Clinical trial NCT00729586
Conditions: Endometrial Carcinoma Recurrent Uterine Corpus Carcinoma Stage IIIA Uterine Corpus Cancer Stage IIIB Uterine Corpus Cancer Stage IIIC1 Uterine Corpus Cancer Stage IIIC2 Uterine Corpus Cancer Stage IVA Uterine Corpus Cancer Stage IVB Uterine Corpus Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2008-09-01; Completion date: 2017-02-01
Enrollment: 73 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well temsirolimus with or without megestrol acetate and tamoxifen citrate works in treating patients with endometrial cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment, has returned after a period of improvement, or is persistent. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of endometrial cancer cells. Hormone therapy using megestrol acetate and tamoxifen citrate may fight endometrial cancer by blocking the use of estrogen by the tumor cells. It is not yet known whether temsirolimus is more effective when given alone or together with megestrol acetate and tamoxifen citrate in treating endometrial cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the 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 temsirolimus intravenously (IV) weekly, Arm #2 megestrol (megestrol acetate)/tamoxifen (tamoxifen citrate) plus temsirolimus IV weekly.

II. Time to progression and number of patients remaining on study therapy at 24 weeks.

SECONDARY OBJECTIVE:

I. To describe the toxicities of each of the arms of the trial when used for patients with advanced/metastatic endometrial cancer.

TERTIARY OBJECTIVES:

I. Explore whether immunohistochemical expression of hormone receptors (estrogen receptor-alpha, estrogen receptor-beta, progesterone receptors-A, progesterone receptor-B and the alternative estrogen receptor, G protein-coupled estrogen receptor \[GPR\]-30) or components of the mammalian target of rapamycin (mTOR) signaling pathway (normal and mutant phosphatase and tensin homolog \[PTEN\], total and phosphorylated v-akt murine thymoma viral oncogene homolog 1 \[Akt\] as well as total and phosphorylated p70S6 kinase) are associated with treatment, outcome or clinical characteristics.

II. Explore whether single nucleotide polymorphisms (SNPs) in the FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1) and regulatory associated protein of mTOR (RAPTOR) genes, mutations in phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), PTEN and paxillin or copy number abnormalities in PTEN and paxillin are associated with treatment, outcome or clinical characteristics.

OUTLINE: Patients are randomized to 1 of 2 treatment arms. (Closed to accrual as of 11/22/2010)

ARM I: Patients receive temsirolimus IV over 30 minutes once weekly for 6 weeks. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

ARM II (Closed to accrual as of 12/21/2009): Patients receive temsirolimus as in Arm I and megestrol acetate orally (PO) twice daily (BID) for 3 weeks alternating with tamoxifen citrate PO BID for 3 weeks. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

Arms: arm 1: Patients receive temsirolimus IV over 30 minutes once weekly for 6 weeks. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive temsirolimus as in Arm I and megestrol acetate PO BID for 3 weeks alternating with tamoxifen citrate PO BID for 3 weeks. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Megestrol Acetate intervention 3: Tamoxifen Citrate intervention 4: Temsirolimus
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Given PO intervention 4: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
Philip J. DiSaia, M.D. 
President 
 
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. 
Vice President  
 
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 
 
 
 
SUMMARY OF CHANGES 
 
For Protocol Revision #9 to: 
 
NCI Protocol #: GOG-0248 
Local Protocol #: GOG-0248 
 
NCI Version Date: December 22, 2014 
Protocol Date: December 22, 2014 
 
# 
Section 
Page(s) 
Change 
1. 
Title Page 
1-2 
NCI version date has been updated. 
 
Includes Revisions #1-9. 
 
Lead Organization has been added. 
 
Revised footer has been added. 
 
ICD 
 
NCI version date has been update on the Informed Consent 
 


Philip J. DiSaia, M.D. 
President 
 
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. 
Vice President  
 
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-0248 
 
A RANDOMIZED PHASE II TRIAL OF TEMSIROLIMUS (NCI-SUPPLIED AGENT,  
NSC # 683864, IND # 61010) OR THE COMBINATION OF HORMONAL THERAPY PLUS 
TEMSIROLIMUS IN WOMEN WITH ADVANCED, PERSISTENT, OR RECURRENT 
ENDOMETRIAL CARCINOMA 
NCI Version Date: December 22, 2014 
(Includes Revisions # 1-9) 
POINTS: 
PER CAPITA – 10 
MEMBERSHIP – 3 
TRANSLATIONAL RESEARCH PER CAPITA – Award based on specimen submissions. Distribution: 1.0 point for a 
block or 20 unstained slides of formalin-fixed and paraffin-embedded (FFPE) primary (1st choice), metastatic (2nd choice), 
and/or recurrent tumor (3rd choice), and 0.5 point for a frozen blood specimen. 
Lead Organization: NRG/NRG Oncology 
STUDY CHAIR 
 
NURSE CONTACT 
GINI FLEMING, M.D.                                            
JONI SHORTT, R.N., B.S.N. 
 
UNIVERSITY OF CHICAGO 
 
MEMORIAL HEALTH UNIVERSITY MEDICAL CTR 
SECTION OF MEDICAL ONCOLOGY (MC2115) 
CURTIS AND ELIZABETH ANDERSON CANCER INST 
5841 S. MARYLAND AVE. (ROOM I-211) 
 
ONCOLOGY RESEARCH DEPARTMENT 
CHICAGO, IL  60637                                               
4700 WATERS AVENUE 
(773) 702-6712 
 
SAVANNAH, GA 31404-3089  
 
FAX: (773) 702-0963 
 
(912) 350-8913  
E-MAIL: gfleming@medicine.bsd.uchicago.edu  
FAX : (912) 350-8183  
 
 
E-MAIL: shortJo1@memorialhealth.com 
 
 
TRANSLATIONAL RESEARCH CO-CHAIR  
PATHOLOGIST 
KIMBERLY K. LESLIE, M.D. 
 
 RICHARD ZAINO, M.D. 
See GOG Website Directory 
 
See GOG Website Directory 
 
 
 
 
 
 
 
 
TRANSLATONAL RESEARCH SCIENTIST  
STATISTICIAN 
 
 
 
 
KATHLEEN M. DARCY, PH.D. 
 
GINNY FILIACI, M.A. 
See GOG Website Directory 
 
See GOG Website Directory 
 
 
 
 
 
 
PAGE 1 OF 2 
 
 
 
 
 
 
 


Philip J. DiSaia, M.D. 
President 
 
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. 
Vice President  
 
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-0248 
 
A RANDOMIZED PHASE II TRIAL OF TEMSIROLIMUS (NCI-SUPPLIED AGENT,  
NSC # 683864, IND # 61010) OR THE COMBINATION OF HORMONAL THERAPY PLUS 
TEMSIROLIMUS IN WOMEN WITH ADVANCED, PERSISTENT, OR RECURRENT 
ENDOMETRIAL CARCINOMA 
NCI Version Date: December 22, 2014 
(Includes Revisions # 1-9) 
 
 
 
SCIENTIFIC COLLABORATORS 
EDGAR G. FISCHER, M.D. 
 
RAVI SALGIA, PH.D.  
ANNA DI RIENZO, PH.D. 
See GOG Website Directory 
 
See GOG Website Directory 
See GOG Website Directory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OPEN TO PATIENT ENTRY SEPTEMBER 29, 2008  
 
REVISED JUNE 22, 2009 
REVISED NOVEMBER 24, 2008 
 
 
 
 
TEMPORARILY CLOSED TO PATIENT ENTRY OCTOBER 19, 2009 
RE-OPENED TO PATIENT ENTRY MAY 24, 2010  
REVISED MAY 24, 2010; REVISED SEPTEMBER 26, 2011 
REVISED 
 
 
 
 
 
 
PAGE 2 OF 2 
 
 
This protocol was designed and developed by the Gynecologic Oncology Group (GOG). 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* 
Arm 1:  Temsirolimus IV 25 mg (flat dose) weekly 
 
Arm 2:  CLOSED TO ACCRUAL AS OF 12/21/09  Megestrol Acetate (MA)  80 mg bid for three weeks 
alternating with Tamoxifen (T) 20 mg bid for 3 weeks PLUS Temsirolimus IV 25 mg (flat dose) weekly 
*One cycle = 6 weeks 


 
 
GOG-0248 
 
 
TABLE OF CONTENTS 
   
 
PAGE 
 
 
 
1.0 
OBJECTIVES 
 
 
1 
 
2.0 
BACKGROUND AND RATIONALE  
 
2 
 
3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS  
7 
 
4.0 
STUDY MODALITIES 
 
 
10 
 
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 
19 
 
6.0 
TREATMENT MODIFICATIONS 
 
 
23 
 
7.0 
STUDY PARAMETERS 
 
 
26 
 
8.0 
EVALUATION CRITERIA 
 
 
34 
 
9.0 
DURATION OF STUDY 
 
 
37 
 
10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
38 
 
11.0 
STATISTICAL CONSIDERATIONS  
 
44 
 
12.0 
BIBLIOGRAPHY 
 
 
51 
 
 
 
 
SUGGESTED PATIENT INFORMATION/INFORMED CONSENT 
 
APPENDIX I – Clinical Staging (FIGO 
 
APPENDIX II – Medications Interacting with CYP3A4 and CYP2D6 
 
APPENDIX III – CRADA/CTA Language 
 
APPENDIX IV – Specimen Procedures for GOG-0248  
 
APPENDIX V – Patient Pill Calendar 
 
 
 


                                                                                                                                               GOG-0248 
 
 
-1-
1.0 
OBJECTIVES  
 
1.1 
Clinical Objectives 
 
1.11 
The primary objective is to determine the 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 Temsirolimus IV weekly 
 
• Arm #2 Megestrol Acetate/Tamoxifen plus Temsirolimus IV weekly 
 
1.12   Time to progression and number of patients remaining on study therapy at 24 
weeks will also be collected.  
 
1.13 
A secondary objective is 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 
 
1.21  Explore whether immunohistochemical expression of hormone receptors 
(estrogen receptor-alpha, estrogen receptor-beta, progesterone receptors-A, 
progesterone receptor-B and the alternative estrogen receptor, GPR-30) or 
components of the mTOR signaling pathway (normal and mutant PTEN, total 
and phosphorylated Akt as well as total and phosphorylated p70S6 kinase) are 
associated with treatment, outcome or clinical characteristics.   
 
1.22 
Explore whether single nucleotide polymorphisms (SNPs) in the FRAP1 and 
RAPTOR genes, mutations in PIK3CA, PTEN and paxillin or copy number 
abnormalities in PTEN and paxillin are associated with treatment, outcome or 
clinical characteristics. 
   
 
 
 


                                                                                                                                               GOG-0248 
 
 
-2-
2.0 
BACKGROUND AND RATIONALE 
 
2.1 
Hormonal Therapy 
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.  This regimen produced a 
response rate of 27% in 56 eligible women with no prior chemotherapy or hormonal 
therapy.1 Median PFS was 2.7 months and median overall survival was 14.0 months. 
This trial will combine this hormonal therapy with a generally well-tolerated biologic 
agent that has the potential to increase the benefits of hormonal therapy. 
2.2 
Temsirolimus  
Temsirolimus (CCI-779, sirolimus 42-ester with 2,2-bis(hydroxymethyl) propionic-
acid) is a specific inhibitor of mTOR (mammalian target of rapamycin).2  mTOR is a 
member of the phosphatidylinositol kinase-related kinases.  Its catalytic activity is 
regulated by the mitogen-activated phosphatidylinositol 3 kinase (P13K)/Akt pathway.   
Its downstream targets, p70s6 kinase and 4E-Binding Protein 1, are involved in 
controlling translation.  Another of mTOR's downstream targets, eukaryotic initiation 
factor 4e, can induce transformation when overexpressed in experimental models.3   
 
Rapamycin prevents cyclin-dependent kinase activation and retinoblastoma protein 
phosphorylation, which accelerates turnover of cyclin D1 expression, resulting in a 
decrease cdk 2 complexes inhibiting cell cycle progression.  Temsirolimus is a more 
water soluble ester analog of rapamycin with a broad range of anti-proliferative activity.  
It has more favorable pharmacokinetic properties and toxicity profile compared with 
Rapamycin.4  Temsirolimus was well tolerated with observed activity in various tumor 
types in two Phase I trials evaluating a weekly or a daily x 5 schedule.5,6 Preliminary 
clinical evidence of antitumor activity for temsirolimus has been observed in a number 
of tumor types, including breast cancer,7 renal cell cancer8,  and mantle cell lymphoma.9  
A randomized Phase III trial reported at ASCO 2006 reported a 3.6 month median 
survival advantage for patients with poor-risk metastatic renal cell carcinoma treated 
with temsirolimus 25 mg IV weekly versus those treated with interferon.10  
Temsirolimus has received FDA approval for the treatment of renal cell carcinoma. 
 
Activation of the PI3K/Akt pathway in general predicts for response to mTOR 
inhibitors in vitro. This includes two specific mechanisms of PI3K/Akt pathway 
activation  that have been well described in endometrial carcinomas: PTEN loss,11 
which is very common in endometrioid endometrial carcinomas, and PIK3CA gene 
mutations.12  Interestingly, while in breast cancers PTEN mutations and PI3K3CA 
mutations appear to be mutually exclusive, they have been reported to co-exist at a high 
frequency in endometrial carcinoma.13,14  
 


                                                                                                                                               GOG-0248 
 
 
-3-
Thirty to 50% of sporadic endometrial carcinomas carry somatically acquired 
inactivating mutations and/or deletions of the PTEN tumor suppressor gene.15,16  A 
recent study reports PTEN inactivation in up to 83% of endometrioid endometrial 
adenocarcinomas.17  Because inactivation of the PTEN gene is accompanied by 
complete absence of the protein (truncated proteins are extremely rare), 
immunohistochemistry of paraffin-embedded tissues with anti-PTEN antibody 6h2.1 is 
a sensitive, inexpensive, and rapid means of classifying tumor tissues by PTEN 
status.17,18   PTEN is a dual specificity phosphatase that negatively regulates the 
PI3K/Akt signaling pathway.  In samples where PTEN expression was depressed, 
phosphorylated Akt levels were inversely elevated.  Further proof that PTEN 
inactivation is important to the pathogenesis of endometrial carcinoma was garnered 
using mutant PTEN endometrial carcinoma cell lines.  The expression of exogenous 
PTEN resulted in decreased levels of activated Akt and cell growth inhibition in mutant 
but not wild-type PTEN-containing endometrial carcinoma cell lines.19  Thus, 
endometrial carcinoma represents a rational target for temsirolimus (CCI-779) therapy. 
 
The single agent activity of temsirolimus in endometrial carcinoma has been explored  
in two small, uncontrolled Phase II trials.39 In the first, 33 chemotherapy-naïve patients 
with recurrent or metastatic endometrial cancer were treated. There were 7 PRs in 28 
evaluable patients. Response rate was 25.0% (95% CI: 10.7-44.9%) and 16 patients had 
SD. Median duration of response was 5.6 months  ( 95% CI 3.7- 18.7 months) and of 
stable disease was 8.4 months ( 95% CI 3.1- 10.5 months).  Median PFS was 8 months. 
.20  
 In the second, 27 chemotherapy-treated women with recurrent or metastatic 
endometrial cancer were treated at a dose of 25 mg i.v. weekly. Thirteen had received 
prior radiation and 10 had received prior hormonal therapy. Twenty five patients had 
adenocarcinoma (8 serous carcinoma) and 2 had adeno-squamous carcinoma; 20 
patients had grade 2/3 disease, 5 unknown grade, and 2 grade 1. Two patients have had 
a confirmed partial response (PR) (7.4%; 95% CI 0.9-24.3%) and 12 patients had stable 
disease (SD) (44%), median duration 3.5months (2.4-7.2m) and 10 patients had 
progressive disease (41.7%). Five of the 8 patients with serous disease had SD and of 
the 17 with Grade 3 disease, 1 had a PR and 7 SD. Median PFS was 3.25 months (95% 
CI 2-3.88 months), 6 month PFS was 8% (95% CI  1-23%). There was no correlation 
between PTEN and response.  
 
2.3 
Rationale for the Combination of Hormones and Temsirolimus 
 
In addition to predicting for sensitivity to mTOR inhibitors, PTEN loss and PI3K 
activating mutations can confer in vitro  resistance to a variety of therapies, including 
chemotherapy, trastuzumab, growth factor receptor TKIs, and hormonal therapy.21,22 In 
many models, this resistance can be overcome by use of an mTOR inhibitor such as 
sirolimus or temsirolimus.23,24 Some of the most elegant work has been by Wendel et 
al.25,26  They demonstrated that a reduced dosage of PTEN (loss of even one PTEN 
allelle) which was only modestly tumorigenic in their mouse lymphoma model, resulted 
in lymphomas that were relatively resistant to chemotherapy and only modestly 
sensitive to sirolimus.  However the combination produced a dramatic improvement in 
outcomes, outperforming doxorubicin alone in control tumors (which did not have any 
improvement in outcomes with the addition of rapamycin to chemotherapy). 
 


                                                                                                                                               GOG-0248 
 
 
-4-
There is cross-talk between hormone receptor signalling pathways and the PI3K/Akt 
pathway at multiple levels.27-29 PTEN loss activates ER-alpha. Activation of the 
PI3K/AKT pathway is associated with resistance to tamoxifen or estrogen deprivation 
in breast cancer models.28-30 This resistance can be overcome by temsirolimus in 
vitro.31-32 A randomized Phase III trial of oral temsirolimus plus letrozole versus 
letrozole alone in women with advanced breast cancer was prematurely stopped for lack 
of benefit; this may be related to variability of absorption of the oral compound.  
 
2.4 
Translational Research  
The G1 to S cell cycle checkpoint plays a critical role in controlling endometrial cancer 
cell proliferation.33  Progesterone, the principal hormonal inhibitor of endometrial cell 
growth, inhibits cyclin D1 and is a strong inducer of the tumor suppressors PTEN and 
p53, and the cyclin dependent kinase inhibitors p21 and p27.  When expressed at high 
levels, p53, p21, and p27 prevent cell cycle progression at this checkpoint, and PTEN 
inhibits activation of Akt and mammalian target of rapamycin (mTOR).  Unfortunately, 
the growth-limiting effects of progesterone are often lost in endometrial cancers due to 
down-regulation of estrogen and progesterone receptors (ER and PR).   
 
The GOG attempted to use sequential hormonal treatment to maintain ER and PR 
expression in a Phase II trial of women with persistent or recurrent endometrial 
carcinoma (GOG-0119).  The rationale for sequential hormone treatment in this trial 
was based on the thought that tamoxifen, an estrogen surrogate in the uterus, would 
upregulate PR expression and allow the medroxyprogesterone acetate to inhibit G1 to S 
transition (block cell proliferation) and induce cell differentiation by binding to and 
activating PR.34  Treatment with the medroxyprogesterone acetate would then be 
expected to stimulate a negative feedback loop and down regulate PR expression.  
Discontinuation of the medroxyprogesterone acetate and re-exposure to tamoxifen 
would then counteract the negative feedback loop and provide signals to upregulate PR 
expression and responsiveness.  The response rate to sequential hormonal therapy in 
GOG 119 was an impressive 33% with an additional 35% of the patients having stable 
disease.   
 
Immunohistochemistry studies, performed in tumor tissue from women on GOG-0119, 
demonstrated that tumor response to sequential hormonal therapy in GOG-0119 was 
linked to the expression of ER-alpha.35  Baseline expression of ER-alpha in the 
recurrent tumor specimens was correlated with the immunohistochemical expression of 
PR, but tumor response was not associated with PR.35  Unfortunately, regardless of the 
robust initial response, all patients eventually failed treatment.  We hypothesize that 
treatment failure to sequential hormonal therapy in endometrial cancer is related to the 
prevalent constitutive activation of PI3K, Akt and mTOR in endometrial carcinoma, 
which eventually overcomes the growth-limiting effects of progestin.   
 
The PI3K/Akt pathway has been shown to regulate the catalytic activity of mTOR, a 
PIK-related kinase, and to activate other downstream targets including p70S6 kinase 
which controls translation.  PTEN is a dual specificity phosphatase that negatively 
regulates the PI3K/Akt signaling pathway.  Endometrial cancers with low or no PTEN 
expression often express high levels of phosphorylated Akt.  Constitutive activation of 
the PI3K/Akt pathway results from inactivating mutations and/or deletions of the PTEN 
tumor suppressor gene (PTEN loss) and mutations in the PIK3CA gene.11, 12, 15-17  


                                                                                                                                               GOG-0248 
 
 
-5-
Endometrial cancers often exhibit PTEN loss and mutations in PIK3CA.15-17  The 
finding that activation of the PI3K/Akt pathway is associated with response to mTOR 
inhibitors in vitro coupled with the data indicating that endometrial cancers often 
exhibit PTEN loss and mutations in PIK3CA 15-17 provide strong rationale for evaluating 
mTOR inhibitors in advanced or recurrent endometrial cancer.  
 
To test these hypotheses in a Cooperative Group setting, the expression of hormone 
receptors (ER-alpha, ER-beta, PR-A, PR-B and the alternative estrogen receptor, GPR-
30) and components of the mTOR pathway (normal and mutant PTEN, total and 
phosphorylated Akt as well as phosphorylated p70S6 kinase) will be examined by 
immunohistochemistry in archival formalin-fixed and paraffin-embedded (FFPE) tumor 
tissue from women in this cohort.  The associations between the immunohistochemical 
expression of these biomarkers and between these biomarkers and treatment, outcome 
or clinical characteristics will be explored.  
 
FRAP1 and RAPTOR are the genes that encode mTOR and the regulatory associated 
protein of mTOR (RAPTOR), respectively.  Natural variations, such as single 
nucleotide polymorphorisms (SNPs), have been described for both of these genes.  The 
mTOR and RAPTOR proteins form a complex that is inhibited by mTOR inhibitors 
and, therefore, are strong candidates for variation in response to temsirolimus treatment.  
Genotyping of normal DNA using the Sequenom iPLEX Gold technology will capture 
the genetic variations in up to 167 tag SNPs and 11 tag SNPs in the RAPTOR and 
FRAP1 genes, respectively.  SNPs in other genes in the mTOR pathway may also be 
genotyped if initial results are promising.  Genotypes at the tag SNPs will be compared 
with treatment, outcome or clinical characteristics in the patients in this clinical trial.  
Normal DNA will be extracted from a buffy coat prepared from whole blood drawn 
from women in this cohort. 
 
Mutation analysis and copy number abnormalities will also be determined in genes 
involved in mTOR signaling (PIK3CA, PTEN and paxillin).  As indicated above, loss of 
PTEN (due to an inactivating mutation or deletion) and mutation of PIK3CA are 
common mechanisms for activation of the PI3K/Akt pathway in endometrial cancers.  
Paxillin is another gene involved in mTOR signaling that has been implicated in the 
regulation of cell growth and invasion.  In lung cancer tissues, paxillin was highly 
expressed compared with normal lung, amplified (12.1%, 8 of 66) or mutated (somatic 
mutation rate of 9.4%, 18 of 191); paxillin mutations (90.5%, 19 of 21) were clustered 
between the functional LD motifs 1 and 2 and the LIM domains.38 We hypothesize that 
similar defects exist in endometrial cancer and contribute to the dysregulation in cell 
growth and invasion observed in this disease.  In this Phase II trial, DNA will be 
extracted from archival FFPE tumor tissue to examine mutations and/or copy number 
abnormalities in genes involved in mTOR signaling.  The associations between 
mutations in PIK3CA, PTEN and paxillin or copy number abnormalities in PTEN and 
paxillin and treatment, outcome or clinical characteristics will be examined in this 
cohort. 


                                                                                                                                               GOG-0248 
 
 
-6-
 
2.5 
Inclusion of Women and Minorities 
 
The Gynecologic Oncology Group and GOG participating institutions will not exclude 
potential subjects from participating in this or any study solely on the basis of ethnic 
origin or socioeconomic status.  Every attempt will be made to enter all eligible patients 
into this protocol and therefore address the study objectives in a patient population 
representative of the entire endometrial cancer population treated by participating 
institutions. 
 
 
 


                                                                                                                                               GOG-0248 
 
 
-7-
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 as at 
least one lesion that can be accurately measured in at least one dimension 
(longest dimension to be recorded). Each lesion must be ≥ 20 mm when 
measured by conventional techniques, including palpation, plain x-ray, CT, and 
MRI, or ≥ 10 mm when measured by spiral CT. 
 
Patients must have at least one “target lesion” to be used to assess response on 
this protocol as defined by RECIST (Section 8.1). Tumors within a previously 
irradiated field will be designated as “non-target” lesions unless progression is 
documented. 
 
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 chemoradiotherapy) is permitted.  (06/22/09) 
 
3.14 
Patient must be able to take p.o. medications. 
 
3.15 
Performance status must be 0-2. 
 
 
 
3.16 
Patients must have adequate organ and marrow function as defined below: 
 
• absolute neutrophil count ≥1,500/mcl 
• platelets ≥100,000/mcl 
• total bilirubin within normal institutional limits 
•    AST(SGOT) and alkaline phosphatase  2.5 times institutional upper limit 
of normal, v 3.0 (< 5  times ULN for subjects with liver metastases)  
• creatinine ≤ 1.5 x  normal institutional upper limit of normal,  
• cholesterol ≤ 350 mg/dL (fasting) 
• triglycerides ≤ 400 mg/dL (fasting) 
• albumin ≥ 3.0 mg/dL 
 


                                                                                                                                               GOG-0248 
 
 
-8-
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: a port-a-
cath placement). 
 
3.18 
Patients who have met the pre-entry requirements specified in Section 7.0. 
 
3.19 
Patients must have signed an approved informed consent including HIPAA 
authorization. 
 
3.2 
Ineligible Patients  
 
3.21 
Patients with GOG Performance status of 3 or 4. 
 
3.22 
Temsirolimus is primarily metabolized by CYP3A4.  Patients cannot be 
receiving enzyme-inducing antiepileptic drugs (EIAEDs; e.g., phenytoin, 
carbamazepine, phenobarbital) nor any other CYP3A4 inducer such as rifampin 
or St. John’s wort, as these may decrease temsirolimus levels. A partial list of 
agents which interact with cytochrome P450 (CYP3A) is found in Appendix II.  
All medications in the inducer section of Appendix II may be considered 
potent.  Use of agents that potently inhibit CYP3A (and hence may raise 
temsirolimus levels), such as ketoconazole, is discouraged, but not specifically 
prohibited. Temsirolimus can inhibit CYP2D6, and may decrease metabolism 
(and increase drug levels) of drugs that are substrates for CYP2D6. The 
appropriateness of use of such agents is left to physician discretion. A selected 
list of drugs that may have potential interactions with CYP2D6 is found in 
Appendix II.  The following website can also be consulted:  
www.medicine.iupui.edu/flockhart/table.htm   (11/24/08) 
 
  
All concomitant medications must be recorded at baseline. 
 
3.23 
Because of the theoretical risk of immunosuppression from mTOR inhibitors, 
patients on maintenance corticosteroids are ineligible with the exception of short 
term use (fewer than 5 days).  
 
3.24 
Patients known to have congestive heart failure. Patients with baseline 
requirement for oxygen. Patients with serious concomitant illness that, in the 
opinion of the treating physician, will place patient at unreasonable risk from 
therapy on this protocol.  
 
3.25 
Patients with a history of unprovoked DVT or PE, unless patient is maintained 
on anticoagulation for the duration of the trial. While the exact definition of 
“provoked” is left to the treating physician, a DVT in the setting of pelvic 
surgery or trauma would be considered “provoked.” 
 
3.26 
Women of child-bearing potential must have a negative pregnancy test prior to 
treatment on study. 
 


                                                                                                                                               GOG-0248 
 
 
-9-
Because there is an unknown but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with temsirolimus, breastfeeding 
should be discontinued if the mother is treated with temsirolimus. 
 
The effects of temsirolimus on the developing human fetus at the recommended 
therapeutic dose are unknown.  For this reason and because mTOR inhibitors 
may have antiangiogenic activity, and other antiangiogenic agents are known to 
be teratogenic, women of child-bearing potential and men must agree to use 
adequate contraception [barrier method of birth control or abstinence; oral 
contraceptives (also known as “the pill”) are not acceptable] prior to study entry 
and for the duration of study participation.  Should a woman become pregnant or 
suspect she is pregnant while participating in this study, she should inform her 
treating physician immediately.  
 
3.27 
Patients with a 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 therapy. 
 
3.28 
Patients who have received hormonal therapy or biologic therapy as treatment 
for endometrial carcinoma. 
 
3.29 
Patients who have received chemotherapy directed at metastatic or recurrent 
endometrial carcinoma, except as noted in Section 3.13.  (06/22/09) 
 . 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                                                                                                               GOG-0248 
 
 
-10-
4.0 
STUDY MODALITIES   
 
4.1  
Megestrol Acetate (Megace®) 
 
 
 
 
 
4.11 
Formulation: Tablets of 40 mg megestrol acetate  
 
 
 
 
 
 
4.12 
Storage: Room temperature protected from heat and light. 
 
4.13 
Adverse Effects: Weight gain, thromboembolic phenomena, nausea and 
vomiting, edema, break through bleeding, dyspnea, tumor flare, hyperglycemia, 
carpal tunnel syndrome, and rash. 
 
4.14 
Supplier: Commercially available.  See package insert for further information. 
 
4.15 
Administration: See section 5.2 
 
4.2  
Tamoxifen Citrate (Nolvadex®) (NSC #180973) 
 
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. 
 
4.25 
Administration: See Section 5.2.  
 
4.3 
Temsirolimus [COMMERCIAL Torisel (NSC # 683864, IND #61010) will be 
distributed by the NCI for this study] 
 
4.31 
Formulation: Chemical Name: Sirolimus 42-ester with 2,2-bis (hydroxymethyl)-
propionic acid 
 
 
 
Other Names: CCI-779, Torisel®, rapamycin analog, WAY-130779 
 
Classification: Cell cycle inhibitor 
 
Molecular Formula: C56H87NO16  M.W.: 1030.30 daltons 
 
 


                                                                                                                                               GOG-0248 
 
 
-11-
Mode of Action: Temsirolimus (an ester of the immunosuppressive compound 
sirolimus [rapamycin, Rapamune®]) blocks cell cycle progression from the G1 
to the S phase by binding to the intracellular cytoplasmic protein, FK506 
binding protein (FKBP)12. This complex inhibits activity of the enzyme mTOR 
(mammalian target of rapamycin), inhibiting translation of several key proteins 
that regulate progression through the G1 phase in response to growth factors. 
Sirolimus, temsirolimus’ major metabolite, also binds to FKBP12.  
 
4.32     How Supplied: TORISEL (temsirolimus) is supplied by the NCI as a 
commercially labeled kit consisting of the following: 
 
• TORISEL (temsirolimus) injection (25 mg/ml).  The TORISEL vial includes 
an overfill of 0.2 mL.  Inert ingredients in the drug vial include dehydrated 
alcohol, d,l-alpha-tocopherol, propylene glycol, and anhydrous citric acid. 
 
• DILUENT for TORISEL.  The DILUENT vial includes a deliverable volume 
of 1.8 mL.  The diluent vial contains polysorbate 80 NF, polyethylene glycol 
400 NF, and absolute alcohol USP. 
 
TORISEL will be supplied by the Division of Cancer Treatment and Diagnosis, 
(DCTD), NCI.  Please do not obtain commercially available TORISEL through 
any other mechanism.  (Please see Section 4.311) 
 
4.33 
Preparation: These mixing instructions apply to commercial TORISEL only; 
commercial drug will be supplied by the NCI for this study.   
 
Protect from excessive room light and sunlight during preparation. 
 
 
 
 
Follow this two step dilution process (TORISEL should only be diluted with the 
supplied diluent): 
 
Step 1 
Inject 1.8 mL of DILUENT for TORISEL into the vial of TORISEL injection (25 
mg/mL).  Due to the intentional 0.2 mL overfill in the TORISEL injection vial, the 
resulting drug concentration will be 10 mg/mL.  A total volume of 3 mL will be 
obtained.  Mix well by gentle inversion of the vial. DO NOT SHAKE. Allow 
sufficient time for air bubbles to subside. 
 
Step 2 
Withdraw the required amount of TORISEL from the 10 mg/mL drug 
solution/diluent mixture prepared in Step 1.  Further dilute with 0.9% sodium 
chloride injection immediately in glass or polyolefin containers to a final 
concentration between 0.04 mg/mL and 1 mg/mL.   
 
TORISEL will be supplied by the Division of Cancer Treatment and Diagnosis, 
(DCTD), NCI.  Please do not obtain commercially available TORISEL through 
any other mechanism.  (Please see Section 4.311) 
 
 


                                                                                                                                               GOG-0248 
 
 
-12-
4.34 
Storage: Refrigerate intact TORISEL kit at 2º-8ºC and protect from light. 
 
4.35 
Stability: The 10 mg/mL drug solution/diluent mixture is stable for 24 hours at 
room temperature.  
 
Administer within 6 hours of the final dilution in 0.9% NaCl.  Store at room 
temperature (20º-25ºC) and protect from light.    
 
4.36 
Route of Administration: Intravenous with an appropriate in-line filter (i.e. 0.2 to 5 
micron) for all temsirolimus doses equal to or greater than 10 mg.  Do not use an 
inline filter for temsirolimus doses less than 10 mg.  Protect from light during 
administration. 
 
4.37 
Patient Care Implications:  For hypersensitivity prophylaxis, give 
diphenhydramine 25-50 mg I.V. (or comparable antihistamine) approximately 
30 minutes before starting temsirolimus infusion.  Infuse over 30 minutes. 
 
If a patient develops a hypersensitivity reaction despite diphenhydramine 
pretreatment, stop the infusion and wait 30 to 60 minutes (depending upon the 
reaction severity).  At the physician’s discretion, it may be possible to resume 
treatment by administering an H2 blocker approximately 30 minutes before 
restarting the infusion.  The manufacturer recommends famotidine 20 mg IV, 
rather than cimetidine, because it lacks reported drug interactions.  If famotidine 
is unavailable, administer ranitidine 50 mg IV. Re-attempt infusion at a slower 
rate, possibly over one hour. (Please see Section 5.3 for temsirolimus 
administration and management of hypersensitivity reactions) 
 
4.38 
Incompatibilities: Avoid contact of the diluted product with polyvinyl chloride 
(PVC) equipment or devices that are plasticized with di- (2-ethylhexyl)pthalate 
(DEHP) to prevent DEHP leaching.  Store diluted temsirolimus solutions in 
bottles (glass) or plastic bags (polyolefin or polypropylene).   
 
Temsirolimus is compatible with most infusion sets that are acceptable with 
paclitaxel. Infusion sets which have been qualified for use with temsirolimus 
include the following:  
•Baxter vented paclitaxel set 
•Baxter unvented paclitaxel set 
•Abbott #11947 tubing set 
•Alaris #72953 tubing set 
 
Other non-PVC tubings can be used with the following in-line filters: 
•IV 6200 Disposable I.V. Filter 0.2 micron by EPS®, Inc  
•IV 6120 Disposable I.V. Filter 1.2 micron by EPS®, Inc  
•LV 5000 Large Volume 5 micron Conical Filter by B.Braun  
•Baxter Paclitaxel IV 0.2 micron filter set (2C7555) 
•Codan 5 micron monofilter 
•Alaris extension filter set #20350E 
Other polyethersulfone filters may be used.  
   


                                                                                                                                               GOG-0248 
 
 
-13-
4.39 
Potential Drug Interactions: Temsirolimus is a CYP3A4 substrate.  Avoid 
concomitant treatment of temsirolimus with potent CYP3A4 inhibitors and 
agents that have CYP3A4 induction potential.  
 
The combination of temsirolimus and sunitinib resulted in dose limiting toxicity 
at low doses of both agents.  Avoid concomitant sunitinib during temsirolimus 
treatment.   
 
Temsirolimus and warfarin may interact to increase INR. Monitor warfarin 
patient’s PT/INR after starting and stopping temsirolimus. 
 
 
4.310 Reported Adverse Events and Potential Risks:  (05/24/10) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
 Temsirolimus (CCI-779, NSC 683864) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported and/or potential 
adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Agent Specific Adverse Event List (ASAEL), appears in a separate column and is 
identified with bold and italicized text. This subset of AEs (ASAEL) contains events that are considered 'expected' for 
expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.info.nih.gov/protocolDevelopment/default.htm#adverse_events_adeers  for further clarification. Frequency is 
provided based on 1288 patients. Below is the CAEPR for temsirolimus (CCI-779). 
 
Version 2.2, January 22, 20101 
 
 Adverse Events with Possible  
 Relationship to Temsirolimus (CCI-779) 
 (CTCAE 4.0 Term) 
[n= 1288] 
 
 
 
 EXPECTED AEs FOR 
ADEERS REPORTING  
 
Agent Specific Adverse 
Event List 
(ASAEL) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Expected 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia 
 
Febrile neutropenia 
 
 Febrile neutropenia 
ENDOCRINE DISORDERS 
  
 
Endocrine disorders - Other 
(decreased testosterone) 
 
 Endocrine disorders - Other 
(decreased testosterone) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
 Abdominal distension 
 
Abdominal pain 
 
 Abdominal pain 
 
Constipation 
 
 Constipation 
Diarrhea 
 
 
 Diarrhea 
Gastrointestinal disorders – Other 
(Mucositis/stomatitis – Select)2 
 
 
 Gastrointestinal disorders – 
Other (Mucositis/stomatitis – 
Select)2 
 
 
Gastrointestinal disorders – Other 
(Perforation, GI – Select)3 
 Gastrointestinal disorders – 
Other (Perforation, GI – Select)3 
Nausea 
 
 
 Nausea 
 
Vomiting 
 
 Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills 


                                                                                                                                               GOG-0248 
 
 
-14-
 
Edema face 
 
 Edema face 
 
Edema limbs 
 
 Edema limbs 
Fatigue 
 
 
 Fatigue 
 
Fever 
 
 Fever 
 
Flu like symptoms 
 
 Flu like symptoms 
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction4 
 
 Allergic reaction4 
INFECTIONS AND INFESTATIONS5 
  
 
Infections and infestations – Other 
(Infection – Select) 
 
 Infections and infestations – 
Other (Infection – Select) 
 
Infections and infestations - Other 
(Opportunistic infection 
associated with >=Grade 2 
Lymphopenia) 
 
 Infections and infestations - 
Other (Opportunistic infection 
associated with >=Grade 2 
Lymphopenia) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Wound dehiscence6 
 
 Wound dehiscence6 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased 
 
Alkaline phosphatase increased 
 
 Alkaline phosphatase increased 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased 
Cholesterol high7 
 
 
 Cholesterol high7 
 
Creatinine increased 
 
 Creatinine increased 
 
Fibrinogen decreased 
 
 Fibrinogen decreased 
 
GGT increased 
 
 GGT increased 
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased 
 
Neutrophil count decreased8 
 
 Neutrophil count decreased8 
Platelet count decreased8 
 
 
 Platelet count decreased8 
 
Weight loss 
 
 Weight loss 
 
White blood cell decreased 
 
 White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS 
  
 
Acidosis 
 
 Acidosis 
Anorexia 
 
 
 Anorexia 
 
Glucose intolerance9 
 
 Glucose intolerance9 
 
Hyperglycemia9 
 
 Hyperglycemia9 
 
Hypertriglyceridemia7 
 
 Hypertriglyceridemia7 
 
Hypocalcemia 
 
 Hypocalcemia 
 
Hypokalemia 
 
 Hypokalemia 
 
Hypophosphatemia 
 
 Hypophosphatemia 
 
Metabolism and nutrition 
disorders- Other (hyperlipidemia)7 
 
 Metabolism and nutrition 
disorders- Other 
(hyperlipidemia)7 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia 
 
Back pain 
 
 Back pain 
 
Myalgia 
 
 Myalgia 
NERVOUS SYSTEM DISORDERS 
  
 
Depressed level of consciousness  
 Depressed level of consciousness 
 
Dysgeusia 
 
 Dysgeusia 
 
Headache 
 
 Headache 
PSYCHIATRIC DISORDERS 
  
 
Depression 
 
 Depression 
 
Insomnia 
 
 Insomnia 
 
Libido decreased 
 
 Libido decreased 
RENAL AND URINARY DISORDERS 
  


                                                                                                                                               GOG-0248 
 
 
-15-
 
 
Acute kidney injury10 
  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
Erectile dysfunction 
 
 Erectile dysfunction 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Allergic rhinitis 
 
  
 
Cough 
 
 Cough 
 
Dyspnea 
 
 Dyspnea 
 
Epistaxis 
 
 Epistaxis 
 
Pleural effusion 
 
 Pleural effusion 
 
Pneumonitis11 
 
 Pneumonitis11 
 
Sinus disorder 
 
 Sinus disorder 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
 Dry skin 
 
Nail loss 
 
 Nail loss 
 
Pruritus 
 
 Pruritus 
 
Rash acneiform 
 
 Rash acneiform 
Rash maculo-papular 
 
 
 Rash maculo-papular 
 
Urticaria 
 
 Urticaria 
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension 
 
Hypotension 
 
 Hypotension 
 
 
Thromboembolic event 
 Thromboembolic event 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your 
name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2Mucositis/stomatitis:  Gingivitis, mucositis/stomatitis, ulcers in mouth and throat, pharyngitis, and dysphagia have been 
reported in subjects receiving temsirolimus. 
 
3Perforation, GI - Select:  GI perforation (including fatal outcome) has been observed in subjects who received 
temsirolimus. 
 
4Hypersensitivity /infusion reactions (including some life threatening and rare fatal reactions), including and not limited to 
flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity, and anaphylaxis, have been 
associated with the administration of temsirolimus.  These reactions can occur very early in the first infusion, but may also 
occur with subsequent infusions.  Patients should be monitored early during infusion and appropriate supportive care 
should be available.  Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and 
appropriate medical care administered.  A risk-benefit assessment should be done prior to the continuation of temsirolimus 
therapy in patients with severe life-threatening reactions. 
 
5Infections:  Bacterial and viral infections including opportunistic infections have been reported in subjects. Infections may 
originate in a variety of organ systems/body regions and may be associated with normal or grade 3-4 neutropenia. Bacterial 
and viral infections have included cellulitis, herpes zoster, herpes simplex, bronchitis, abscess, pharyngitis, urinary tract 
infection (including dysuria hematuria, cystitis, and urinary frequency), rhinitis folliculitis, pneumonia, and upper 
respiratory tract infection. 
 
6Wound Dehiscence:  The use of temsirolimus has been associated with abnormal wound healing. Therefore, caution 
should be exercised with the use of temsirolimus in the perisurgical period. 
 
7Cholesterol High:  The use of temsirolimus in subjects has been associated with increases in serum levels 
of triglycerides and cholesterol. This may require initiation of or increase in the dose of lipid-lowering agents. 
 
8Thrombocytopenia and Neutropenia:  Grades 3 and 4 thrombocytopenia and/or neutropenia have been observed at higher 
frequency in subjects with mantle cell lymphoma (MCL). 
 


                                                                                                                                               GOG-0248 
 
 
-16-
9Hyperglycemia/Glucose Intolerance:  The use of temsirolimus in subjects was associated with increases in serum glucose 
level. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent 
therapy.  
 
10Acute Kidney Injury:  Renal failure (including fatal outcome) has been observed in subjects receiving temsirolimus for 
advanced RCC and/or with pre-existing renal insufficiency. 
 
11Interstitial Lung Disease:  There have been cases of nonspecific interstitial pneumonitis, including rare fatal reports. Some 
subjects were asymptomatic with pneumonitis detected on computed tomography scan or chest radiograph. Others 
presented with symptoms such as dyspnea, cough, and fever. Some subjects required discontinuation of temsirolimus or 
treatment with corticosteroids and/or antibiotics, while some subjects continued treatment without additional intervention. 
 
Also reported on temsirolimus (CCI-779) trials but with the relationship to temsirolimus (CCI-779) still 
undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Hemolysis 
CARDIAC DISORDERS - Left ventricular systolic dysfunction; Pericardial effusion; Right ventricular dysfunction; Sinus 
tachycardia 
EYE DISORDERS - Blurred vision; Conjunctivitis 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Dry mouth; Dyspepsia; Dysphagia; Enterocolitis; Esophagitis; 
Gastritis; Gastrointestinal disorders – Other (Hemorrhage, GI – Select); Oral pain; Pancreatitis; Periodontal disease; Rectal 
hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Gait disturbance 
HEPATOBILIARY DISORDERS - Hepatic failure 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture 
INVESTIGATIONS – Activated partial thromboplastin time prolonged; Blood bilirubin increased; INR increased 
(potential interaction with Coumadin); Investigations - Other (lactic dehydrogenase increased) 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; Hypoalbuminemia; 
Hypomagnesemia; Hyponatremia; Metabolism and nutrition disorders - Other (hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Generalized muscle weakness; 
Musculoskeletal and connective tissue disorder - Other (bursitis) 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dizziness; Intracranial hemorrhage; Ischemia 
cerebrovascular; Peripheral sensory neuropathy; Seizure; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Personality change; Psychosis 
RENAL AND URINARY DISORDERS – Cystitis noninfective5; Proteinuria; Renal and urinary disorders – Other 
(Hemorrhage, GU – Select); Urinary frequency; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; Hypoxia; 
Pleuritic pain; Pulmonary hypertension; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis 
 
 
Note:  Intracerebral Bleeding:  Subjects with central nervous system (CNS) tumors (primary CNS tumors or metastases) 
and/or receiving anticoagulation therapy may be at an increased risk of intracerebral bleeding (including fatal outcomes) 
while receiving therapy with temsirolimus. 
 
Note: Temsirolimus (CCI-779) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously associated with 
either agent. 
. 
 
Note:  Temsirolimus (CCI-779) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. During the first phase of the combination arm of this trial a clot rate of at least 7/22 
was observed in the combination arm. (05/24/10) 
 
 


                                                                                                                                               GOG-0248 
 
 
-17-
4.311 Availability:  
 
Temsirolimus is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI.  In this trial a 
commercial supply of Temsirolimus is provided, but the agent is used in an 
investigational way. 
 
Temsirolimus is provided to the NCI under a Cooperative Research and 
Development Agreement (CRADA) between Wyeth Pharmaceuticals, Inc. and 
the DCTD, NCI. (Please see Appendix III).  
 
4.312 Drug Ordering and Accountability: NCI-supplied agents may be requested by 
the Principal Investigator or their authorized designee at each participating 
institution.  Pharmaceutical Management Branch (PMB) policy requires that 
drug be shipped directly to the institution where the patient is being treated.  
PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP assigned protocol number must be 
used for ordering all CTEP-supplied investigational agents.  The responsible 
investigator at each participating institution must be registered with CTEP, 
DCTD, through an annual submission of FDA Form 1572, Supplemental 
Investigator Data Form (IDF), and Financial Disclosure Form.  If there are 
several participating investigators at one institution, CTEP supplied 
investigational agents for the study should be ordered under the name of one 
lead investigator at that institution. 
 
 
Drug may be requested by completing a Clinical Drug Request (CDR [NIH-
986]) (print from the CTEP website at http://ctep.cancer.gov/requisition/) and 
mailing it to the Pharmaceutical Management Branch, DCTD, NCI, EPN, Room 
7149, Bethesda, MD 20892 or faxing it to (301) 480-4612. Beginning 11/10/03, 
all CDR’s for PMB-distributed agents sent to the PMB must be signed by the 
investigator in whose name the agent is ordered OR by the shipping designee 
OR by an ordering designee whom the investigator has listed on their most 
recent IDF on file with the PMB.  
 
 
If the investigator has not designated the individual signing the CDR as a 
shipping or ordering designee, or if the shipping or ordering designees at a 
clinical site change, the first two pages of the IDF should be updated to reflect 
the current designees, the IDF should be signed and dated by the investigator 
and returned to the PMB by fax at (301) 402-4870.  For questions (on the first 
two pages of the investigator’s current IDF) call the PMB at (301) 496-5725 
Monday through Friday from 8:30 am to 4:30 pm Eastern Time. 
 
 
 
 
 
 
 
The Investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of all agents received 
from the PMB using the NCI Drug Accountability Record Form (DARF). See 
the CTEP web site for Policy and Guidelines for Accountability and Storage of 
Investigational Drugs at http://ctep.cancer.gov/requisition/ 
 


                                                                                                                                               GOG-0248 
 
 
-18-
 
 
 
 
 
 
Requests for Investigator’s Brochures (IB) should be e-mailed to 
ibcoordinator@mail.nih.gov or you may call the IB coordinator at 301-496-
5725. 
 
4.4 
Pathology Requirements 
 
 
4.41 
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. 
 
4.42 
Ineligible disease characteristics: Patients with a sarcoma, carcinosarcoma 
(MMMT), or leiomyosarcoma of the uterine corpus are not eligible.  Patients 
with early stage (FIGO stage I or II) endometrial carcinoma are also not 
eligible.  
 
4.43 
Requirements: Stained pathology slides are required for central review by the 
GOG Pathology Committee to confirm eligibility.  At least one representative 
H&E stained slide (or slides) demonstrating primary site, histologic cell type 
and grade will be required.  At least one representative H&E stained slide 
documenting the most advanced stage of disease will be required if the most 
advanced stage is documented by histology or cytology.  If the patient is 
enrolled with recurrent disease, at least one representative H&E stained 
slide demonstrating recurrent disease will be required if recurrent disease is 
documented by histology.  See Sections 7.2 and 10.2 for additional instructions 
for submitting the stained pathology slides to the GOG Statistical and Data 
Center in Buffalo, NY.  
 
4.44 
See Section 7.3 and Appendix IV for information and instructions regarding the 
specimen requirements for Translational Research. (05/24/10) 


                                                                                                                                               GOG-0248 
 
 
-19-
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE     
 
All initial and continuing reviews must be submitted to the CTSU Regulatory Office. A CTSU 
IRB/Regulatory Approval Transmittal Sheet should be submitted along with the CTSU IRB 
Certification Form or its equivalent. (CTSU forms can be downloaded at 
https://www.ctsu.org/public/rss2_page.aspx). IRB submissions can be faxed or mailed to:  
 
CTSU Regulatory Office 
Coalition of National Cancer Cooperative Groups 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
1-888-823-5923 
  FAX 215-569-0206 (05/24/10) 
 
5.1 
Patient Entry and Registration 
 
When a suitable candidate has been obtained for protocol entry, the following steps 
should be taken: 
 
5.11 
Patient must have signed an approved informed consent and authorization 
permitting release of personal health information.  Current FDA, NCI 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. 
 
 
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 number, and assigned 
regimen in the appropriate place in their Log Book to verify the patient's entry. 
 
5.2 
Treatment Plan 
 
Stage I Accrual (Patients enrolled prior to 12/21/09):  (05/24/10) 
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 
for pelvic recurrence. (05/24/10) 
Prior radiotherapy in the absence of chemotherapy is not considered in this 
stratification. 
 
 


                                                                                                                                               GOG-0248 
 
 
-20-
 
Study therapy will be randomized between: 
 
Arm 1:  Temsirolimus IV 25 mg (flat dose) weekly 
 
 
and 
Arm 2:  Megestrol Acetate (MA)  80 mg bid for 3 weeks alternating with Tamoxifen 
(T) 20 mg bid for 3 weeks PLUS Temsirolimus IV 25 mg (flat dose) weekly. 
 
Therapy is to be continued until tumor progression or undue toxicity. For purposes of 
evaluation, a cycle will be considered six weeks. Re-evaluation for disease response and 
status will be every six weeks for the first 24 weeks of therapy, then every 12 weeks for 
patients who are receiving protocol therapy longer than 24 weeks. 
 
Stage II accrual (Patients enrolled after 12/21/09): (05/24/10) 
As of December 18, 2009, there have been seven venous-thrombosis-related events 
reported among the 22 women assigned to the megestrol 
acetate/tamoxifen/temsirolimus arm of this study and none among the 21 women on the 
temsirolimus alone arm.  The combination arm was therefore permanently closed to 
new accrual. The single agent temsirolimus arm has met the criteria to proceed with the 
second stage and will be reopened to accrual. 
 
Patients 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 
for pelvic recurrence. (05/24/10) 
Prior radiotherapy in the absence of chemotherapy is not considered in this 
stratification. 
 
All patients enrolled after 12/21/2009 will receive 
 
Arm 1:  Temsirolimus IV 25 mg (flat dose) weekly 
 
Therapy is to be continued until tumor progression or undue toxicity. For purposes of 
evaluation, a cycle will be considered six weeks. Re-evaluation for disease response and 
status will be every six weeks for the first 24 weeks of therapy, then every 12 weeks for 
patients who are receiving protocol therapy longer than 24 weeks. 
 
  
 
 
5.3  
Temsirolimus Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 4.310.  Appropriate dose modifications for 
temsirolimus are described in Section 6.0.  Patients receiving temsirolimus on this 
protocol may not receive any other investigational agents either for the treatment of the 
patient’s cancer or for any other indication.  Patients on this protocol may not be treated 
with any other anti-cancer therapy. 
 


                                                                                                                                               GOG-0248 
 
 
-21-
Patients will receive temsirolimus at their assigned dose administered over 30 minutes 
IV weekly continuously. It may be given up to 2 days early or late due to holiday or 
scheduling reasons.   
 
Temsirolimus is incompatible with polyvinyl chloride (PVC) equipment or devices that 
are plasticized with di- (2-ethylhexyl) pthalate (DEHP).  Please see Section 4.38 
(Incompatibilities) for a list of compatible tubings and filings.  
 
Patients should be premedicated with diphenhydramine 25 – 50 mg IV or PO (or a 
similar antihistamine) approximately 30 minutes before the start of the tesmirolimus 
infusion.  If the subject begins to develop a hypersensitivity reaction despite 
pretreatment with diphenhydramine, the infusion should be stopped for at least 30 – 60 
minutes, depending upon the severity of the reaction.  The infusion may be resumed by 
administering a histamine H2-receptor antagonist approximately 30 minutes before 
restarting the tesmsirolimus infusion.  Famotidine 20 mg IV or ranitidine 50 mg IV are 
recommended rather than cimetidine because of the lack of likely 
metabolic/pharmacologic interactions with the former drugs.  The rate of the 
temsirolimus infusion may also be slowed from 30 minutes to over an hour.  All 
subjects should be monitored while receiving the temsirolimus infusion and emergency 
medical equipment and health care personnel must be readily available to respond to 
hypersensitivity reactions or other medical emergencies. 
 
 
5.4 
Megestrol Acetate and Tamoxifen Compliance 
 
The use of a patient pill calendar (See Appendix V) during study therapy will be 
utilized by the patient and the treating clinic to help promote and monitor compliance 
with Megestrol Acetate and Tamoxifen.  
 
 
5.5 
Concomitant Medications 
 
In vitro studies with temsirolimus in human liver microsomes indicate that CYP3A4 
may be the primary enzyme responsible for the agent’s metabolism, suggesting that 
compounds known to modulate CYP3A4 activity may therefore affect the metabolism 
of temsirolimus.  Inhibitors of CYP3A4 may decrease the metabolism and increase 
temsirolimus levels, while inducers of CYP3A4 may increase the metabolism and 
decrease temsirolimus levels.  Temsirolimus or its metabolites may also interact with 
the CYP450 enzyme system by inhibiting CYP2D6. While caution is indicated in many 
circumstances, the only medications prohibited on this protocol are the potent CYP3A4 
inducers.  A selected list is included in 3.22 and Appendix II.  The following website 
can also be consulted:  www.medicine.iupui.edu/flockhart/table.htm. (11/24/08) 
 
Therapeutic anticoagulation: Patients on warfarin should have PT/INR monitored 
closely during warfarin therapy (e.g., at baseline, weekly for the first three weeks of the 
first cycle, weekly for the first three weeks of any cycle following a dose reduction, and 
for a minimum of two weeks after stopping temsirolimus.). Temsirolimus therapy should 
be held if the coagulation parameters are meaningfully higher than the intended 
therapeutic range as defined by the treating physician. 
 


                                                                                                                                               GOG-0248 
 
 
-22-
 
 
5.6 
Supportive Care Guidelines 
 
Nausea/vomiting: Nausea induced by study agents should be treated initially with a 
phenothiazine (prochlorperazine 10 mg q8h PO prn or promethazine 12.5-25 mg IV q6h 
prn).  If this is inadequate, a serotonin type-3 (5-HT(3)) antagonist or benzodiazepine 
should be added until acute nausea is controlled.  Should this prove inadequate acutely, 
a corticosteroid may be added (e.g., dexamethasone 4 mg q6h prn).  Treatment with 
corticosteroids should be limited to fewer than 5 days.  
 
After acute nausea has resolved, consideration should be given to initiation of 
prophylactic antiemetic therapy.  If nausea recurs despite reasonable medical 
intervention (as outlined above), dose reduction will be needed as described in Section 
6. 
 
Routine supportive measures for cancer patients such as analgesics, blood transfusions, 
antibiotics, bisphosphonates, and erythropoeitic colony stimulating factors for treatment 
of anemia (according to national guidelines) are permitted.  However, given emerging 
data about adverse outcomes in a number of cancer types with erythropoietic colony 
stimulating factors, these should be used with caution, and only to avoid transfusion. 
 
The administration of anticancer therapies, other investigational agents, or prophylactic 
use of granulocyte colony stimulating factors are not permitted. Use of granulocyte 
colony stimulating factors for neutropenic fever is permitted. 
 
 
 
 


                                                                                                                                               GOG-0248 
 
 
-23-
6.0 
TREATMENT MODIFICATIONS    
 
6.1   
Tamoxifen/Megestrol Acetate 
 
There are no dose modifications for the tamoxifen/megestrol 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) till they are ambulatory 
again.  Patients receiving both tamoxifen/megestrol acetate and temsirolimus should 
have their temsirolimus held during the same time period during which the 
tamoxifen/megestrol acetate is held.  However, in general, if temsirolimus is held for 
any reason on Arm # 2, the tamoxifen/megestrol acetate should still continue.  
Suspected severe and unusual toxicities from either agent (e.g. hives from tamoxifen) 
should be discussed with the study chair. 
 
6.2   
Temsirolimus (CCI-779) 
 
Additional cycles of therapy may be administered provided that the patient meets the 
following criteria before each dose (counts done up to 24 hours ahead of time are 
acceptable): 
 
• 
ANC > 1,000/mcl 
• 
Platelets > 100,000/mcl 
• 
Non-hematologic toxicity recovered to < grade 1 (or tolerable grade 2) 
• 
No evidence of progressive disease 
 
In the event of toxicity, the doses of temsirolimus will be adjusted according to 
the guidelines shown in the Dose Delays/Dose Modifications tables that follow.  
If an adverse event is not covered in the table, doses may be reduced or held at 
the discretion of the investigator for the subject’s safety.  Dose adjustments for 
hematological toxicity are based on the blood counts obtained in preparation for 
the day of treatment.  
 
Patients requiring dose reductions should not have the dose re-escalated with 
subsequent treatments. 
 
Subjects with toxicities that are manageable with supportive therapy may not require 
dose reductions (e.g., hyperlipidemia may be treated with statins, nausea/vomiting may 
be treated with antiemetics, diarrhea with loperamide rather than by dose reduction).   
 
Loperamide should be started for diarrhea as follows: 4 mg at first onset, then 2 mg 
every 2-4 house until diarrhea is controlled (maximum = 16 mg loperamide/day). 
 
When triglyceride and cholesterol lowering is desired, use pravastatin, fluvastatin, or 
atorvastatin with the addition of a fibrate if necessary.  Pravastatin and fluvastatin are 
not metabolized by CYP3A4 and are preferred.  Fenofibrate is preferred in combination 
with statins. Avoid nicotinic acid as it may exacerbate hyperglycemia. Anti-lipid 
therapy should not be started without fasting lipid values. 
 


                                                                                                                                               GOG-0248 
 
 
-24-
When ONLY triglyceride lowering is desired, use a fibrate (fenofibrate or gemfibrozil).  
Please note that only very high triglyceride levels (>500 mg/kL) have been definitively 
associated with increased morbidity while moderate triglyceride increases (200-499 
mg/dL) have only been associated with increased cardiac events in patients with risk 
factors for atherosclerotic cardiac disease or with high LDL. 
 
Subjects with glucose elevation who are already on antidiabetic medications should 
have such medications cautiously adjusted if they are to stay on protocol, with a 
planned decrease in dosage at the time the patients comes off temsirolimus therapy. If 
the glucose is over 400, they should be instructed to call their doctor.  Those who are 
not on antidiabetic medication, but with blood glucose levels over 200, should have 
dietary instruction (avoid concentrated sugars); if the glucose is persistently over 200 
and it is the judgment of their physician that they are benefiting from temsirolimus 
therapy, oral hypoglycemics with appropriate monitoring can be used.  Again, these 
must be stopped with cessation of temsirolimus therapy.  (11/24/08) 
 
Subjects who experience a clot may, at the discretion of the investigator, be 
continued on study with the addition of anticoagulation.  If warfarin is chosen as 
the method of anticoagulation, INR must be in-range (target as determined by 
investigator, usually 2.0-3.0) prior to re-initiation of therapy. (05/24/10) 
 
Weight loss, in the absence of other toxicity, does not require treatment to be held. 
(05/24/10) 
 
For laboratory abnormalities other than hematologic parameters, study therapy should 
be discontinued in subjects who fail to recover to CTCAE Grade 0-1 or tolerable grade 
2 (or within 1 grade of starting values for pre-existing laboratory abnormalities other 
than as described above) from a treatment-related toxicity within 14 days OR  they 
experience agent related adverse events requiring dose modification despite two 
previous dose reductions (i.e. would require a 3rd dose reduction) unless the treating 
physician,  study chair, and CTEP monitor agree that the subject should remain in the 
study because of evidence that the patient is/may continue deriving benefit from 
continuing study treatment. The appropriate reduced dose will be determined after 
discussion between the treating physician, study chair, and CTEP monitor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                                                                                                               GOG-0248 
 
 
-25-
Adverse Event 
Agent 
Treatment Modifications 
Blood/Bone Marrow2 
Neutrophils 
 
ANC 500-999 
Platelets 
 
50,000-99,999 
 
 
 
 
Temsirolimus 
• Delay temsirolimus until recovery to ANC 
≥ 1,000 and plt ≥ 100,000 
• Retreat at a one dose level reduction 
• If recovery requires > 14 days,1 discontinue 
all study treatment. 
Neutrophils 
 
ANC <500 
Platelets 
 
<50,000 
• Delay temsirolimus until recovery to ANC 
≥ 1,000 and plt ≥ 100,000 
• Retreat at two dose levels reduction 
• If recovery requires > 14 days,1 discontinue 
all study treatment. 
Pulmonary/Upper Respiratory 
Grade 2 or higher 
Pneumonitis 
(cough, dyspnea, 
fever) 
 
 
Temsirolimus 
Discontinue temsirolimus pending 
investigation.  If diagnosis is confirmed and 
events are considered at least possibly due to 
temsirolimus, the agent is discontinued. 
 
Adverse Event 
Agent 
Treatment Modifications 
All other non-hematologic adverse events 
Grade 0-2 
 
 
 
Temsirolimus 
Grade 2 toxicities that are persistent and 
intolerable (i.e. stomatitis) can result in dose 
delays and dose reductions to the next lower 
dose level 
Grade 3-4 
Hold dose.   
• Re-evaluate until AE resolved to < 1 or 
tolerable grade 2.   
• Re-treat at a one dose level reduction 
• If recovery requires > 14 days, discontinue 
all study treatment. 
• Patients with grade 4 AEs related to agent 
may discontinue study therapy at 
investigator’s discretion. 
 
           1. 14 days from when the dose was due, or 21 days from the previous dose. 
 2. Hold the study drug if coagulation parameters are meaningfully higher than the intended therapeutic range, as 
determined by the treating physician for patients on warfarin (See Section 5.5). Conduct INR testing weekly for the first 
three weeks of any cycle following a dose reduction. 
Dose Reductions for Temsirolimus-related Toxicity 
 
Dose Level 
Temsirolimus Dose 
(mg) 
Starting dose 
25 
-1 
20 
-2 
15 
 
 
 
 


                                                                                                                                               GOG-0248 
 
 
-26-
7.0 
STUDY PARAMETERS 
 
7.1 
The following observations and tests are to be performed and recorded on the 
appropriate form(s): See Section 7.3 for the specimen requirements for translational 
research for this study. Stained pathology slides will be required for central review by 
the GOG Pathology Committee to confirm eligibility (see Sections 7.2 and 10.2).: 
 
 
Observations and Tests 
 
Pre-
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
 4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Off  Study 
treatmentf 
 
Temsirolimusi 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent medsa 
 
X 
 
X--------------------------------------------------------------------------------------X 
 
 
 
Physical examb 
 
X** 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsb 
 
X** 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Height 
 
X** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weightb 
 
X** 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance statusb 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/diff, pltsi,c 
 
X* 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Serum chemistryj,c 
 
X* 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Serum lipid levelsb,d,c 
 
X*** 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
INRh 
 
 X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Toxicity Assessmentk 
 
 
  X -------------------------------------------------------------------------------------X 
 
X 
 
Tumor measurements 
 
X*** 
 
Tumor measurements are repeated every six weeks for 24 weeks, and then 
repeated every 12 weeks for patients on study therapy longer than 24 weeks.  
 
X 
 
Radiologic evaluationg 
 
X*** 
 
Radiologic evaluation should be performed every six weeks for the first 24 
weeks and then repeated every 12 weeks for patients on study therapy longer 
than 24 weeks.  
 
X 
 
B-HCG 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*     Within 7 days prior to initiating protocol therapy. 
**   Within 14 days prior to initiating protocol therapy. 
*** Within 28 days prior to initiating protocol therapy. 
a:  Document in patient’s medical chart at each scheduled visit with special attention to drugs that interact with CYP3A4 and CYP2D6.  
b: Physical exam weekly for the first 4 doses, with dose 7, then every 6 weeks. Physical exam includes weight, and assessment of PS 
and toxicity; pelvic exam is not required except for tumor measurement or as clinically indicated. Vital signs (temperature, pulse, and 
blood pressure) should be taken with each infusion. Full physician or nurse practitioner physical exam should be at least every three 
weeks for cycle one, then at least six weeks for subsequent cycles; weeks 1, 2, and 3 require only a brief assessment to include vital 
signs and blood tests. 
c:  Pre-treatment labs for subsequent cycles can be obtained up to 24 hours ahead of treatment. 
d:  Serum cholesterol and triglycerides should be collected every 3 weeks for the first 2 cycles, then every 6 weeks. 
e:  Serum or urine pregnancy test (women of childbearing potential).  To be done within 48 hours before starting treatment. 
f:  If patient comes off study treatment prior to progression, continue tumor measurements and radiologic evaluations on schedule until 
progression.. Toxicity assessments will be continued until resolution.  Patients will be followed after last drug dose until toxicity 
resolution, until progression if patient withdraws before progressive disease, and for one year after the end of treatment for survival, 
or until study withdrawal if it occurs before this time. (05/24/10) 
g:  Baseline assessment must include an evaluation of the chest by x-ray, CT scan, or MRI, and an evaluation of the abdomen and pelvis 
by MRI or CT scan); repeat assessments must include areas with  target and non-target lesions found at baseline.  Radiologic tumor 
evaluations are repeated every six weeks for the first 24 weeks and then repeated every 12 weeks. Repeat after treatment 
discontinuation if patient was taken off study for reasons other than progressive disease as seen in radiologic imaging.  
h.. Only for patients on warfarin.  This is to be done at baseline, weekly for the first three weeks, weekly for the first three weeks of any 
cycle following a dose reduction, and for a minimum of two weeks after stopping temsirolimus (See Section 5.5). 
i.   Continuing weekly while patient is on therapy. 
 
j.   Serum chemistry includes albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 


                                                                                                                                               GOG-0248 
 
 
-27-
phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT], sodium. Continuing every 3 weeks while on study. 
k.  Weekly for the first four weeks, then with dose 7, then continuing every 6 weeks while on study; when patient is taken off study, 
continue about once a month until toxicity resolution. If appropriate, toxicity assessments can be conducted by telephone. (05/24/10) 
 
  
7.2  
Stained Pathology Slide Requirements for Central Review to Confirm Protocol 
Eligibility (05/24/10) 
 
Stained pathology slides are required for central review by the GOG Pathology 
Committee to confirm eligibility for the protocol.  At least one representative H&E 
stained slide (or slides) demonstrating primary site histologic cell type and grade will be 
required for ALL patients, with additional slides documenting most advanced stage or 
recurrence if documented by histology or cytology.  If the most advanced stage of 
disease is not documented by histology, the method of stage documentation needs to be 
stated (e.g. CT, MRI, etc.).  If this protocol allows patients with recurrent or persistent 
disease, slides from recurrence and/or persistent disease will be required only if 
recurrence/persistent disease is confirmed by histology or cytology.  
 
When submitting pathology material to the GOG Statistical and Data Center individual 
slides must be labeled with GOG Patient ID, patient initials and the surgical / pathology 
accession number (e.g., S08-2355) and block identifier (e.g., A6).  Do not label the 
slides with disease site (e.g., right ovary) or procedure date.   
 
Pack the labeled slides into plastic slide cassette(s).  Tape plastic slide cassettes shut 
and wrap in bubble wrap or another type of padded material prior to shipping.  Please 
include the GOG Patient ID, patient initials, and protocol number on all pages of the 
pathology report and black out the patient’s name.  Ship pathology slides, two copies of 
both the Pathology Form F (if required for the protocol) and the official pathology 
report in your own shipping containing using postal mail at your own expense directly 
to the Pathology Materials Coordinator at the GOG Statistical and Data Center, 
Roswell Park Cancer Institute, Research Studies Center, Carlton and Elm Streets, 
Buffalo, New York, 14263; phone (716) 845-5702.  The GOG Upload Application in 
SEDES is an alternative method for submitting pathology reports to the GOG Statistical 
and Data Center.  Please see Sections 4.4 and 10.2 for additional requirements and 
instructions. 
 
7.3  
Translational Research 
 
7.31 
Specimen Requirements 
 
Please see below for a summary of the specimen requirements for GOG-0248 if 
the patient gives permission for her specimens to be submitted and used for this 
research study. Patients may participate in this treatment protocol even if they 
don’t give permission for their specimens to be submitted and used for this 
research study. If this is the case, indicate “patient refused” as the reason in 
Item 5 on the SP Form.  
 
Refer to Appendix IV for a description of the Specimen Procedures for this 
protocol including instructions for obtaining a GOG Bank ID, ordering 


                                                                                                                                               GOG-0248 
 
 
-28-
Specimen Kits for GOG-0248, submitting SP Forms as well as preparing, 
shipping, banking and distributing the GOG-0248 specimens.   
 
Quick Scan Summary of the Specimen Requirements for GOG-0248 (05/24/10) 
 
 
1  
Label each specimen with the protocol number (GOG-0248), a GOG Bank ID (# # # # - # # – G # # #), a specimen 
code (see above) and the collection date (mm/dd/yyyy).  
 
2  
Please complete Form SP for EACH specimen and include a copy when the specimen is submitted to the GOG 
Tissue Bank as described in Appendix IV.   
 
3   The unstained slides or block of primary, metastatic, and/or recurrent tumor will need to be shipped to the GOG 
Tissue Bank in your own shipping container using the US Postal Service at your expense.  GOG Tissue Bank / 
Protocol GOG-0248, Nationwide Children’s Hospital, 700 Children’s Drive, WA1340, Columbus, OH 43205, 
Phone: (614) 722-2865, FAX: (614) 722-2897, E-mail: gogbank@nationwidechildrens.org.  Primary tumor is the 
1st choice, metastatic tumor is the 2nd choice and recurrent tumor is the 3rd choice.  We strongly encourage the 
submission of more than one type of tumor tissue whenever possible.  In this situation, please label the tumor 
specimens sequentially using FT01 for primary tumor tissue, FT02 for metastatic tumor and FT03 for recurrent 
tumor, and contact the GOG Statistical and Data Center to have the additional “optional” SP Forms for FT02 and 
FT03 added to the patient form schedule.  In the event that it is not possible to submit the archival FFPE tumor 
specimen, submit the SP form via SEDES with the reason the specimen was not collected in item 5 (e.g., patient 
Required Specimens 
(Specimen Codes)1 
Form SP Label  
in Forms  
Tracking 
System2 
Collection Time Points 
and Requirements 
Deadlines and 
Recommendations2 
Archival Formalin-Fixed and 
Paraffin-Embedded (FFPE) 
Primary, Metastatic, and/or 
Recurrent Tumor (FT01):3   
1st choice: Block 
2nd choice: 20 Unstained Slide 
- 15 unstained 5 micrometer 
sections on charged slides for 
immunohistochemistry assays 
- 5 unstained 10 micrometer 
sections on clean glass slides 
suitable for laser capture 
microdissection and/or 
nucleic acid extractions 
SP-FT01-0248 
(05/24/10) 
Tumor must have been 
removed prior to 
starting treatment on 
this phase II trial 
Ship FT01 to the GOG Tissue 
Bank using your own shipping 
container via US Postal Mail at 
your own expense within 8 weeks 
of study entry. 3 
 
Form SP for FT01 will need to be 
submitted to the GOG Statistical 
and Data Center (SDC) online 
using the SDC Electronic Data 
Entry System (SEDES) within 8 
weeks of study entry. 
Room Temperature Blood 
(WB01) for immediate 
submission and DNA 
extraction by the Bank4    
(05/24/10) 
 
Draw 10 ml blood into your 
own purple-top Vacutainer® 
tube(s) with EDTA  
 
SP-WB01-0248 
Collect prior to starting 
treatment on this phase 
II trial 
Ship WB01 to the GOG Tissue 
Bank at ambient temperature the 
day the blood is collected in your 
own shipping container.4 
 
Form SP for WB01 will need to be 
submitted to the SDC online using 
SEDES the day the blood is 
collected. 
Frozen Blood (WB02)5  
(05/24/10) 
 
Draw 10 ml blood into your 
own purple-top Vacutainer® 
tubes with EDTA   
 
SP-WB02-0248 
Collect prior to starting 
treatment on this Phase 
II trial 
Ship WB02 to the GOG Tissue 
Bank using a Single Chamber Kit 
provided for this trial within 1 
week of starting treatment.5 
 
Form SP for WB02 will need to be 
submitted to the SDC online using 
SEDES within 1 week of treatment 
start. 


                                                                                                                                               GOG-0248 
 
 
-29-
refused or referring site won’t release tumor). If the quantity of FFPE tumor is limited, please call a GOG 
Translational Research Scientist for advice (716-845-5702). (05/24/10) 
 
4 
Room temperature. whole blood specimen for GOG-0248 MUST be shipped to the GOG Tissue Bank (address 
provided above) with a completed SP Form for WB01.  This blood specimen must be shipped at ambient 
temperature the day the blood is collected as it will be immediately processed upon receipt at the GOG Tissue 
Bank.  Whole blood will need to be shipped to the GOG Tissue Bank FedEx Priority Overnight on a Monday 
through Friday schedule for Tuesday through Saturday delivery using the GOG Tissue Bank’s Federal Express 
Account Number (1290-2562-0).  Refer to Section V and Section VII in Appendix IV for instructions for 
preparing and shipping the whole blood specimen to the GOG Tissue Bank for GOG-0248 as the GOG Tissue 
Bank cannot provide Shipping Kits for submitting the room temperature whole blood specimen for this protocol.  
In the event that it is not possible to submit the whole blood specimen, submit the SP form via SEDES with the 
reason the specimen was not collected in item 5 (e.g., patient refused, tried but not able to draw blood, non-US 
site, logistically infeasible or IRB refused).  (05/24/10) 
 
5 
Frozen whole blood specimen for GOG-0248 MUST be shipped to the GOG Tissue Bank (address provided 
above) with a completed SP Form for WB02 via Federal Express for next morning delivery using the GOG Tissue 
Bank’s Federal Express Account Number (1290-2562-0) on a Monday through Thursday schedule for Tuesday 
through Friday delivery.  Please store the blood in an ultra-cold freezer or in an appropriate container/cooler 
surrounded by excess dry ice until the blood can be shipped to the GOG Tissue Bank.  In the event that it is not 
possible to submit the whole blood specimens, submit the SP form via SEDES with the reason the specimen was 
not collected in Item 5 (see above for examples). (05/24/10) 
 
7.32 
Laboratory Testing 
 
Staff at the GOG Tissue Bank will coordinate with the Chairs of the GOG 
Committee for Experimental Medicine and the Tissue Utilization Subcommittee 
as well as staff in the GOG Statistical and Data Center to distribute appropriate 
specimens to approved investigators for testing for this trial (see below for 
details).  The translational research component of this Phase II protocol 
does involve genetic testing to study genetic changes that are inherited and 
passed on in families.  (11/24/08) 
 
7.321 Immunohistochemistry Assays 
 
Staff at the GOG Tissue Bank will prepare and distribute fifteen 
unstained sections 5 micrometers in thickness on charged slides suitable 
for standard immunohistochemistry assays to Dr. Kimberly Leslie at the 
University of Iowa Hospitals and Clinics.  (05/24/10) 
 
Validated immunohistochemistry assays will be performed and evaluated 
for ER-alpha, ER-beta, PR-A, PR-B, GPR-30, normal and mutant PTEN, 
total and phosphorylated Akt as well as total and phosphorylated p70S6 
kinase in the GOG Receptor Core Laboratory under the supervision of 
Dr. Leslie and her designee.  (05/24/10) 
 
The following is a general description of the immunohistochemistry 
procedure to evaluate steroid receptor isoform expression.  Appropriate 
unstained slides will be baked at 60ºC for 20 minutes and then 
deparaffinized through three changes of xylene and graded alcohols to 
water.  Sections will then be treated with 3% H2O2 to inactivate the 
endogenous peroxidase activity.  Antigen retrieval will be performed in a 
Decloaking chamber in which the slides will be immersed in 10 mM 
Citrate solution (pH 6.0) and boiled for 20 minutes at 120ºC (20-25 
p.s.i). The slides will then be cooled in buffer for 20 minutes and rinsed 


                                                                                                                                               GOG-0248 
 
 
-30-
in three changes of deionized water and phosphate buffered saline (PBS).  
Non-specific binding will be minimized by incubating the sections with 
5% normal goat serum, in PBS, for 30 min.  PBS will be used to rinse 
and wash the sections between each of the subsequent incubations.  
Slides will be incubated overnight at 4ºC with optimal concentrations of 
primary antibodies, with an appropriate secondary antibody for 1 hour 
and then with 3,3-diaminobenzidine solution, the chromogen substrate, 
for 10 minutes.  Slides will then be rinsed with deionized water and PBS 
and counterstained with hematoxylin, dehydrated through graded 
alcohols and permounted.  Positive and negative controls will be 
included in each run.  For the negative control sections, the primary 
antibody will be substituted with immune serum.    
 
PTEN will be detected and evaluated using an immunohistochemistry 
assay optimized by Dr. George Mutter at Brighman and Womens 
Hospital in Boston, MA.  Total and phosphorylated Akt and p70S6K will 
be detected using commercially available antibodies.  The assays to 
detect total and phosphorylated Akt and p70S6K will be optimized with 
respect to antibody concentration as well as antigen retrieval method and 
time by the GOG Receptor Core Laboratory. Appropriate positive and 
negative controls will be included in each run.   
 
Immunohistochemical staining for each biomarker will be evaluated by 
approved reviewers in a blinded manner.  The H-score will be used to 
evaluate the immunohistochemical expression of the steroid receptor 
isoforms.  The H-score is calculated based on estimates of percentages of 
positive stained epithelial and stromal cells in each of 5 intensity 
categories (0, 1+, 2+, 3+, and 4+).  The H-score represents the sum of 
each of the percentages multiplied by the weighted intensity of staining, 
as follows: H-score = (i+1)Pi, where i=1,2,3,4, and Pi varies from 0 to 
100%.  Another more quantitative method involves the use of computer 
program imaging to quantify immunohistochemical expression of steroid 
receptors.  We are currently testing such a program at the GOG Tissue 
Bank and have the opportunity to incorporate this methodology in the 
future.  (05/24/10) 
 
The criteria for evaluating the immunohistochemical expression of 
normal and mutant PTEN, total and phosphorylated Akt and total and 
phosphorylated p70S6K will be documented and reviewed by 
appropriate staff in the GOG Statistical and Data Center prior to 
initiating the review of the stained slides for this trial. 
 
Dr Leslie will be responsible for providing an electronic copy of the 
consensus immunohistochemical data for this phase II trial linked with 
accurate specimen identifiers (protocol code, Bank ID, specimen code 
and collection date) and relevant information regarding assay dates and 
controls to the GOG Statistical and Data Center for analysis.  Dr. Leslie 
will also be responsible to returning any residual unstained slides with 
accurate identifiers to the GOG Tissue Bank. 


                                                                                                                                               GOG-0248 
 
 
-31-
 
7.322 Genotyping for Single Nucleotide Polymorphisms (SNPs) 
 
Staff at the GOG Tissue Bank will exact DNA from room temperature 
blood specimens submitted for this protocol on the day the blood is 
received at the Bank, and will distribute approved aliquots of DNA and 
banked frozen blood specimens for this trial to Dr. Anna Di Rienzo in 
the Department of Human Genetics at the University of Chicago.  Dr. Di 
Rienzo will supervise the extraction of genomic DNA and the SNP 
analysis for FRAP1 and RAPTOR.  Genomic DNA will be extracted 
from each frozen blood sample using the Blood & Cell Culture midi kit 
from Qiagen, which yields 160-200 µg of DNA from 10 ml of blood.  
Genotyping of normal DNA using the Sequenom iPLEX Gold 
technology will capture the genetic variations in up to 11 tag SNPs and 
167 tag SNPs in the FRAP1 and RAPTOR genes, respectively.  SNPs in 
other genes in the mTOR pathway may also be genotyped if initial 
results are promising.  (05/24/10) 
 
Dr. Di Rienzo will also be responsible for the following: (1) providing an 
appropriate aliquot of normal DNA to Drs. Rajani Kanteti and Ravi 
Salgia for the mutation analysis described in Section 7.223, (2) 
submitting an electronic copy of the SNP data for this phase II trial 
linked with accurate specimen identifiers (protocol code, Bank ID, 
specimen code and collection date) and relevant information regarding 
assay dates and controls to the GOG Statistical and Data Center for 
analysis, and (3) shipping the residual DNA for this trial with appropriate 
identifiers and documentation regarding DNA concentration and quality 
to the GOG Tissue Bank.   
 
7.323 DNA Sequencing and Mutational Analysis, and Quantitative Real-Time 
Polymerase Chain Reaction (PCR)  
 
Staff at the GOG Tissue Bank will distribute 5 unstained sections 10 
micrometers in thickness on clean glass slides suitable for laser capture 
microdissection and/or nucleic acid extractions to Drs. Rajani Kanteti 
and Ravi Salgia in the Section of Hematology / Oncology at the 
University of Chicago to perform the genomic assessments for PTEN, 
PI3KCA, and paxillin. 
 
Drs. Kanteti and Salgia will supervise the DNA extractions as well as the 
analysis of somatic mutations in PTEN, PI3KCA, and paxillin and the 
assessment of copy number abnormalities in PTEN and paxillin.  
 
Once the unstained thick sections for this trial are distributed to the 
laboratory, the DNA extraction will be carried out according to Sato 
(Sato, Y et al., Diagnostic Molecular Pathology 10: 265-271, 2001) with 
minor modifications. The tissue sections will be re-suspended in 0.3 ml 
of digestion buffer (50mM Tris/Hcl, pH 8.5, 1 mM EDTA and 1% 
Tween 20).  The tube will be tightly capped with a pinhole at the center. 


                                                                                                                                               GOG-0248 
 
 
-32-
High power microwave irradiation will be carried out for 1 to 1.5 min 
with irradiation time split into 15 seconds segment to prevent over 
boiling. The tubes will be centrifuged while they are warm, at 12000 x g 
for 10 minutes and placed on ice.  Using a sterile tooth pick the solid 
paraffin wax ring that forms above the buffer will be removed.  
Proteinase K will be added to each sample to get the final concentration 
of 0.5 mg/ml and the tubes will be incubated at 55°C in a water bath for 
48 hours with constant shaking. After two days of digestion with 
proteinase K, Chelex -100 (BioRad) will be added to each sample to 
final concentration of 5% and the mixture will be vortexed and heated at 
95°C for 10 minutes to inactivate the proteinase K. The samples will 
then be centrifuged for 5 minutes at 12,000 x g and the supernatant 
containing DNA will be transferred to a new tube and stored at -20°C or 
4°C.  The amount of DNA extracted will be quantified by running an 
aliquot on 0.8% agarose gel.  The above steps will ensure the suitability 
of extracted DNA for amplification of specific genes.   
 
Appropriate PCR primers covering the exons spanning the entire coding 
region of PTEN, PI3KCA and paxillin will be used and sequenced.  
Aliquots of normal DNA will also be obtained from Dr. Di Rienzo (see 
Section 7.222) for sequencing.  All mutations will be confirmed by 
sequencing in both directions.   
 
Quantitative real-time PCR will be performed for gene copy number 
measurement of PTEN and paxillin using DNA extracted from the FFPE 
tumor specimens using the Stratagene Mx3000P system and the iQ 
SYBR green PCR kit (Bio-Rad Laboratories).  Relative gene copy 
number for PTEN or paxillin was calculated from the real-time PCR 
efficiencies for each individual run and based on the deviations of the 
target gene and reference gene (LINE-1) in the a test sample versus a 
control.  LINE-1 is a repetitive element and copy numbers per diploid 
genome are similar in healthy and malignant human cells.  Reactions will 
be performed in triplicate under standard thermocycling conditions and 
the mean threshold cycle number will be used.  
 
Drs. Kanteti and Salgia will be responsible for the following: (1) 
submitting an electronic copy of the mutation analysis in PTEN, 
PI3KCA, and paxillin, and the assessment of copy number abnormalities 
in PTEN and paxillin for this phase II trial linked with accurate specimen 
identifiers (protocol code, Bank ID, specimen code and collection date) 
and relevant information regarding assay dates and controls to the GOG 
Statistical and Data Center for analysis, and (2) shipping any residual 
DNA and unused unstained slides for this trial with appropriate 
identifiers and documentation regarding DNA concentration and quality 
to the GOG Tissue Bank.   
 
 
 
 


                                                                                                                                               GOG-0248 
 
 
-33-
 
7.33 
Future Research 
 
See Section X in Appendix IV for important details regarding the banking and 
distribution of residual FFPE tumor tissue, DNA and whole blood specimens for 
future research. (05/24/10) 
7.4       Quality of Life (05/24/10) 
 
This protocol does not include quality of life research. 
 
 


                                                                                                                                               GOG-0248 
 
 
-34-
8.0 
EVALUATION CRITERIA   
 
8.1 
Parameters of Response – GOG RECIST Criteria 
 
8.11 
Measurable disease is defined as at least one lesion that can be accurately 
measured in at least one dimension (longest dimension to be recorded).  Each 
lesion must be  20 mm when measured by conventional techniques, including 
palpation, plain x-ray, CT, and MRI, or  10 mm when measured by spiral CT.   
 
8.12 
Baseline documentation of “Target” and “Non-Target” lesions 
 
All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in 
total representative of all involved organs should be identified as target lesions 
and will be recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest dimension) and their 
suitability for accurate repetitive measurements by one consistent method of 
assessment (either by imaging techniques or clinically).  A sum of the longest 
dimension (LD) for all target lesions will be calculated and reported as the 
baseline sum LD.  The baseline sum LD will be used as reference to further 
characterize the objective tumor response of the measurable dimension of the 
disease. 
 
All other lesions (or sites of disease) should be identified as non-target lesions 
and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as “present” or “absent”. 
 
All baseline evaluations of disease status should be performed as close as 
possible to the start of treatment and never more than 4 weeks before the 
beginning of treatment. 
 
8.13 
Best Response 
 
Measurement of the longest dimension of each lesion size is required for 
follow-up.  Change in the sum of these dimensions affords some estimate of 
change in tumor size and hence therapeutic efficacy.  All disease must be 
assessed using the same technique as baseline. Reporting of these changes in an 
individual case should be in terms of the best response achieved by that case 
since entering the study.    
 
8.131 Complete Response (CR) is disappearance of all target and non-target 
lesions and no evidence of new lesions documented by two disease 
assessments at least 4 weeks apart. 


                                                                                                                                               GOG-0248 
 
 
-35-
8.132 Partial Response (PR) is at least a 30% decrease in the sum of longest 
dimensions (LD) of all target measurable lesions taking as reference the 
baseline sum of LD.  There can be no unequivocal progression of non-
target lesions and no new lesions.  Documentation by two disease 
assessments at least 4 weeks apart is required.  In the case where the 
ONLY target lesion is a solitary pelvic mass measured by physical exam, 
which is not radiographically measurable, a 50% decrease in the LD is 
required. 
 
8.133 Increasing Disease is at least a 20% increase in the sum of LD of target 
lesions taking as references the smallest sum LD or the appearance of 
new lesions within 6 weeks of study entry.  Unequivocal progression of 
existing non-target lesions, other than pleural effusions without 
cytological proof of neoplastic origin, in the opinion of the treating 
physician within 6 weeks of study entry is also considered increasing 
disease (in this circumstance an explanation must be provided).  In the 
case where the ONLY target lesion is a solitary pelvic mass measured by 
physical exam, which is not radiographically measurable, a 50% increase 
in the LD is required. 
 
8.134 Symptomatic deterioration is defined as a global deterioration in health 
status attributable to the disease requiring a change in therapy without 
objective evidence of progression. 
 
8.135 Stable Disease is any condition not meeting the above criteria. 
 
8.136 Inevaluable for response is defined as having no repeat tumor 
assessments following initiation of study therapy for reasons unrelated 
to symptoms or signs of disease.   
 
8.14 
Progression (measurable disease studies) is defined as ANY of the following: 
 
• At least a 20% increase in the sum of LD target lesions taking as reference 
the smallest sum LD recorded since study entry  
• In the case where the ONLY target lesion is a solitary pelvic mass measured 
by physical exam which is not radiographically measurable, a 50% increase 
in the LD is required taking as reference the smallest LD recorded since 
study entry 
• The appearance of one or more new lesions   
• Death due to disease without prior objective documentation of progression 
• Global deterioration in health status attributable to the disease requiring a 
change in therapy without objective evidence of progression  


                                                                                                                                               GOG-0248 
 
 
-36-
• Unequivocal progression of existing non-target lesions, other than pleural 
effusions without cytological proof of neoplastic origin, in the opinion of the 
treating physician (in this circumstance an explanation must be provided) 
 
8.15 
Recurrence (non-measurable disease studies) is defined as increasing clinical, 
radiological or histological evidence of disease since study entry.   
 
 
 
 
8.16 
Survival is the observed length of life from entry into the study to death or the 
date of last contact. 
 
8.17 
Progression-Free Survival (measurable disease studies) is the period from study 
entry until disease progression, death or date of last contact. 
 
8.18 
Recurrence-Free Survival (non-measurable disease studies) is the period from 
study entry until disease recurrence, death or date of last contact. 
 
8.19 
Subjective Parameters including performance status, specific symptoms, and 
side effects are graded according to the CTCAE v3.0. 
 
 
 


                                                                                                                                               GOG-0248 
 
 
-37-
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 decides to withdraw from 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 
Patients will be followed after last drug dose until toxicity resolution and for one year 
after the end of treatment, or until study withdrawal if it occurs before this time. 
   
 
 
 
 
 


                                                                                                                                               GOG-0248 
 
 
-38-
10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
 
10.1 
ADVERSE EVENT REPORTING FOR AN INVESTIGATIONAL AGENT 
   
10.11 Definition of Adverse Events (AE) 
 
An adverse event (AE) is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease that occurs in a patient 
administered a medical treatment, whether the event is considered related or 
unrelated to the medical treatment.  
 
10.12 Reporting Expedited Adverse Events 
 
Depending on the phase of the study, use of investigational agents, and role of 
the pharmaceutical sponsor, an expedited AE report may need to reach multiple 
destinations.  For patients participating on a GOG trial, all expedited AE reports 
should be submitted by using the CTEP automated system for expedited 
reporting (AdEERS).  All AdEERS submissions are reviewed by GOG before   
final submission to CTEP.  Submitting a report through AdEERS serves as 
notification to GOG, and satisfies the GOG requirements for expedited AE 
reporting.  All adverse reactions will be immediately directed to the Study Chair 
for further action. 
 
The requirement for timely reporting of AEs to the study sponsor is specified in 
the Statement of Investigator, Form FDA-1572.  In signing the FDA-1572, the 
investigator assumes the responsibility for reporting AEs to the NCI.  In 
compliance with FDA regulations, as contained in 21 CFR 312.64, AEs should 
be reported by the investigator. 
 
 
10.13 Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND:  AdEERS  
 
 
Expedited Reporting Requirements for Adverse Events That Occur Within 
 
 
30 Days of the Last Dose of the Investigational Agent 
 
Reporting Requirements for Adverse Events that occur within 30 Days¹ of the 
Last Dose of the Investigational Agent on Phase 2 and 3 Trials 
 
From the period of protocol activation through September 30, 2011, Common 
Terminology Criteria for Adverse Events (CTCAE) version 3.0 (CTCAE v3.0) 
are utilized for defining and grading specific adverse events reported through the 
AdEERS system. (9/26/2011) 
 
Beginning October 1, 2011, the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) v 4.0 will be utilized for AE reporting through the 
AdEERS system. CTCAE v 4.0 is located on the CTEP website at 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
.  All appropriate treatment areas should have access to a copy of this 
Version of CTCAE.  CTCAE v 4.0 definition is also available on the GOG 


                                                                                                                                               GOG-0248 
 
 
-39-
member web site (https://gogmember.gog.org under MANUALS). 
(9/26/2011) 
 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected  
and Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected Expected 
With  
Hospitali-
zation 
Without 
Hospitali- 
zation 
With  
Hospitali- 
zation 
Without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
7 Calendar 
Days 
Not 
Required 
7 Calendar 
Days 
Not 
Required 
7 Calendar 
Days 
7 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
7 Calendar 
Days 
Not 
Required 
7 Calendar 
Days 
7 Calendar 
Days 
7 Calendar 
Days 
Not 
Required 
24-Hrs; 
3 Calendar 
Days 
7 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of 
treatment with an agent under a CTEP IND require reporting as follows: 
AdEERS 24-hour notification followed by complete report within 3 calendar days for: 
• Grade 4 and Grade 5 unexpected events  
 
AdEERS 7 calendar day report: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• Grade 5 expected events 
 
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report 
is required as outlined in the table. 
 
     Please see exceptions below under section entitled “Additional Instructions or Exceptions to AdEERS 
Expedited Reporting Requirements for Phase 2 and 3 Trials Utilizing an Agent under a CTEP  IND.” 
 
March 2005 
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  
 
Attribution to treatment or other cause must be provided. 
 
• 
Expedited AE reporting timelines defined: 
- “24 hours; 3 calendar days” – The investigator must initially report the AE via AdEERS 
within 24 hours of learning of the event followed by a complete AdEERS report within 3 
calendar days of the initial 24-hour report. 
 - “7 calendar days” - A complete AdEERS report on the AE must be submitted within  
      
7 calendar days of the investigator learning of the event.  
 
• 
Any medical event equivalent to CTCAE Grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, 
or birth defects must be reported via AdEERS if the event occurs following treatment with an 
agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 


                                                                                                                                               GOG-0248 
 
 
-40-
registration on all reports. 
Additional Instructions or Exceptions to AdEERS Expedited Reporting Requirements for Phase 2 and 
3 Trials Utilizing an Agent under a CTEP-IND: 
 
• There are no additional instructions or exceptions to AdEERS expedited reporting requirements 
for this protocol. 
 
10.14 Procedures for Expedited Adverse Event Reporting: 
 
10.141 AdEERS Expedited Reports: Expedited reports are to be submitted using 
AdEERS available at http://ctep.cancer.gov. The CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements for expedited adverse event 
reporting requirements are also available at this site.  
Up until September 30, 2011, AML/MDS events must be reported via 
AdEERS (in addition to your routine AE reporting mechanisms).  In 
CTCAE v3.0, the event can be reported as:  “Secondary malignancy-
Other (specify)”. (9/26/2011) 
 
Starting October 1, 2011 when use of CTCAE v4.0 begins: AML/MDS 
events must be reported via AdEERS (in addition to your routine AE 
reporting mechanisms). In CTCAE v4.0, the event(s) may be reported as 
either: 1) Leukemia secondary to oncology chemotherapy, 2) 
Myelodysplatic syndrome, or 3) Treatment related secondary 
malignancy. (9/26/2011) 
 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made to GOG by telephone at: 215-854-0770. An 
electronic report MUST be submitted immediately upon re-establishment 
of internet connection. Please note that all paper AdEERS forms have 
been removed from the CTEP website and will NO LONGER be 
accepted. (9/26/2011) 
 
For the purposes of expedited reporting of adverse events to CTEP, 
unexpected events are those not listed in the Agent Specific Adverse 
Event List (ASAEL). The ASAEL is a subset of AEs within the 
Comprehensive Adverse Event and Potential Risks List (CAEPR). This 
list of events is based on CTEP’s clinical experience with this agent and 
defines “expected” Grade 2 and 3 AEs not requiring hospitalization as 
exempt from expedited reporting. The CAEPR is a complete list of 
reported and/or potential AEs associated with an agent under a CTEP 
IND. For questions or comments regarding the ASAEL or CAEPR, 
please contact the AdEERS MD Help Desk at adeersmd@tech-res.com. 
The CAEPR for temsirolimus is located in Section 4.310. 
 
 
 
10.15 Automated CDUS reporting  
 
For studies using investigational agents, the GOG Statistical and Data Center 
(SDC) routinely reports adverse events electronically to the CTEP Clinical Data 
Update System (CDUS Version 3.0).  The SDC submits this data quarterly.  The 


                                                                                                                                               GOG-0248 
 
 
-41-
AEs reported through AdEERS will also be included with the quarterly CDUS 
data submissions. 
 
As of 10/1/2011, this study will cease using CTCAE v3 and switch to CTCAE 
v4 for the purposes of reporting through AdEERS and/or CDUS.  The GOG 
Statistical and Data Center will internally convert the adverse event terms and 
grades reported through AdEERS for this study from April 1, 2011 onward from 
version 4 to version 3.   Additionally, the Statistical and Data Center will map 
all CTCAE v3 data reported for this study on GOG case report forms to CTCAE 
v4 defined terms and grades for CDUS reporting purposes.  This will allow use 
of a consistently defined set of criteria for reporting adverse events throughout 
the study with minimal impact on the participating sites. (9/26/2011) 
 
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 materials 
(Form F, path report, and stained path slides** to confirm eligibility) should be 
submitted together via postal mail.  The Upload feature in SEDES is an alternate 
method for submitting Form F and Pathology reports (not applicable for slides). 
(05/24/10) 
 
 
Form± 
Due within 
Copies* 
Comments 
Weeks 
Event 
Form R (Registration 
Form) 
2 
 
Registration 
 
1 
 
Mandatory Submission via SEDES 
Specimen Consent 
Application 
1 
Registration 
N/A 
Complete online 
Form OSR (Recurrent 
Gynecologic Cancer On-
Study Form) 
2 
 
Registration 
 
1 
 
Mandatory Submission via SEDES 
 
Form DR (Pre-Treatment 
Summary Form) 
2 
Registration 
1 
Mandatory Submission via SEDES 
 
Form CONM 
(Concomitant Medication 
Form) - baseline 
2 
Registration 
1 
Mandatory Submission via SEDES 
 
Form D2M (Solid Tumor 
Evaluation Form) - 
baseline 
2 
Registration 
1 
Mandatory Submission via SEDES 


                                                                                                                                               GOG-0248 
 
 
-42-
Primary/Advanced 
Disease: 
Form F (Pathology 
Form) 
Pathology Report** 
Stained Path Slides 
to confirm eligibility 
and advanced disease  
Persistent or Recurrent 
Disease: 
Form F  
Pathology Report 
Stained Path Slides to 
confirm eligibility, if 
documented by 
histology or cytology 
 
 
6 
 
6 
6 
 
 
 
 
6 
6 
6 
 
 
Registration 
 
Registration 
Registration 
 
 
 
 
Registration 
Registration 
Registration 
 
 
2 
 
2  
** 
 
 
 
 
2** 
2** 
** 
 
 
Available in SEDES for print only 
 
Submit via postal mail to GOG SDC 
in Buffalo, New York** 
 
 
 
 
Available in SEDES for print only 
 
Submit via postal mail to GOG SDC 
in Buffalo, New York** 
 
Form D2R (Cycle Dose 
Drug Form) 
2 
Completion of each cycle 
of therapy 
1 
Mandatory Submission via SEDES 
Form D2M (Solid Tumor 
Evaluation Form) 
2 
Tumor response or 
progression assessment 
1 
Mandatory Submission via SEDES 
Form SP-FT01-0248†  
for archival formalin-fixed 
and paraffin-embedded 
(FFPE) primary, metastatic 
and/or recurrent tumor 
(block or unstained slides) 
(05/24/10) 
8 
Registration 
1 
Submit via SEDES  
Ship block or unstained slides for 
translational research with a copy of 
the SP Form for FT01 to the GOG 
Tissue Bank in Columbus Ohio † 
 
Form SP-WB01-0248‡ 
for room temperature 
blood for immediate 
submission and DNA 
extraction by the Bank 
(05/24/10) 
1 
Start of treatment 
1 
Submit via SEDES  
Ship WB01 blood for translational 
research at ambient temperature the 
day the blood is collected with a copy 
of the SP Form for WB01 to the GOG 
Tissue Bank in Columbus Ohio 
‡(05/24/10) 
Form SP-WB02-0248‡‡ 
for frozen blood 
(05/24/10) 
1 
Start of treatment 
1 
Submit via SEDES  
Ship WB02 frozen blood for 
translational research with a copy of 
the SP Form for WB02 to the GOG 
Tissue Bank in Columbus Ohio ‡‡ 
Form T (Common 
Toxicity Reporting Form) 
2 
Beginning of each 
subsequent cycle 
1 
 
Mandatory Submission via SEDES 
Form Q0 (Treatment 
Completion Form) 
2 
Completion of study Rx 
and change in Rx 
1 
Mandatory Submission via SEDES 
Form Q (Follow-Up Form) 
2 
Disease progression; 
death; normal follow-up; 
change in treatment 
1 
Submit via SEDES  
for one year from end of treatment 
 
* 
The number of required copies including the original form which must be sent to the Statistical and Data Center. 
** 
Stained pathology slides are required for central review by the GOG Pathology Committee to confirm eligibility.  
See Sections 4.4 and 7.2 for additional requirements and instructions. If F form and path reports are uploaded, only 
one copy of the F form should be submitted with slides. (05/24/10)   
         Form SP must be submitted online to the GOG SDC using SEDES regardless of whether the specimen is submitted 
for research.  


                                                                                                                                               GOG-0248 
 
 
-43-
†         See Footnote 3 in the Quick Scan Summary in Section 7.31 of the protocol and Appendix IV for important details 
about submitting up to three tumor specimens (FT01, FT02 and FT03), loading optional SP Forms for FT02 (second 
type of FFPE tumor) and FT03 (third type of FFPE tumor), and instructions for shipping the block or unstained 
sections of primary, metastatic and/or recurrent tumor in your own shipping container to the GOG Tissue Bank and 
for completing the corresponding SP Form(s). (05/24/10) 
‡         See Footnote 4 in the Quick Scan Summary in Section 7.31 of the protocol and Appendix IV for important details 
for preparing and shipping the room temperature blood (WB01) the day the blood is collected in your own shipping 
container to the GOG Tissue Bank, and for completing the corresponding SP Form. (05/24/10) 
‡‡        See Footnote 5 in the Quick Scan Summary in Section 7.31 of the protocol and Appendix IV for important details 
for preparing and shipping the frozen blood (WB02) in a Single Chamber Kit provided for this trial to the GOG 
Tissue Bank within 1 week of starting treatment, and for completing the corresponding SP Form. (05/24/10) 
 
 
This study will be monitored by the Complete Clinical Data Update System (CDUS) Version 3.0 
CDUS data will be submitted quarterly to CTEP by electronic means. 
 
This study utilizes the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) 
for defining and grading adverse events to be reported on GOG case report forms. A GOG CTCAE 
v3.0 Manual is available on the GOG member web site (http://www.gog.org under MANUALS) and 
can be mailed to the institution registering a patient to this study if requested.  (9/26/2011) 


                                                                                                                                               GOG-0248 
 
 
-44-
11.0 
STATISTICAL CONSIDERATIONS   
 
Overview, Study Registration and Randomization:  This study is a two-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.  If both 
regimens are deemed active following completion of stage II, one regimen will be selected for 
further investigation as a means of prioritization in the event that resources are limited.  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 chemoradiation either at time of initial 
diagnosis or for a pelvic recurrence of endometrial cancer and 2) Patients who have never 
received adjuvant chemotherapy or chemoradiation for treatment of endometrial cancer or its 
subsequent recurrence.  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 of measurable 
disease, tumor grade, histological cell type, estrogen and progesterone 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 in patients who 
received any amount of study drug graded according to CTCAE v3.0.  
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 GPR30 (H-Score); immunohistochemical expression of , total 
Akt, phosphorylated Akt, total p70S6 kinase and phosphorylated p70S6 kinase 
(scoring criteria to be defined); genotype for 11 tag SNPs for FRAP1 and 167 
tag SNPs for RAPTOR; type and localization of mutations in PTEN, PI3KCA, 
and paxillin; the ratio of the number of copies of PTEN to LINE-1 and paxillin 
to LINE-1.   
 
11.2 
Accrual Rate: Previous GOG phase II studies of hormonal agents differed in their 
requirement for biopsied tissue which had an impact on the accrual rate.  This study 
does not require sampling metastatic tumor for the purposes of testing the receptor 
status but does require a tissue block from either primary, metastatic or recurrent tumor.  
Accrual to previous phase II studies of hormonal agents that did not require biopsied 
tissue and did not select for receptor positive patients ranged from 36 to 62 patients 
annually.   


                                                                                                                                               GOG-0248 
 
 
-45-
 
The accrual rate of the most recently completed phase II study requiring biopsied tumor 
averaged 10 patients per year among the patients with estrogen receptor positive 
metastatic tumor. The accrual rate on the currently active phase II study among those 
with receptor positive metastatic tumors is now 44 patients per year (based on 1st and 
2nd quarters of 2007).  
 
The accrual rate on this study is expected to be higher than the previous study given that 
it does not require a biopsy (primary uterine tissue can be tested for receptors) and the 
fact that this study incorporates a new targeted biologic agent.  The accrual rate for this 
study is based upon that observed in GOG 153 (49) and current accrual on GOG 188 
(44), 46 patients per year.   
 
11.3 
Study Design and Sample Size: This study will implement a two-stage design with 
early stopping guidelines intended to limit the accrual of patients to inactive regimens. 
Additionally, if at the end of stage II, both regimens are deemed to have sufficient 
activity, a selection procedure will be employed to prioritize the regimens for further 
investigation. 
 
Hormonal agents studied by the GOG have yielded response rates ranging from 11% to 
33%.  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.   
 
Data describing response to temsirolimus were provided by Janet Dancey 
(IDB/CTEP/DCTD/NCI) suggest that response may differ depending on whether or not 
a patient has received previous chemotherapy (alone or in combination with radiation) 
for endometrial carcinoma.  The observed proportions of endometrial cancer patients 
responding were 25% (7) of 33 patient without a history of chemotherapy and 7.5% (2) 
of 27 patients who had previously been treated with chemotherapy.  Patients with or 
without a history of chemotherapy or chemoradiation are eligible for this study.  Sixty 
percent of patients enrolled on GOG 188 in 2007 had received adjuvant chemotherapy.  
Accrual trends observed on GOG 188 and the increasing use of adjuvant chemotherapy 
for endometrial carcinoma suggest 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 to get sufficient 
patients in each trial.  Therefore, a two-stage conditional stratified phase II trial as 
proposed by London and Chang36 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 and R2 corresponding to the responses produced in 
stages 1 and 2 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
















 


                                                                                                                                               GOG-0248 
 
 
-46-
 
Where i indexes the number of important stratification levels under consideration and j 
indexes the stage of accrual.  The distribution of Rj depends on the probabilities of 
response, pi, within each stratum.  Stratum 1 will correspond with those patients who 
have never been treated with chemotherapy whereas stratum 2 will correspond with 
those patients who have 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 = 0.20 
and p2 = 0.10.  Under the alternative hypothesis of H1: p1 = 0.40 and p2 = 0.30, the 
following design will limit the probability of type I error to 0.06 and type II to 0.10.  
According to London and Chang36, the first stage rejection boundary, a1, is found with 
the following equation: 
 


1
1
0
|
i
i
i
P R
a
p
p





 
 
where p10 = 0.20, Δ1 = 0.20, p20 = 0.10, Δ2 = 0.20, and β is the probability of a type II 
error.  There is interest in spending 50% of the total beta in the first stage, so γ = 0.50.  
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






 
 
For each treatment arm we will target 21 patients during each stage of accrual and 
expect n11 = 8 without previous chemotherapy and n21 = 13 who have received 
chemotherapy in the past.   Approximating the equation above gives a1 = 4 (note: ≈ 
means ‘less than and as close as possible’).  According to the decision rule provided by 
this method, if there were 3 or fewer responses, the agent would have been deemed 
clinically uninteresting.  Accordingly, the probability of early termination under the null 
hypothesis would be 67%.  If the proportions in each stratum differ from those 
expected, the rules above will be recalculated for the observed proportion of patients in 
each stratum while maintaining probability of type I and type II error limits as closely 
as possible. 
 
For a given total sample size, the rejection boundary, b2, is found by searching for the 
smallest marginal total across all strata (over both stages) such that the following 
equation is satisfied: 
 


1
1
2
0
,
|
i
i
P a
R R
b
p
p





 
 
where R = R1 + R2.  The decision rule at the end of the study is to recommend further 
study (if medical judgment indicates) when R > b2.  Otherwise, the agent is deemed 
clinically uninteresting.  Power of the study is determined by looking at the probability: 
 




1
1
0
1
1
2
0
1
|
,
|
.
i
i
i
i
i
i
P R
a
p
p
P a
R R
b
p
p









 
 


                                                                                                                                               GOG-0248 
 
 
-47-
The cumulative targeted accrual for the second stage will be 42 patients.  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 n1 is the sample size for stage 1,  n11 is the number of patients in the first stage 
that are from stratum 1 (no prior chemotherapy), n21 is the number of patients in the first 
stage that are from stratum 2 (prior chemotherapy), nTot is the cumulative sample size, 
n12 is the number of patients in the second stage that are from stratum 1 (no prior 
chemotherapy), n22 is the number of patients in the second stage that are from stratum 2 
(prior chemotherapy), α is the probability of a type I error, and β is the probability of a 
type II error: 
Table 11.1 
 
Stage I 
Stage 2 
n1 
n11 n21 a1 nTot n12 n22 
b2 
α 
β 
20 
8 
12 
3 
41 
14 
27 
9 
0.039 0.083 
20 
8 
12 
3 
41 
15 
26 
9 
0.043 0.079 
20 
8 
12 
3 
41 
16 
25 
9 
0.047 0.074 
20 
8 
12 
3 
41 
17 
24 
9 
0.052 0.070 
20 
8 
12 
3 
41 
18 
23 
9 
0.058 0.067 
21 
8 
13 
4 
42 
14 
28 
9 
0.041 0.087 
21 
8 
13 
4 
42 
15 
27 
9 
0.045 0.083 
21 
8 
13 
4 
42 
16 
26 
9 
0.049 0.080 
21 
8 
13 
4 
42 
17 
25 
9 
0.053 0.077 
21 
8 
13 
4 
42 
18 
24 
9 
0.058 0.075 
22 
9 
13 
4 
43 
6 
15 
9 
0.051 0.067 
22 
9 
13 
4 
43 
7 
14 
9 
0.056 0.064 
22 
9 
13 
4 
43 
8 
13 10 0.028 0.900 
22 
9 
13 
4 
43 
9 
12 10 0.031 0.096 
22 
9 
13 
4 
34 
10 
11 10 0.034 0.091 
 
 
Table 11.2 displays the operating characteristics for the highlighted design and decision 
rule in Table 11.1 under different alternative hypotheses. 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                                                                                                               GOG-0248 
 
 
-48-
 
Table 11.2 
 
A
 
A B

 
Pr(neither A 
nor A+B are 
deemed active 
|
, 
A
A B


) 
Pr(both A and 
A+B are 
deemed active 
|
, 
A
A B


) 
Pr(A is 
deemed active 
and A+B is 
not deemed 
active|
, 
A
A B


) 
Pr(A+B is 
deemed 
active and A 
is not 
deemed 
active|
, 
A
A B


) 
0.1,0.2 
0.1,0.2 
0.905 
0.002 
0.046 
0.046 
0.1,0.2 
0.3,0.4 
0.076 
0.045 
0.004 
0.874 
0.1,0.2 
0.5,0.6 
<0.001 
0.049 
<0.001 
0.951 
0.3,0.4 
0.1,0.2 
0.076 
0.045 
0.874 
0.004 
0.3,0.4 
0.3,0.4 
0.006 
0.846 
0.074 
0.074 
0.3,0.4 
0.5,0.6 
<0.001 
0.919 
<0.001 
0.080 
0.5,0.6 
0.1,0.2 
<0.001 
0.049 
0.951 
<0.001 
0.5,0.6 
0.3,0.4 
<0.001 
0.919 
0.080 
<0.001 
0.5,0.6 
0.5,0.6 
<0.001 
>0.999 
<0.001 
<0.001 
A

=probabilities of response on regimen A (stratum 2,stratum 1); 
A B


=probabilities of response on regimen 
A+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. 
 
Selection 
In the event that both regimens are found to have sufficient activity following 
completion of stage II of accrual, the following rule will be used to select one of the two 
regimens for prioritized further investigation.  The combination regimen will be chosen 
for further study if the difference in proportion responding weighted by stratum size is 
at least 0.07 (3 more responses among 42 patients per arm) favoring the combination 
arm.  Otherwise the single agent regimen will be selected for further study.  Table 11.3 
displays the operating characteristics for this selection rule. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                                                                                                               GOG-0248 
 
 
-49-
 
Table 11.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*based upon simulation of 10,000 samples;  *Pr(selecting A| A and A+B were found active, 
,  
A
A
B


) =  
1- Pr(selecting A+B| A and A+B were found active, 
,  
A
A
B


) 
 
95% Confidence intervals for proportion responding to each regimen will be calculated 
with adjustment for interim analyses.37 
 
 
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 particular, adverse events on the 
combination arm will be closely monitored by the Study Chair by review of patient 
summaries every two to three months during the first stage of accrual.  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 Data and Safety 
Monitoring Board (DSMB) in conjunction with each semi-annual GOG meeting. For 
studies sponsored by the Cancer Therapy Evaluation Program (CTEP) of the National 
Cancer Institute (NCI), standardized toxicity reports are also submitted to the drug and 
disease monitors at the Investigational Drug Branch (IDB) and Clinical Investigation 
Branch (CIB). An overall review of toxicity is usually performed after completion of 
the first stage of accrual, at which point accrual is generally suspended pending formal 
analysis of response and toxicity.   
 
All AdEERS reports of serious and/or unexpected 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 
A
 
A B

 
Pr(selecting A+B| A and 
A+B were deemed 
active, 
, 
A
A B


)* 
0.1,0.2 
0.1,0.2 
0.077 
0.1,0.2 
0.3,0.4 
0.512 
0.1,0.2 
0.5,0.6 
0.996 
0.3,0.4 
0.1,0.2 
0.000 
0.3,0.4 
0.3,0.4 
0.152 
0.3,0.4 
0.5,0.6 
0.825 
0.5,0.6 
0.1,0.2 
0.000 
0.5,0.6 
0.3,0.4 
0.003 
0.5,0.6 
0.5,0.6 
0.188 


                                                                                                                                               GOG-0248 
 
 
-50-
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 12 months for Stage I (42 
patients) and 12 months for Stage II (42 additional patients) if necessary.  Six months or 
less will be necessary to observe the results of Stage I in order to make a decision to 
continue or discontinue accrual. 
 
11.6 
Translational Research Analysis:  The expression of candidate markers will be 
determined by standard semi-quantitative methods for IHC evaluation of estrogen and 
progesterone receptors; GPR30; normal and mutant PTEN; total and phosphorylated 
Akt and p70S6 kinase.  Additionally, genotypes for 11 tag SNPs for FRAP1 and 167 tag 
SNPs for RAPTOR; type and localization of mutations in PTEN, PI3KCA, and paxillin; 
the number of copies of PTEN to LINE-1 and paxillin to LINE-1 will also be 
determined.  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/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-0248 
 
 
-51-
12.0 
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