
 
Institutions can amend a patient’s choices regarding the future use of her specimens at any 
time if the patient changes her mind. 
 


 
GOG-3007 
 
 
-67-
If the patient revokes permission to use her specimens, the Biopathology Center will destroy or 
return any remaining specimens. The patient’s specimens will not be used for any further 
research; however, any specimens distributed for research prior to revoking consent cannot be 
returned or destroyed. In addition, the patient cannot be removed from any research that has been 
done with her specimens distributed prior to revoking consent. 
 
Note: If return of specimens is requested, shipping will be at the institution’s expense. 
 
 


 
GOG-3007 
 
 
-68-
APPENDIX V – CT Scan Date Calculator 
 
Please refer to separate spreadsheet for CT Scan Date Calculator.