A Phase II Study of Letrozole and RAD001 (Everolimus) in Patients With Advanced or Recurrent Endometrial Cancer
Phase: PHASE2
Conditions: Endometrial Cancer
Sponsor: M.D. Anderson Cancer Center

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 1 of 56 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Phase II Study of Letrozole and RAD001 (Everolimus) in Patients with 
Advanced or Recurrent Endometrial Cancer 
 
 
 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 2 of 56 
 
A Phase II Study of Letrozole and RAD001 (Everolimus) in Patients with 
Advanced or Recurrent Endometrial Cancer 
 
 
 
Study Co-Chairs:  
 
Pamela Soliman, MD 
Brian Slomovitz, MD 
Department of Gynecologic Oncology 
Women’s Cancer Center 
Unit 1362 
Morristown Memorial Hospital  
MD Anderson Cancer Center 
100 Madison Avenue, Box 109 
1155 Herman Pressler 
Morristown, NJ 07962 
Houston, TX 77030 
(P): 973-971-5900 
713-745-5266 
(F): 973-290-7257 
psoliman@mdanderson.org 
Brian.slomovitz@atlantichealth.org 
 
 
 
 
Collaborators: 
Judith Wolf, MD  
Karen H. Lu, MD  
Department of Gynecologic Oncology 
Department of Gynecologic Oncology 
Unit 1362 
Unit 1362 
MD Anderson Cancer Center 
MD Anderson Cancer Center 
1155 Herman Pressler 
1155 Herman Pressler 
Houston, TX 77030 
Houston, TX 77030 
(P): 713-792-7310 
(P): 713-745-8902 
(F): 713-745-4480 
(F): 713-745-4480 
jwolf@mdanderson.org 
klu@mdanderson.org 
 
Lois Ramondetta, MD 
Priya Bhosale, MD 
Department of Gynecologic Oncology 
Department of Diagnostic Radiology 
Unit 1362 
Unit 368 
MD Anderson Cancer Center 
MD Anderson Cancer Center 
1155 Herman Pressler 
1515 Holcombe Blvd 
Houston, TX 77030 
Houston, TX 77030 
(P): 713-745-0307 
(P): 713-792-0221 
lramonde@mdanderson.org 
priya.bhosale@mdanderson.org 
 
 
 
 
Daniel Tobias, MD 
Paul Heller, MD 
Morristown Memorial Hospital,  
Morristown Memorial Hospital, 
Women’s Cancer 
Women’s Cancer 
100 Madison Avenue, Box 109 
100 Madison Avenue, Box 109 
Morristown, NJ 07962 
Morristown, NJ 07962 
(P): 973-971-5900 
(P): 973-971-5900 
(F): 973-290-7257 
(F): 973-290-7257 
Daniel.tobias@atlantichealth.org 
Paul.heller@atlantichealth.org 
 
 
Steve Papish, MD 
Hematology Oncology Associates of Northern New Jersey 
100 Madison Avenue – 2nd Floor 
PO Box 1089  
Morristown, NJ 07962 
(P): 973-538-5210 
(F): 973-644-9657 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 3 of 56 
 
Steven.papish@atlantichealth.org 
 
 
 
Participating Institutions:  
M. D. Anderson Cancer Center 
 
Morristown Memorial Hospital, Women’s Cancer  
 

MDACC Protocol # 2009-0059 
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Page 4 of 56 
 
Table of Contents 
1 
INTRODUCTION 
7 
1.1 
Endometrial Cancer 
7 
1.2 
Treatment of Recurrent or Advanced Endometrial Cancer 
7 
1.3 
PTEN/AKT/Mtor Pathway 
8 
1.4 
RAD001 (everolimus) 
8 
1.4.1 
Pharmacology of RAD001 
8 
1.4.2 
Clinical pharmacology of RAD001 
10 
1.4.3 
Clinical experience with RAD0001 in non-oncology indications 
11 
1.4.4 
Phase 1 study in oncology (Protocols 2101, 2102) 
11 
1.4.4.1 Phase 1 single agent studies (protocols 2101/2102, 2106 and 2107) 
12 
1.4.4.2 Safety findings 
12 
1.4.4.3 Laboratory findings 
16 
1.4.4.4 Efficacy findings 
17 
1.4.4.5 Pharmacodynamic findings 
17 
1.5 
RAD001 – Rationale for use in endometrial cancer 
19 
1.6 
Letrozole (Femara) 
20 
1.7 
Combination of Letrozole and RAD001 
20 
1.7.1 
Pharmacology 
21 
1.7.2 
Potential for drug-drug interaction 
21 
1.7.3 
Combination Phase1b study 
21 
2 
STUDY OBJECTIVES 
22 
2.1 
Primary Objective 
22 
2.2 
Secondary Objectives 
22 
3 
INVESTIGATIONAL PLAN 
23 
4 
SELECTION OF PATIENTS 
23 
4.1 
Patient Population 
23 
4.2 
Inclusion Criteria 
23 
4.3 
Exclusion Criteria 
25 
4.4 
Withdrawal of Patients from Treatment 
26 
5 
TREATMENT PLAN 
27 
5.1 
Multi-Center Patient Registration Procedures 
27 
5.2 
RAD001 and letrozole administration 
29 
5.3 
Dose Modifications / Management of Adverse Reactions 
30 
5.3.1 
Management of Non-Infectious Pneumonitis 
33 
5.3.2 
Management of Hepatitis Reactivation 
34 
5.3.3 
Monitoring for Hepatitis C 
35 

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5.3.4 
Concomitant Therapy 
35 
5.3.5 
Inducers & Inhibitors of CYP3A4 and/or PgP and Other Relevant Drug 
Interactions 
36 
5.4 
Treatment Compliance 
39 
5.5 
Supportive Care Guidelines / Concomitant Medications 
40 
5.5.1 
Growth Factors 
40 
5.5.2 
Antiemetics 
40 
5.5.3 
Other Concomitant Medications 
40 
5.6 
Drug Information 
40 
5.6.1 
Physical, Chemical and Pharmeceutical Properties of Letrozole 
40 
5.6.2 
Physical, Chemical and Pharmeceutical Properties of Everolimus 
41 
6 
STUDY PROCEDURES 
41 
6.1 
Schedule of Assessments 
42 
6.2 
Screening / Baseline 
43 
6.3 
Treatment Evaluations 
43 
6.4 
End of Treatment 
44 
6.5 
Follow-up 
45 
6.6 
Correlative Studies 
45 
7 
EFFICACY AND SAFETY ASSESSMENTS – RECIST 1.1 
46 
7.1 
Antitumor Effect Solid Tumors 
46 
7.1.1 
Definitions 
46 
7.1.2 
Disease Parameters 
46 
7.1.3 
Methods for Evaluation of Measurable Disease 
48 
7.1.4 
Response Criteria 
49 
7.1.4.1 Evaluation of Target Lesions 
49 
7.1.4.2 Evaluation of Non-Target Lesions 
49 
7.1.4.3 Evaluation of Best Overall Response 
50 
7.1.5 
Duration of Response 
52 
7.1.6 
Other efficacy parameters 
52 
7.1.7 
Safety Assessments 
52 
7.1.7.1 Adverse Events 
52 
8 
STUDY MONITORING 
52 
9 
DATA MANAGEMENT 
53 
9.1 
Registration 
53 
9.2 
Confidentiality Procedures 
53 
9.3 
Data Safety and Monitoring Committee 
53 
10 STATISTICAL METHODOLOGY 
54 

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10.1 
Definition of Populations for Analyses 
54 
10.2 
Efficacy Analyses 
55 
10.2.1 Definitions of Endpoints 
55 
10.3 
Safety Analyses 
55 
11 SPECIAL SAFETY RELATED PROCEDURES 
55 
11.1 
Instructions for rapid notification of serious adverse events 
55 
12 REFERENCES 
56 

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1 
INTRODUCTION 
The identification of novel targets in malignant tumors has led to the development of 
inhibitors for the treatment of a wide range of cancers. The rationale for targeting 
dysregulated pathways has led to the development and testing of several targeted 
agents. The challenges of developing rational targets for therapeutic intervention in 
specific solid tumors remain an area of intense research. The current study will evaluate 
the impact targeting two dominant pathways, hormonal regulation and mTOR, has on 
endometrial cancer growth in women with recurrent and progressive disease. 
 
1.1 
Endometrial Cancer 
Endometrial cancer is the most common gynecologic malignancy in the United States 
with 40,100 new cases and 7,470 deaths estimated for 2008.1 The standard treatment 
for primary endometrial cancer consists of a total hysterectomy with bilateral salpingo-
oophorectomy and possible lymph node dissection. This may be followed by radiation 
therapy depending on tumor histology, grade and stage. Treatment failure in low-risk 
patients is exceedingly rare 2. Tumor recurrence is most common in women with 
advanced-stage disease or those with high risk features in their primary tumor 3. The 
patterns of recurrence depend on the initial disease distribution. Women with advanced 
primary disease tend to have abdominal or systemic failure. In women whose primary 
disease was limited to the uterus, one third tend to have recurrences limited to the 
pelvis and two thirds have distant failure. Women with isolated pelvic recurrences can 
potentially be salvaged with radiation therapy or radical surgery. However, in women 
with distant recurrent disease, treatment is largely palliative. 
 
 
1.2 
Treatment of Recurrent or Advanced Endometrial Cancer 
Several chemotherapeutic agents or combinations of agents have been studied in the 
treatment of women with recurrent or advanced endometrial cancer. Doxorubicin was 
one of the first agents identified to have activity in endometrial cancer and treated 
patients had a 22% response rate and a progression free survival of 3.2 months 4. 
Single agent cisplatin and carboplatin when used as first-line agents have also been 
shown to have anti-tumor activity, with response rates of 20-42% and progression free 
survival rates of 3-5 months 3,5,6. A phase III study combining cisplatin with doxorubicin 
showed improved progression-free survival but no difference in overall survival 7. 
Paclitaxel has also been shown to have activity in endometrial cancer and has been 
incorporated into combination therapy regimens. The Gynecologic Oncology Group 
(GOG) is currently performing a phase III study comparing 
doxorubicin/cisplatin/paclitaxel to carboplatin/paclitaxel. 
 
In addition, some endometrial cancers are hormonally sensitive. Treating recurrent and 
progressive tumors with progestins and progestins in combination with tamoxifen (a 
selective estrogen receptor modulator) has had limited results. In a phase II study by 
the Gynecologic Oncology Group, an aromatase inhibitor (anastrozole) had limited 
activity as a single agent against recurrent and progressive endometrial cancer. In this 
study, of the 23 patients enrolled, 2 had partial responses and 2 had short-term stable 
disease. 

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Although response rates have improved, more effective systemic agents with longer 
durations of response are needed. Prognosis remains very poor for patients who fail 
first-line chemotherapy for progressive or recurrent endometrial cancer 3,8. 
 
 
1.3 
PTEN/AKT/mTOR Pathway: 
PTEN, a tumor suppressor gene, has been shown to play several roles in tumor 
suppression, including cell cycle arrest and promotion of apoptosis. Inactivating 
mutations in PTEN occur frequently in many human cancers. In particular, mutations in 
PTEN occur in 80% of endometrial carcinomas.3 
 
Tumor cells lacking PTEN contain high levels of activated Akt. This suggests that PTEN 
is necessary for the appropriate regulation of the phosphatidylinositol 3-kinase/Akt 
pathway. Recent studies have identified the AKT kinase as a potential mediator of 
tumorigenesis in endometrial cancer cell lines.3,9 The finding of PTEN mutations in the 
majority of endometrial cancer suggests that the loss of PTEN function may be one 
mechanism by which AKT activity is increased in this disease. Because PTEN-deficient 
cancer cells may have upregulated activity of the mammalian target of rapamycin 
(mTOR), which is downstream of AKT, these cells may be sensitive to mTOR 
inhibition.10,11  
 
 
1.4 
RAD001 (everolimus) 
RAD001 (everolimus) has been in clinical development since 1996 in solid organ 
transplantation. Since 2003, the drug is approved in several countries, including the 
majority of European Union states, as prophylaxis of rejection in renal and cardiac 
transplantation in combination with cyclosporin A and glucocorticosteroids. Its first 
commercialization (as Certican
¨) dates from March 2004 in Germany.  
Everolimus 5mg and 10mg tablets were recently approved under the trade name 
Afinitor® for patients with advanced renal cell carcinoma (RCC) after failure of treatment 
with Sutent® (sunitinib) or Nexavar® (sorafenib) in the US, EU and several other 
countries and is undergoing registration in other regions worldwide. 
 
The following is a brief summary of the main characteristics of RAD001. Fuller 
information can be obtained from the [Investigator’s Brochure].  
 
 
1.4.1  Pharmacology of RAD001  
RAD001 (INN: everolimus) is a novel macrolide formulated for oral administration, which 
is being developed as an antiproliferative drug with applications as an 
immunosuppressant and anticancer agent. 
 
At the cellular and molecular level, RAD001 has the same mechanism of action as an 
immunosuppressant and as an anti-tumor agent. It acts by selectively inhibiting mTOR 
(mammalian target of rapamycin), an intracellular protein kinase implicated in the 
control of cellular proliferation of activated T-lymphocytes or neoplastic cells. TOR is a 
ubiquitous protein kinase implicated in cell cycle control and specifically in the 
progression of cells from the G1 to S phase. TOR is considered to be a downstream 

MDACC Protocol # 2009-0059 
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Page 9 of 56 
 
component of the PI3/Akt pathway, its own primary downstream substrates being the 
eIF-4E-binding protein (4E-BP1) and p70 S6 kinase 1 (S6K1) which both play a role in 
the translational regulation of mRNAs encoding proteins involved in G1-phase 
progression (see Figure 1-1). 
 
Figure 1 RAD001 as an inhibitor of cellular proliferation 
 
GF: Growth factor; PI-3 kinase: Phosphoinositide 3-kinase; FKBP-12: FK506-binding 
protein 12; 4E-BP1: eIF-4E binding protein 1; mTOR: mammalian “Target of 
Rapamycin”. Upper Panel: situation in presence of growth factors (mTOR pathway and 
translational machinery are induced; cells proliferate). Lower Panel: situation in 
presence of RAD001 (mTOR pathway is inhibited by RAD001/FKBP-12 complex [large 
X]; translational machinery is inhibited and cells are blocked or delayed in G1 resulting 
in a block/reduction of proliferation [small X]). 
 
 
RAD001 acts on interleukin and growth-factor-dependent proliferation of cells through 
high affinity for an intracellular receptor protein, the immunophilin FKBP-12. The 
resulting FKBP-12/RAD001 complex then binds with mTOR to inhibit downstream 
signaling events. 
 
In vitro studies have shown that RAD001 can inhibit the proliferation of numerous cell 
lines originating from solid tumors, including breast cancer, with the most sensitive cell 
lines having IC50's at the sub nanomolar/low nanomolar level. In addition, experiments 
in vitro with human umbilical endothelial cells (HUVECS) and in animal models of 
angiogenesis suggest an additional anti-angiogenic effect, presumably through mTOR 

MDACC Protocol # 2009-0059 
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inhibition in proliferating endothelial cells.  
 
In vivo studies in rodent models have shown orally administered RAD001 to be a potent 
inhibitor of tumor growth at well-tolerated doses. This has included several different 
mouse xenograft models, including pancreatic, colon, epidermoid (including a Pgp-170 
over expressing, cytotoxic-resistant variant) and two syngeneic models (CA20948 rat 
pancreatic, B16/BL6 mouse melanoma). In general, RAD001 was better tolerated in 
mouse xenograft models than standard cytotoxic agents (i.e. doxorubicin and 5-
fluorouracil), while possessing similar antitumor activity. Only one instance of in vivo 
resistance has been observed (MAXF 401 mammary xenograft model), otherwise the 
activity of RAD001 was general inhibition of tumor growth (persistent regressions in one 
tumor model, T/C values of 9 to 45% in 12 tumor models). Xenograft models sensitive 
to RAD001 treatment included tumors derived from cell lines exhibiting comparative 
resistance in vitro (KB-31 and HCT116).  
 
The preclinical studies also demonstrated that inhibition of p70S6kinase 1 (S6K1), 
downstream of mTOR, was a marker of drug activity. In vitro, short-term exposure to 
RAD001 led to S6K1 inactivation for as long as 120 hours. In vivo, in the rat syngeneic 
setting, a single dose of RAD001 led to S6K1 inhibition for up to 72 hours in tumors and 
skin and for up to seven days in peripheral blood mononuclear cells (PBMCs). 
 
 
 
1.4.2  Clinical pharmacology of RAD001  
RAD001 is administered orally, its bioavailability being estimated at approximately 11%. 
Absorption is intestinal. Absorption is delayed moderately by food (60% reduction in 
Cmax and 16% reduction in AUC when drug administration follows a fat-rich meal). The 
AUC is consistently dose-linear with moderate inter-patient variability (CV approx 50%). 
Cmax is dose-linear until 20mg increasing in a non-linear manner thereafter. The 
terminal half- life is 30-35 hours. The main elimination route for RAD001 is by hepatic 
metabolism, mainly hydroxylation. The parent compound is the major component in the 
blood. Metabolism to rapamycin is of minor importance. The main metabolites are not 
bioactive. Excretion is (>80%) through the bile and the intestinal tract.  
 
RAD001 is a substrate of the CYP3A4 isoenzyme and P-gp and its metabolism is 
sensitive to 3A4 inhibitors/inducers. In combination with microemulsion cyclosporine A 
(Neoral®), a 3A4 and P-gp inhibitor, the bioavailability of RAD001 is significantly 
increased: for AUC by a mean of 168% (range: 46-365%); for Cmax by 82% (range: 25-
158%). RAD001 itself does not appear to have an enzyme-inducing/inhibiting effect at 
the levels achieved in solid organ transplantation and current oncology studies. Mild-
moderate hepatic impairment will increase exposure. Ethnic differences exist with 
clearance in blacks approximately 20% higher than that in Caucasians and Japanese 
patients who appear to be similar as regards clearance. Renal function has only 
marginal influence on the clearance of RAD001 so that no dosage adjustment is 
necessary in patients with renal failure.  

MDACC Protocol # 2009-0059 
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Page 11 of 56 
 
 
 
 
1.4.3  Clinical experience with RAD001 in non-oncology indications  
There is extensive safety data on RAD001 because of the advanced stage of its 
development in solid organ transplantation. Safety data includes animal testing, single-
dose studies in non-transplant patients, and short- and long-term studies in transplant 
patients where RAD001 was administered daily as a part of an immunosuppressant, 
multi-drug regimen consistently including cyclosporin A and glucocorticoids, and other 
drugs (azathioprine, basiliximab) on occasions. Controlled studies in the transplant 
setting consisted of dosage comparisons and comparisons between RAD001 and 
mycophenolate mofetil or azathioprine, but never placebo, as additions to cyclosporin 
and steroids.  
The tolerability of RAD001, when used alone and given daily, appeared to be good with 
only mild to moderate suspected adverse drug reactions, mostly headache. Treatment 
with RAD001, given daily, has been associated with a decrease in absolute neutrophil 
counts and platelet counts. This is most likely due to a pharmacodynamic action on 
hematopoiesis. This rarely led to severe leucopenia or thrombocytopenia, defined in the 
transplant setting as CTC grade 2. Chronic treatment with RAD001, given daily is 
associated with an increase in serum lipid levels. Hyperlipidemia responded to lipid-
lowering drugs. Long-term treatment with RAD001 was associated with reduced 
testosterone levels, probably the result of interference with sterol metabolism. This did 
not appear to translate into increased sexual dysfunction. Long-term RAD001 treatment 
of renal transplant patients with RAD001 and cyclosporin A was associated with an 
increase in renal dysfunction in comparison with comparator drugs (azathioprine, 
mycophenolate mofetil) combined with cyclosporin A. The preclinical findings and 
effects observed on reducing cyclosporin levels suggest this to be a potentiation of 
cyclosporin nephrotoxicity rather than an effect of RAD001 itself. 
 
 
1.4.4  Phase 1 study in oncology (Protocols 2101, 2102) 
Clinical studies of RAD001 in Oncology have been ongoing since 2002.  
Because of the anticipated long pharmacodynamic (PD) effect (as shown in preclinical 
studies by the prolonged inhibition of downstream markers in tumor and other tissues) 
the first phase 1 study investigated RAD001 administered weekly. For reasons 
described below the phase 1 program has been extended to explore daily dosing also. 
The phase 1 program investigates the effects of dose and schedule on safety and 
pharmacokinetics as well as the pharmacodynamic effects in order to identify an optimal 
biological dosage (OBD). The OBD is defined as the minimum dosage of RAD001 
resulting in target inhibition and which is satisfactorily safe. This program is still ongoing.  
A certain number of combination studies have also been initiated, and are summarized 
in the [Investigator’s Brochure].  

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Revised April 28, 2020 
Page 12 of 56 
 
 
RAD001C: Protocols 2101/2: Steady-state pharmacokinetics (whole blood) 
Parameter 
5 mg/week 
10 mg/week 
20 mg/week 
30 mg/week 
N 
4 
4 
22 
5 
tmax (h) 
1 (1-2) 
1 (1) 
1 (1) 
2 (1-2) 
Cmaxss (ng/ml) 
32.3 ± 15.4 
69.0 ± 8.1 
93.5 ± 0.4 
80.0 ± 19.71 
Cmaxss/Dose (ng/ml/mg) 
6.5 ± 3.1 
6.9 ± 0.8 
4.7 ± 0.0 
2.7 ± 0.71 
AUCss (ng·h/ml) 
283 ± 48 
573 ± 258 
1001 ± 301 
1798 ± 827 
AUCss/Dose (ng·h/ml/mg) 
56.6 ± 9.7 
57.3 ± 25.8 
50.1 ± 15.1 
59.9 ± 27.6 
t1/2 (h) 
26.3 ± 2.9 
37.9 ± 13.6 
30.5 ± 12.0 
36.8 ± 6.1 
Values are median (range) for tmax and mean ± standard deviation for all others. 
1. Two values above the upper assay quantification limit of 100 ng/ml were omitted. 
2. samples for PK measurement of 2 patients lost in transport. 
 
 
 
 
1.4.4.1  Phase 1 single agent studies (protocols 2101/2102, 2106 
and 2107) 
Two phase 1 studies (2101/2102 and 2107) are being conducted in patients with 
advanced solid cancers in whom the treatment may prove therapeutic. Study 2106 
investigates the PD activity of RAD001 in a setting (4 weeks treatment pre-resection of 
newly diagnosed prostate cancer) in which the treatment cannot be expected to be 
therapeutic. The studies are open-label, sequential cohort studies in which the dosage 
of RAD001 is escalated from one cohort to the next according to the presence or 
absence of patients with dose-limiting toxicity (DLT). More details on these studies are 
included in the [Investigator’s Brochure].  
 
 
 
 
1.4.4.2  Safety findings  
All adverse events occurring in more than 10% of patients in studies 2101/2, 2106 and 
2107 are summarized by schedule and dosage (according to the NCI Common 
Terminology Criteria, version 3) in Table 1-2.  
 
Suspected adverse drug reactions (ADR) occurring in ≥10% of patients are summarized 
in Table 1-3. In order of frequency these include: rashes (37%), stomatitis/mucositis 
(27%), fatigue (26%), headache (19%), nausea (12%), diarrhea (10%) and vomiting 
(10%). The majority of suspected ADRs were of mild to moderate severity (CTC grade 
1-2) with only isolated grade 3 events. The data suggest dose-relationship for rash, 
stomatitis/mucositis and fatigue. 
 
The most frequently-reported ADR was rash &/or erythema. Mostly the nature of the 
rash was not specified. Descriptions were given for 7 patients: macular &/or papular 
(n=4), erythematous (n=2), acneiforme (n=1), pustular (n=1), pruritic (n=4), associated 
with dry skin in 3 cases. Rash was always grade 1-2. The localization was given for 16 
patients, this involved: face/neck (n=9), upper limbs (n=6), lower limbs (n=6), 
trunk/back/buttocks (n=4). In 4 patients the rash was generalized (≥3 zones involved). 
Events reported as mucositis, stomatitis or mouth ulceration, were grade 1-2 in all but 
four patients. Grade 3 stomatitis occurred in 2 patients at 70mg/wk and in one patient 

MDACC Protocol # 2009-0059 
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each at 50mg/wk and 10mg/d. It is the main dose-limiting toxicity. 
 
Table 1-2  All adverse events in greater than or equal 10% of patients (grade 3-4 in 
brackets) Phase 1 monotherapy studies (June 04) 
Weekly regimen 
 
 
 
Daily regimen 
Total 
No of patients 
5mg 
10mg 
20mg 
30mg 
50mg 
70mg 
5mg 
10mg 
 
Study 2101/2 
4 
4 
5 
5 
6 
7 
4 
6 
41 
Study 2107 
0 
0 
8 
0 
6 
7 
6 
6 
33 
Study 2106 
0 
0 
0 
4 
1 
0 
4 
1 
10 
Total 
4 
4 
13 
9 
13 
14 
14 
13 
84 
Weekly regimen 
 
 
 
Daily regimen 
Total 
Reported events 
 
 
 
 
 
 
 
 
 
Rash (all)1 
0 
0 
1 
3 
7 
7 
8 
8 
34 
Fatigue 
1 
0 
7(1) 
4 
6(1) 
4(1) 
4(1) 
6 
32(4) 
Headache 
1 
2 
3 
3(1) 
6 
4 
5 
3 
25(1) 
Stomatitis/mucositis 
0 
0 
2 
3 
4(1) 
5(2) 
4 
5(1) 
24(4) 
Nausea 
3(1) 
2 
2 
2 
3 
4(1) 
2 
2 
20(2) 
Anorexia 
3 
0 
1 
1 
4 
2 
1 
3 
15 
Constipation 
2 
0 
2 
1 
1 
2 
4 
2 
14 
Diarrhea 
2 
0 
0 
1 
7 
0 
1 
2 
13 
Vomiting 
3 
0 
1 
1 
4 
2 
0 
2 
13 
Cough 
0 
1 
2 
2 
3 
2 
1 
2 
13 
Dyspnea NOS 
2 
0 
2 
2(1) 
3(1) 
2(1) 
1(1) 
1(1) 
13(5) 
Abdominal pain NOS 
3 
0 
1 
0 
1 
0 
2 
2 
9 
Pruritus 
0 
1 
1 
2 
1 
0 
3 
1 
9 
Pyrexia 
1 
1 
1 
2 
1 
0 
1 
2 
9 
Back pain 
1 
1 
0 
1 
3 
0 
1 
1 
8 
Abdominal 
distension 
0 
0 
0 
0 
3 
1 
1 
3 
8 
1. Rash (all) includes: all types of reported rash & erythema 

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Table 1-3  Suspected adverse drug reactions
1 
in greater than or equal 10% of patients 
(grade 3-4 in brackets) Phase 1 monotherapy studies (June 04) 
 
Weekly Regimen 
Daily RegimenTotal 
No of patients 
5mg 
10mg 
20mg 
30mg 
50mg 
70mg 
5mg 
10mg    Total 
Study 2101/2 
4 
4 
5 
5 
6 
7 
4 
6 
41 
Study 2107 
0 
0 
8 
0 
6 
7 
6 
6 
33 
Study 2106 
0 
0 
0 
4 
1 
0 
4 
1 
10 
Total 
4 
4 
13 
9 
13 
14 
14 
13 
84 
Reported events 
 
 
 
 
 
 
 
 
 
Rash (all)2 
0 
0 
2 
2 
5 
7 
7 
8 
31 
Stomatitis/mucositis 
0 
0 
2 
3 
3(1) 
5(2) 
3 
5(1) 
23(4) 
Fatigue 
1 
0 
2 
4 
5 
4 
0 
6 
22(1) 
Headache 
0 
0 
1 
3 
3 
2 
5 
2 
16 
Nausea 
2 
1 
1 
1 
2 
1 
1 
1 
10 
Diarrhea NOS 
0 
0 
0 
1 
5 
0 
0 
2 
8 
Vomiting NOS 
2 
0 
1 
1 
2 
1 
0 
1 
8 
1 
Suspected drug-causality according to investigators. 
2 
Rash (all) includes: all types of reported rash & erythema 
 
The data described below reflect exposure to everolimus (n=274) and placebo (n=137) 
in a randomized phase III study for the treatment of metastatic renal cell carcinoma. In 
total, 165 patients were exposed to everolimus 10 mg/day for ≥4 months. The median 
age of patients was 61 years (range 27 to 85). The most common adverse reactions 
(incidence ≥10%) were stomatitis, rash, fatigue, asthenia, diarrhea, anorexia, nausea, 
mucosal inflammation, vomiting, cough, peripheral edema, infections, dry skin, 
epistaxis, pruritus, and dyspnoea. The most common grade 3-4 adverse reactions 
(incidence ≥2%) were infections, stomatitis, fatigue, and pneumonitis. 
The median duration of blinded study treatment was 141 days (range 19 to 451) for 
patients receiving everolimus and 60 days (range 21 to 295) for those receiving 
placebo. The rates of treatment-emergent adverse reactions resulting in permanent 
discontinuation were 7% and 0% for the everolimus and placebo treatment groups, 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 15 of 56 
 
respectively. Most treatment-emergent adverse reactions were grade 1 or 2 in severity. 
Grade 3 or 4 treatment-emergent adverse reactions were reported in 39% versus 7% of 
patients receiving everolimus and placebo, respectively. Deaths due to acute respiratory 
failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the 
everolimus arm. 
Everolimus has immunosuppressive properties and may predispose patients to 
bacterial, fungal, viral or protozoan infections, including infections with opportunistic 
pathogens. Localized and systemic infections, including pneumonia, other bacterial 
infections, invasive fungal infections, such as aspergillosis or candidiasis and viral 
infections including reactivation of hepatitis B virus, have been described in patients 
taking everolimus. Some of these infections have been severe (e.g. leading to 
respiratory or hepatic failure) and occasionally have had a fatal outcome. 
Physicians and patients should be aware of the increased risk of infection with 
everolimus. Treat pre-existing infections prior to starting treatment with everolimus. 
While taking everolimus, be vigilant for symptoms and signs of infection; if a diagnosis 
of infection is made, institute appropriate treatment promptly and consider interruption 
or discontinuation of everolimus. If a diagnosis of invasive systemic fungal infection is 
made, discontinue everolimus and treat with appropriate antifungal therapy. 
 
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving 
chemotherapy (Yeo 2004). Sporadic cases of Hepatitis B reactivation have also been 
seen in this setting with everolimus. Use of antivirals during anti-cancer therapy has 
been shown to reduce the risk of Hepatitis B virus reactivation and associated morbidity 
and mortality (Loomba 2008). A detailed assessment of Hepatitis B/C medical history 
and risk factors must be done for all patients at screening, with testing performed prior 
to the first dose of everolimus.  
Hypersensitivity reactions manifested by symptoms including, but not limited to, 
anaphylaxis, dyspnea, flushing, chest pain or angioedema (e.g. swelling of the airways 
or tongue, with or without respiratory impairment) have been observed with everolimus. 
Hyperglycemia has been reported in clinical trials. Monitoring of fasting serum glucose 
is recommended prior to the start of everolimus therapy and periodically thereafter. 
Optimal glycemic control should be achieved before starting a patient on everolimus. 
Mouth ulcers, stomatitis and oral mucositis have been seen in patients treated with 
everolimus. In such cases topical treatments are recommended, but alcohol- or 
peroxide-containing 
Elevations of serum creatinine, usually mild, have been reported in clinical trials. 
Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or 
serum creatinine, is recommended prior to the start of everolimus therapy and 
periodically thereafter. 
Decreased hemoglobin, lymphocytes, platelets and neutrophils have been reported in 
clinical trials. Monitoring of complete blood count is recommended prior to the start of 
everolimus therapy and periodically thereafter. 

MDACC Protocol # 2009-0059 
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Everolimus is not recommended in patients with severe hepatic impairment, (Child-
Pugh class C). 
The use of live vaccines and close contact with those who have received live vaccines 
should be avoided during treatment with everolimus. 
 
1.4.4.3  Laboratory findings 
Blood cell counts were monitored regularly because of the known myelosuppressive 
effect of rapamycins. Abnormal counts were reported as adverse events in only four 
patients (grade 1 thrombocytopenia in 3 patients at 20 mg/wk, 70 mg/wk, 5 mg/d 
respectively) in study 2101/2, and a transient grade 3 neutropenia in patients at 70 
mg/wk in study 2107 which was dose-limiting. Preliminary evaluation of the recorded 
values indicate that in a significant fraction (approx 50%) of patients, the platelet count 
falls with initiation of treatment but that this is generally limited to the normal range, 
occasionally grade 1, not worsening with continuing therapy nor requiring therapeutic 
intervention. In some patients a similar decrease of the neutrophil count, within the 
normal range, was also observed. The occurrence of a grade 3 thrombocytopenia in a 
patient receiving RAD001 and letrozole (Section 1.5.3) does suggest that some 
individuals may be particularly sensitive to the myelosuppressive effects of RAD001 (a 
pharmacodynamic interaction with letrozole being unlikely as letrozole is not believed to 
influence hematopoiesis). 
Serum lipid levels were monitored because of the known hyperlipidemic effect of 
rapamycins. Hyperlipidemia was reported as an adverse event in 8 patients 
(hypercholesterolemia in n=7, hypertriglyceridemia in n=1). Preliminary evaluations of 
recorded laboratory values suggest that approximately 23% of patients acquire grade 1-
2 hyperlipidemia on treatment of which 19% have raised cholesterol, 10% raised 
triglycerides, and 6% have both. Only one grade 3 value was recorded. 
Five patients have received lipid-lowering drugs concomitantly with RAD001: 
 1 pt for gr.3 hypertriglyceridemia at 5mg/d 
 4 pts for gr.1-2 hypercholesterolemia at 5mg/d (n=2), 10mg/d (n=1), 50mg/wk (n=1). 
 
Non-hematological laboratory abnormalities other than hyperlipidemia have not 
been recorded as suspected adverse events. 
Infections 
RAD001 has immunosuppressive properties because of its ability to inhibit the 
proliferation of activated T-lymphocytes. In the 84 patients treated in the mono-agent 
studies, infectious events have been recorded on 26 occasions. These have been 
mostly common infections, half of them bronchopulmonary (n=6) and urinary tract (n=7). 
Herpes simplex or zoster infections were not particularly frequent (n=5) and were not 
severe. Oral candidiasis was reported on 3 occasions, but this may represent under-
reporting, as it may have been a component of the frequently reported oral stomatitis. 
The only serious and only grade 3 infection recorded was that of pneumonia in a patient 
with advanced NSCLC. 
 

MDACC Protocol # 2009-0059 
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1.4.4.4  Efficacy findings 
Efficacy assessment was not the primary purpose of phase 1. However, in studies 
2101/2 and 2107 patients undergo regular clinical and CT appraisal for assessment 
according to RECIST. No complete responses have been observed. The numbers of 
patients with partial response (PR) or prolonged stable disease (SD) as of June 2004 
are summarized in Table 1-4. 
 
1.4.4.5  Pharmacodynamic findings 
In part 1 of study 2101/2102, 16 patients (4 pts in each dosage cohort) could be 
assessed for changes in S6K1 activity in PBMC by radioimmunoassay. 
There was variation in activity as shown by the differences in the two baseline (pre-
treatment) values obtained for each patient. However, there was striking inhibition of 
activity in all patients at the 24 hr post-dose assessment. The dose influenced the 
duration of inhibition. At steady state, the duration of total S6K1 inhibition was from 3-5 
days in patients at doses of 510mg and for ≥7 days in patients at 20-30mg. 
 
PK/PD modeling to predict intratumoral inhibition in patients 
Subsequent modeling has been carried out, combining the pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study with preclinical data. 
Preclinical studies showed that RAD001 has an antiproliferative effect on tumor cells in 
vitro and in tumor-bearing rodents, including CA20948 pancreatic tumor-bearing rats 
(Section 1.2.1). Inhibition of S6K1 by RAD001 was shown in tumor, skin and PBMC. 
The in vivo relationship between unbound drug levels and S6K1 inhibition was 
assessed in the rat CA20948 tumor setting in order to build a basic concentration-effect 
model in PBMC, skin and tumor. In rats, the unbound drug level at 50 % S6K1 inhibition 
(IC50) in tumor was 0.05 ng/g, similar to that in skin, while IC50 in PBMC was 0.01 
ng/mL. 
Unbound drug levels estimated from the rodent PK model were scaled up to humans. In 
patients, S6K1 inhibitions in PBMC, predicted by the PK/PD model derived from the rat 

MDACC Protocol # 2009-0059 
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Page 18 of 56 
 
in vivo study, were comparable to values measured in the clinical studies. Model-
derived intratumoral PK/PD values for patients were compared to those in rats. 
Assuming that to be efficacious, the drug should achieve target inhibition at least as 
great as that associated with efficacy in the rat experiment, and that a similar PK/PD 
relationship for tumor exists in patients as in rats, 20mg in patients was predicted to be 
the minimum effective dose. Hence, 20mg was taken as the initial weekly dose to take 
forward into the subsequent phase 1 study (2107) in which the PD effect of RAD001 is 
being investigated in tumor itself obtained by biopsy. 
The PK/PD model also suggests that a greater degree of sustained inhibition should 
result from daily administration compared to an increase in the weekly dosage above 
20mg, for the same total drug consumption (i.e. 10mg/d compared to 70mg weekly). 
These results are summarized in Figure 1-2 and Figure 1-3. 
 
 

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1.5 
RAD001 – Rationale for use in endometrial cancer 
Our group recently found that RAD001 decreased the progression of endometrial 
hyperplasia in the Pten heterozygote murine model by increasing the rate of apoptosis 
and decreasing cell proliferation. The decrease in phospho-p70 S6 Kinase in the treated 
group compared to the untreated group also suggests a target specific down regulation 
of the mTOR pathway with the treatment of RAD001.  
 
In endometrial cancer cell lines, rapamycin demonstrated a growth-inhibitory effect 
through induction of cell cycle arrest12. This effect, however, was independent of PTEN 
status because PTEN-positive cells were as sensitive to rapamycin as PTEN-null cells. 
This suggested that rapamycin may be effective against a broad range of endometrial 
cancers. In addition, rapamycin inhibited phosphorylation of downstream targets of 
mTOR (S6K and 4E-BP1). In a mouse model, tumors from PTEN deficient mice had 
elevated levels of phosphorylated AKT and S6K13. In this model, inactivation of mTOR 
using an mTOR inhibitor reduced neoplastic proliferation, tumor size, and S6K kinase 
activity, but did not alter the status of AKT.  
 
Our group has previously found a relatively high rate of activated mTOR and its 
downstream effector protein, S6 kinase in a series of endometrial cancers. These data 
support the current investigations of mTOR inhibition for the treatment of patients with 
this disease. Future studies will further evaluate markers in this pathway and to possibly 
identify molecular factors that may predict response to therapy.  
 
Clinical trials of mTOR inhibitors in various cancers are in progress. CCI-779, an 
intravenous analog of rapamycin, has been evaluated in a phase II trial in patients with 
metastatic or recurrent endometrial cancer. In this study there was a 25% partial 
response rate (median duration 5.1 months) and a 57% stable disease rate (median 
duration 8.7 months). None of these patients received prior chemotherapy14. 
 
We recently completed a phase II single-agent clinical trial of RAD001 in 35 women with 
recurrent, chemotherapy-refractory measurable disease. The median age of the cohort 
was 58 years. All grade toxicity was infrequent and most commonly represented by 
fatigue (51% any grade, 20% grade 3), pain (375 any grade, 0% Grade 3), nausea 
(34% any grade, 11% grade 3) and stomatitis (26% any grade, 0% grade 3). The most 
common hematological toxicity was anemia (46% any grade), neutropenia (40% any 
grade) and lymphopenia (34% any grade). Dose reduction was required in 17 patients – 
predominately (10 of 17) from stomatitis. Efficacy was measured by clinical benefit rate 
(CBR) which consisted of complete and partial response as well as stable disease. No 
objective responses were observed however, stable disease was observed in 12 or 28 
evaluable patients (CBR: 43%). The median duration of stable disease observed was 4 
cycles (months). Immunohistochemistry translational endpoints demonstrated 76% 
overexpression of mTOR and 41% overexpression of phospho-mTor. No relationship of 
CBR was seen with PTEN mutation (66% of samples). 
 
As expected, measurable clinical responses are uncommon; however, the current rate 
of observed stable disease cases is excellent. Although chemical toxicity (mostly 

MDACC Protocol # 2009-0059 
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Page 20 of 56 
 
hyperlipidemia) has been seen, clinically significant side effects have not been 
problematic. In a preliminary analysis of translational endpoints and response, we are 
finding that patients who have tumors that have PTEN mutations are more likely to 
experience a clinical benefit (i.e., stable disease) than in patients whose tumors do not 
have PTEN mutations. We believe that this single agent activity in pretreated patients 
suggest that RAD001 will have clinical applications in the treatment of this disease. In 
our institution, we plan on evaluating RAD001 in combination with a hormonal agent as 
a first line treatment for patients with recurrent endometrial cancer. Continued 
evaluations of tissue biomarkers will allow us to potential predict response and to 
screen patients based on the molecular profile of their tumors.  
 
1.6 
Letrozole (Femara) 
Letrozole is a highly potent, orally active non-steroidal competitive inhibitor of the 
aromatase enzyme system. It effectively inhibits the conversion of androgens to 
estrogens both in vitro and in vivo. It is indicated both as first-line treatment of 
postmenopausal women with hormone receptor positive or hormone receptor unknown 
locally advanced or metastatic breast cancer as well as for the treatment of advanced 
breast cancer in postmenopausal women with disease progression following 
antiestrogen therapy. 
Letrozole was initially studied at doses of 0.1mg to 5.0mg daily in six non-comparative 
Phase I/II trials in 181 postmenopausal estrogen/progesterone receptor positive or 
unknown advanced breast cancer patients previously treated with at least antiestrogen 
therapy. Patients had received other hormonal therapies and also may have received 
cytotoxic therapy. Eight (20%) of forty patients treated with letrozole 2.5mg daily in 
Phase I/II trials achieved objective tumor response (complete or partial response). 
 
A randomized, double-blinded, multinational trial compared Letrozole 2.5mg with 
tamoxifen 20mg in 916 postmenopausal patients with locally advanced (Stage IIIB or 
loco-regional recurrence not amenable to treatment with surgery or radiation) or 
metastatic breast cancer. Time to progression (TTP) was the primary endpoint of the 
trial. Letrozole was superior to tamoxifen in TTP and rate of objective tumor response.  
 
For further information on letrozole, see Femara
¨ Prescribing Information, Appendix F. 
 
1.7 
Combination of letrozole and RAD001  
 
There is evidence that an enhanced PI3K/Akt/mTOR pathway may be one of the key 
adaptive changes accounting for endocrine-resistant growth in breast cancer. Inhibition 
of this pathway might therefore prevent or delay the onset of resistance to anti-
endocrine therapy.  

MDACC Protocol # 2009-0059 
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1.7.1  Pharmacology  
An in-vitro study of the effects of RAD001, letrozole and combinations of both 
compounds has been carried out in aromatase-expressing breast tumor cells (MCF-7 
cell-line transfected with the aromatase gene) which are stimulated not only by estradiol 
but by androstenedione, the precursor of estradiol and substrate of aromatase. The 
concentration-dependent antiproliferative activity of both compounds given individually 
was enhanced by the combination (Rudloff, et al 2004). Subsequent analysis has 
established the antiproliferative enhancement to be accompanied by a clear increase in 
apoptosis normally associated only minimally with each compound alone (Novartis data 
on file).  
1.7.2  Potential for drug-drug interaction  
Pharmacokinetic interaction between letrozole and RAD001 is not expected. The two 
drugs follow different metabolic routes (RAD001: CYP3A-mediated metabolism and 
hepato-intestinal elimination; letrozole: CYP2A6 mediated metabolism and renal 
elimination).  
1.7.3  Combination Phase 1b study  
An ongoing interaction study (Protocol CRAD001C2108) investigates the combination of 
letrozole (2.5mg/d) with RAD001 at escalating doses in patients receiving letrozole as 
first-line therapy for advanced HR+ breast cancer. To be eligible, patients have to have 
received letrozole already for a minimum of 4 months with sub optimal response, 
defined as: stable disease or progressive disease without urgent indication to go to 
chemotherapy (e.g. bulky or symptomatic disease). All patients continue to receive 
letrozole 2.5 mg once daily, to which RAD001 is added. Successive cohorts are defined 
by the dosage of RAD001: 5mg and then 10mg/d. Assessed over the first 28 days of the 
combined therapy, DLT is defined as any grade 3-4 toxicity with the exception of grade 
3 hypercholesterolemia, hypertriglyceridemia, or lymphopenia as well as any toxicity 
requiring interruption of treatment for more than two weeks.  
The main safety events are summarized in Table 1-5. One patient (RAD001 at 10mg/d) 
has been reported with a DLT, this being a grade 3 thrombocytopenia, the nadir 
(48x109/L) of a progressive decline in the platelet count over 3 weeks treatment. 
Recovery followed interruption of treatment. No other DLT or grade 3-4 adverse events 
have been reported. Suspected ADRs occurring in more than 10% of patients (i.e. ≥2/11 
patients documented so far) include: fatigue/asthenia (n=8), stomatitis/mucositis (n=5), 
headache, rash/skin reaction (n=3 each), diarrhea, nausea (n=2 each). A patient with 
coexisting chronic viral hepatitis was discontinued when her serum transaminase 
activity increased from grade 1 to grade 2.  

MDACC Protocol # 2009-0059 
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Table 1-5. Study 2108 (RAD001 + letrozole) Main safety events (July 04) 
 
Letrozole 2.5 mg/d + RAD 001 
RAD001 5 mg/day 
N=6 
RAD001 10mg/day 
N=9 
DLT 
0/6 
1/9 
Pts with Gr 3/4 suspected ADR 
0 
12 
Discontinuations / Death 
0 
0 
Progressive disease 
2 
2 
Adverse events 
11 
1 
Withdrew consent 
0 
0 
Suspected drug-related SAEs 
0 
13 
 
DLT: 
dose-limiting toxicity in first 4 weeks (# of pts with DLT/mo of those evaluable for DLT) 
ADR: 
adverse drug reaction 
SAE:  serious adverse event (death or potentially fatal; requiring or prolonging hospitalization) 
1. discontinuation for raised serum transaminase activity (patient with chronic viral 
hepatitis) 
2. grade 3 thrombocytopenia 
3. hospitalization of the patient who developed grade 3 thrombocytopenia 
 
Pharmacokinetic profiles of letrozole were investigated before addition of RAD001 and 
after RAD001 reached steady state (day 15). Currently available data in 6 patients for 
letrozole and 3 patients for RAD001 suggested that co-administration of RAD001 with 
2.5 mg/day letrozole does not influence letrozole pharmacokinetics and that exposure to 
RAD001 in the presence of letrozole dose not exceed historical exposure data obtained 
from study 2101.  
 
 
2 STUDY OBJECTIVES 
 
2.1 Primary Objective 
To determine the efficacy of RAD001 and Letrozole in patients with recurrent or 
progressive endometrial carcinoma. 
 
2.2 Secondary Objectives 
2.2.1  To determine the duration of disease control, time to disease progression, 
and survival of this cohort of patients. 
2.2.2 To determine the nature and degree of toxicity of RAD001 and letrozole in 
this cohort of patients. 

MDACC Protocol # 2009-0059 
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3 
INVESTIGATIONAL PLAN 
This is a phase II activity trial of RAD001 in combination with letrozole for patients with 
recurrent or progressive endometrial cancer. We will enroll a minimum of 10 patients 
and a maximum of 35 patients. Patients will be enrolled at M.D. Anderson Cancer 
Center and at Morristown Memorial Hospital, Women’s Cancer Center. Our goal is to 
obtain a response rate or stable disease rate of greater than 20 % in patients with 
recurrent or progressive endometrial cancer. For the purposes of this study, response 
rate will be defined as stable disease, partial response or complete response. Early 
stopping points have been incorporated to stop the trial if there is limited disease 
control. We will also evaluate the toxicity profile of letrozole and RAD001 in this cohort 
of patients with endometrial cancer. Patients will be evaluated for response rate, 
duration of response rate, time to disease progression, and survival.  
 
4 
SELECTION OF PATIENTS 
 
4.1 
Patient population 
The target population is women who are >/= 18 years of age with recurrent or 
progressive endometrial cancer who have not received more than 2 regimens of 
systemic chemotherapy. This does not include chemo-sensitizing radiation. 
Females under the age of 18 are excluded as the safety and efficacy of letrozole 
has not been established in children. 
4.2 
Inclusion Criteria 
To be eligible for the study, patients must fulfill all of the following criteria: 
1. Patients must have signed an approved informed consent. 
2. Histologically confirmed endometrial cancer (endometrioid, serous, or clear 
cell, or mixed histology; any grade) which is considered progressive or 
recurrent. 
3. Patients may have failed no more than two prior chemotherapeutic regimens 
for recurrent or advanced disease (including adjuvant therapy). 
Chemotherapy administered in conjunction with radiation as a radio-sensitizer 
is not counted as a prior treatment for recurrent or advanced disease.  
4. All patients must have measurable disease as defined by RECIST 1.1 (See 
section 7.1) 
5. Patients must have at least one “target lesion” to be used to assess response 
on this protocol as defined by RECIST (Section 7.1). Tumors within a 
previously irradiated field will be designated as “non-target” lesions, unless 
progression is documented or a biopsy is obtained to confirm persistence at 
least 90 days following completion of radiation therapy. 
6. Patients must have a Zubrod performance status of 0, 1, or 2 (Appendix E). 

MDACC Protocol # 2009-0059 
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7. Patients must not be of child bearing potential. Patients are considered not of 
child bearing potential if they are surgically sterile (they have undergone a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are 
postmenopausal for greater than 12 months. Patients in whom ovaries are 
present and were not previously menopausal at the time of hysterectomy, 
should have a serum estradiol < 10 pm/mL to confirm ovarian senescence. 
8. Patients must have a pretreatment granulocyte count (i.e., segmented 
neutrophils + bands) of >1,500/Fl, a hemoglobin level of ≥9gm/dL and a 
platelet count of >100,000/Fl. Close contact with those who have received 
attenuated live vaccines should be avoided during treatment with everolimus. 
Examples of live vaccines include intranasal influenza, measles, mumps, 
rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines. 
9. Patients must have an adequate renal function of >50cc/min as documented 
by the Cockcroft Gault creatinine clearance formula: 
 
       (140 – age) x (weight kg)   
Estimated GFR  =  72 x serum Creatinine (non-IDMS)   x 0.85 (female) 
10. Patients must have adequate hepatic function as documented by a serum 
bilirubin ≤2.5 mg/dL, regardless of whether patients have liver involvement 
secondary to tumor. Note: A detailed assessment of Hepatitis B/C medical 
history and risk factors must be done at screening for all patients.  HBV DNA 
and HCV RNA PCR testing are required at screening for all patients with a 
positive medical history based on risk factors and/or confirmation of prior 
HBV/HCV infection. 
11. Alanine aminotransferase (SGPT) must be <3x institutional upper limit of 
normal unless the liver is involved with tumor, in that case, the alanine 
aminotransferase must be ≤5 x institutional upper limit of normal.. 
12. Prior to beginning therapy, at least 4 weeks must have elapsed since prior 
chemotherapy, surgery, radiation therapy, hormonal therapy or investigational 
therapy. Patients receiving palliative radiation therapy are exempt from the 4 
week waiting period.  
13. Baseline lipid levels (triglycerides, cholesterol) must be ≤ grade 1. Patients 
are allowed to be on lipid lowering drugs.  
14. Patients must be >/= 18 years of age. 
 
4.3 Exclusion Criteria 
Patients meeting any of the following criteria will be ineligible to participate in this 
study: 
 
1. Patients with intact ovarian function. 

MDACC Protocol # 2009-0059 
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2. Patients who have previously received RAD001 or another mTOR inhibitor or 
letrozole or another aromotase inhibitor. Use of progestational or other 
hormonal agents are permitted provided they have not been administered 
within the previous 4 weeks.  
3. Patients who have uterine sarcomas or mixed malignant mullerian tumors. 
4. Patients who have isolated recurrences (vaginal, pelvic, or paraaortic) that 
are amenable to potentially curative treatment with radiation therapy or 
surgery. 
5. Patients with any other severe concurrent disease, which would make the 
patient inappropriate for entry into this study, including significant hepatic, 
renal, or gastrointestinal diseases. 
6. Patients currently receiving chemotherapy or radiotherapy or those in whom 
anti-cancer treatment has occurred within the preceding 4 weeks. 
7. Chronic treatment with systemic steroids or another immunosuppressive 
agent. Patients on systemic steroids or another immuosuppresive agent for 
greater than 3 months. 
8. Patients should not receive immunization with attenuated live vaccines within 
one week of study entry or during study period. 
9. Patients with a history of prior malignancy except for adequately treated basal 
cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for 
which the patient has been disease-free for at least five years. 
10. Patients with an active infection that requires systemic antibiotics.  
11. Patients with a known history of cardiac disease; i.e., uncontrolled 
hypertension (systolic B/P >/= 140 mm Hg and/or diastolic B/P >/= 90 mm 
Hg) or unstable angina. Patients with a history of myocardial infarct within 6 
months before enrollment, New York Heart Association (NYHA) Class II or 
greater heart failure, or symptoms suspicious for congestive heart failure are 
not eligible unless a left ventricular ejection fraction in the past 6 months is 
documented to be 50% or greater. Patients who have had a LVEF (performed 
for any reason) of less than 50% in the past 6 months are ineligible. 
12. Patients with a known history severely impaired lung function (patients who 
are oxygen dependent).  
13. Patients with a known hypersensitivity to RAD001 (everolimus) or other 
rapamycins (sirolimus, temsirolimus) or to its excipients. 
14. Patients who are pregnant or breast-feeding. 
15. Presence of clinically apparent untreated central nervous system metastases. 
16. Patients with carcinomatous meningitis. 
17. Patients with deep venous or arterial thrombosis (including pulmonary 
embolism) within 6 weeks of study entry. Patients may be on maintenance 
anticoagulation therapy. 

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18. Patients with previously documented human immunodeficiency virus (HIV) 
infection. 
19. Patients with an impairment of gastrointestinal function or gastrointestinal 
disease that may significantly alter the absorption of RAD001 (e.g., ulcerative 
disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption 
syndrome). 
 
MDACC and Morristown Memorial Hospital will not exclude any potential subject 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. 
 
4.4 
Withdrawal of Patients from Treatment 
Patients should be removed from therapy if any of the following occurs: 
 Disease progression. Every effort should be made to document 
objective evidence of tumor progression. 
 The occurrence of unacceptable toxicity indicating the need for 
cessation of treatment. 
 The physician feels it is in the best interest of the patient to stop 
treatment. 
 Patient refusal to continue with therapy. 
 Non-compliance by the patient with protocol requirements. 
 Patient is lost to follow-up. If a patient does not return for scheduled 
visits, every effort should be made to re-establish contact. In any 
circumstance, every effort should be made to document patient 
outcome, if possible. 
 Patient becomes pregnant. 
 Termination of the study by investigator or Sponsor – M. D. Anderson 
Cancer Center. 

MDACC Protocol # 2009-0059 
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5.0 
TREATMENT PLAN 
This is a Phase II open label study of combination therapy with RAD001 and 
letrozole in patients with progressive or recurrent endometrial cancer. The initial 
dose of RAD001 is 10 mg daily and the dose of letrozole is 2.5 mg daily, both 
given orally.  
 
5.1 Multi-Center Patient Registration Procedures: All patients from Morristown 
and M. D. Anderson will be registered in CORe at University of Texas, MD 
Anderson Cancer Center. 
 
Centralized Registration Requirements: Patients who are candidates for 
the study will first be evaluated for eligibility by the local investigator. All 
patients must be registered both locally and centrally with MDACC.  
 
Before an institution may begin participating in a MDACC sponsored protocol 
that is coordinated by MDACC, they must complete the following steps: 
 
 Submit the following required regulatory documents to the MDACC 
Office of Multicenter Clinical Research (OMCR)  
 Participate in a site initiation visit, webcast, or conference call 
 Receive training regarding study specific CRF’s and/or databases 
 Execute study specific contractual agreements 
After these requirements have been fulfilled, the participating institution will 
receive by fax, e-mail, or hard copy memo a Site Activation Notification.  
Once the Site Activation Notification has been received, the participating 
institution may begin to register patients to the protocol. 
 
Required Regulatory Documents include: 
 
 FDA 1572 
 Curriculum Vitae (CV) or Biosketch.  The CV/Biosketch must be submitted 
with the individual’s signature and date.   
 Delegation of Authority Log (DAL) 
 Approval Letter signed by the Chairman of the institution's IRB (must be 
updated annually. Patient registrations will be suspended for expired IRB 
approvals) 
o An Expedited IRB first approval is NOT acceptable 
o IRB Approval for amendments 

MDACC Protocol # 2009-0059 
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Page 28 of 56 
 
Informed Consent/Authorization 
 
Prior to protocol enrollment and initiation of treatment, subjects must sign and 
date an Institutional Review Board (IRB) approved consent form. 
 
Patient Registration Procedures 
M. D. Anderson Cancer Center (MDACC) patients will be registered in The 
Clinical Oncology Research System (CORe) by department of Gynecology staff.  
Participating institutions must register patients via phone, fax, and/or email with 
the MDACC Office of Multicenter Clinical Research at: 
 
Fax: (713) 563-4317 
Phone: (713) 792-8519 
Email: OMCR_GYN@mdanderson.org 
 
Registration hours are 8:00 a.m. to 5:00 p.m. Central Standard Time, Monday 
through Friday, except holidays. 
 
Registration is a 2-step process. Step 1 - Initial registration must be completed: 
 After the patient has signed the informed consent and has been 
determined to be eligible by the local investigator.  
 
Once eligibility has been determined, Step 2 is treatment assignment -  
 Before study related treatment is initiated. 
 
At the time of registration the following information will be requested by the 
MDACC Office of Multicenter Clinical Research (OMCR): 
 A faxed or emailed copy of a completed and signed, protocol specific, 
eligibility checklist form 
 One copy of a Pathology report from the patient’s most recent surgery 
or biopsy 
 One copy of the signed and dated Informed Consent/Authorization.  
The eligibility checklist should be prepared and signed prior to faxing or emailing 
to the MDACC OMCR. The fax/email should be followed by a phone call to the 
MDACC OMCR to verify receipt. 
If the patient fails eligibility screening do not proceed to the MDACC registration 
process.  
Patient Number for Participating Institutions 
 
Once eligibility has been established during Registration, the patient from the 
participating institution is assigned a six character MDACC OMCR patient 
number.  This number is unique to the patient and must be written on all data and 
correspondence for the patient. 
 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 29 of 56 
 
Verification of Registration 
 
For participating institutions, a Registration Verification Letter for patients 
registered will be faxed or emailed to the registering institution within one working 
day after registration.   
 
Initiation of Therapy 
 
Treatment may not be initiated until the participating institution receives a faxed 
or emailed copy of the patient’s Registration Verification Letter from the MDACC 
OMCR. Patients must initiate treatment within 10 calendar days after the 
registration is completed.   
 
The MDACC OMCR must be notified in writing of any exceptions to this policy.  
 
Eligibility Exceptions: Eligibility Exceptions will not be granted. 
 
Confidentiality: All documents, investigative reports, or information relating to 
the patient are strictly confidential. Any patient specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the MDACC OMCR 
must have the patient’s full name & social security number “blacked out” and the 
assigned MDACC patient ID number and protocol number written in. Patient 
initials may be included or retained for cross verification of identification. 
 
5.2 
RAD001 and letrozole administration 
5.2.1 Both study medications will be dispensed by the pharmacy. Study 
medication will be supplied in an open label fashion. Patients will 
self administer the both medications at home. 
5.2.2 Patients will be instructed to take the study medication at a 
consistent time each day.  
5.2.3 RAD001 is formulated as tablets of 5 mg strength and supplied in 
blister packs under aluminum foil, which should be opened only at 
the time of administration as drug is both hygroscopic and light-
sensitive. Two 5 mg tablets should be taken orally once daily in a 
fasting state or after no more than a light, fat-free meal. Avoid 
grapefruit-containing products during the treatment period. 
5.2.4 Letrozole is formulated as tablets of 2.5 mg and supplied in bottles. 
The dose of letrozole is one 2.5 mg tablet administered orally once 
daily. The oral single dose of RAD001 should be taken together 
with the daily dose of letrozole 2.5 mg.  
5.2.5 Each cycle will consist of 4 weeks of therapy. Patients will be seen 
prior to each cycle. To allow for holidays, vacations and other 
important life events, patients may be seen +/- 7 days of their return 
visit date. Any other schedule modifications must be approved by 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 30 of 56 
 
the study chair. In these circumstances, patients may be dispensed 
additional medication in order not to interrupt treatment.  
5.2.6 After the second cycle (8 weeks ±7 days), patients will undergo a 
radiologic evaluation using the same imaging technique that was 
used during the initial evaluation (i.e., CT or MRI) unless clinical 
suspicion warrants earlier evaluation.  
5.2.7 For the duration that patients are on study therapy, adverse event 
monitoring will be done continuously. Patients will be evaluated for 
adverse events at each physician visit and are to be instructed to 
call their physician to report any clinically significant adverse events 
between visits. 
5.3 
Dose modifications / Management of Adverse Reactions 
Toxicity will be assessed using the NIH-NCI Common Terminology Criteria for 
Adverse Events, version 3.0 (CTCAEv3.0, 
(http://ctep.cancer.gov/forms/CTCAEv3.pdf)).  
 
Dose Modification Table: 
 
Dose level 
-2 
-1 
0 
RAD001 
Off study 
5 mg daily 
10 mg daily 
Letrozole 
Off study 
2.5 mg daily 
2.5 mg daily 
 
Patients will be removed from study for any: 
 grade 4 treatment-related toxicity (assuming that appropriate 
preventive therapy has been given where possible – e.g. antiemetic 
therapy in case of vomiting, lipid-lowering drug in case of 
hyperlipidemia), or 
 hematologic or non-hematologic toxicity requiring interruption of 
one or both drugs for > 3 weeks. For detailed recommendations on 
dose interruption and modification due to suspected toxicity, please 
refer to the following table. 
 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 31 of 56 
 
Algorithm for interpretation and dose modification 
due to suspected treatment related toxicity: 
Treatment-related toxicity 
Actions 
Non-hematological toxicity 
 
Grade 2  
(except fatigue, hyperlipidemia, 
and non-infectious pneumonitis – 
see Dose Modification Table, page 
30) 
For first occurrence, interrupt RAD001 (continue letrozole) until 
recovery to grade 1 then reintroduce RAD001 (no dose reduction).  
If the event recurs, interrupt study treatment (Letrozole and 
RAD001) until recovery to grade 1 then reintroduce therapy at -1 
dose level.  
If the event recurs a 3rd time, remove patient from study. 
Grade 3 
(except hyperlipidemia and non-
infectious pneumonitis) 
For first occurrence, interrupt study treatment (Letrozole and 
RAD001) until recovery to grade  1. Then reintroduce therapy at -1 
dose level.  
If the event recurs remove from study. 
For pneumonitis consider the use of a short course of 
corticosteroids.  
Grade 4 
Remove from study. 
 
Lipid-lowering drugs  
Increased lipid levels are a known adverse effect of treatment with both RAD001 and aromatase 
inhibitors. In case of hyperlipidemia (≥grade 1 hypercholesterolemia with or without hypertriglyceridemia), 
in addition to dietary advice to patients, an HMG-CoA reductase inhibitor such as atorvastatin, pravastatin 
or fluvastatin may be associated with study treatment.  

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 32 of 56 
 
 
Hematological toxicity 
 
Grade 2 Thrombocytopenia 
(platelets <75, ≥ 50x109/L) 
Interrupt study treatment (Letrozole and RAD001) until recovery to grade 
1 (>75 x109/L) then resume study treatment (no dose reduction). 
If the grade 2 thrombocytopenia recurs, interrupt study treatment 
(Letrozole and RAD001) until recovery to grade 1 then reintroduce 
therapy at -1 dose level.  
If the event recurs a 3rd time, remove patient from study. 
Grade 3 Thrombocytopenia    
(platelets <50, ≥ 25 x1091/L) 
Interrupt study treatment (Letrozole and RAD001) until recovery to grade 
≤1 (platelets ≥ 75 x109/L) then resume study treatment at the -1 dose 
level.  
If grade 3 thrombocytopenia recurs, remove from study.  
Grade 4 Thrombocytopenia 
(platelets < 25 x109/L) 
Remove from study 
Grade 3 Neutropenia 
(neutrophils <1, ≥0.5 x109/L) 
Interrupt study treatment (Letrozole and RAD001) until recovery to grade 
< 1 then resume study treatment (no dose reduction).  
If ANC again returns to Grade 3, hold study treatment (Letrozole and 
RAD001) until the ANC ≥ 1.5 x 109/L then resume study treatment 
(Letrozole and RAD001) at the -1 dose level.  
Remove from study for a third episode of grade 3 neutropenia.  
Grade 4 Neutropenia 
(neutrophils < 0.5 x109/L) 
Interrupt study treatment (Letrozole and RAD001) until recovery to grade 
 1 (neutrophils ≥ 1.5 x 109/L) then resume study treatment (Letrozole 
and RAD001) at the -1 dose level.  
Remove from study if grade 4 neutropenia reoccurs despite this dose 
reduction. 
Grade 3 febrile neutropenia 
(not life-threatening)  
Interrupt study treatment (Letrozole and RAD001) until resolution of fever 
and neutropenia to grade ≤ 1 and hold further study treatment (Letrozole 
and RAD001) until the ANC ≥ 1,500/mm3 and fever has resolved. Then 
resume study treatment (Letrozole and RAD001) at the -1 dose level. 
If febrile neutropenia recurs, remove from study.  
Grade 4 febrile neutropenia 
(life-threatening)  
Remove from study 
Any hematological or non-
hematological toxicity 
requiring interruption for ≥ 3 
weeks 
Remove from study 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 33 of 56 
 
5.3.1 
Management of non-infectious pneumonitis: 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious 
pneumonitis (including interstitial lung disease) have also been described in patients taking 
everolimus (see Section 5 Adverse drug reactions). Some of these have been severe and on 
rare occasions, a fatal outcome was observed.  
A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-
specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnoea, 
and in whom infectious, neoplastic and other non-medicinal causes have been excluded by 
means of appropriate investigations. Patients should be advised to report promptly any new or 
worsening respiratory symptoms.  
Patients who develop radiological changes suggestive of non-infectious pneumonitis and have 
few or no symptoms may continue everolimus therapy without dose alteration. If symptoms are 
moderate (Grade 2), consideration should be given to interruption of therapy until symptoms 
improve. The use of corticosteroids may be indicated. Everolimus may be reintroduced at a 
reduced dose until recovery to Grade 1 or better.  
For cases where symptoms of non-infectious pneumonitis are severe (Grade 3), everolimus 
therapy should be discontinued and the use of corticosteroids may be indicated until clinical 
symptoms resolve. Therapy with everolimus may be re-initiated at a reduced dose depending 
on the individual clinical circumstances. 
 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of Pneumonitis  
Everolimus Dose Adjustment 
Grade 1 
CT scans with lung windows and 
pulmonary function testing 
including: spirometry, DLCO, 
and room air O2 saturation at 
rest. Repeat chest x-ray/CT scan 
every 2 Cycles until return to 
baseline. 
No specific therapy is required 
Administer 100% of everolimus 
dose. 
Grade 2 
CT scan with lung windows and 
pulmonary function testing 
including: spirometry, DLCO, 
and room air O2 saturation at 
rest. Repeat each subsequent 
Cycle until return to baseline. 
Consider bronchoscopy* 
Symptomatic only. Prescribe 
corticosteroids if cough is 
troublesome. 
Reduce everolimus dose until 
recovery to ≤ Grade 1. 
Everolimus may also be 
interrupted if symptoms are 
troublesome. Patients will be 
withdrawn from the study if they 
fail to recover to ≤ Grade 1 within 
3 weeks. 
Grade 3 
CT scan with lung windows and 
pulmonary function testing 
including: spirometry, DLCO, 
and room air O2 saturation at 
rest; Repeat each subsequent 
Cycle until return to baseline. 
Bronchoscopy is recommended* 
Prescribe corticosteroids if 
infective origin is ruled out. 
Taper as medically indicated. 
Hold treatment until recovery to 
≤ Grade 1. May restart protocol 
treatment within 2 weeks at a 
reduced dose (by one level) if 
evidence of clinical benefit. 
Patients will be withdrawn from 
the study if they fail to recover to 
≤ Grade 1 within 2 weeks.  
Grade 4 
CT scan with lung windows and 
required pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 saturation 
at rest. Repeat each subsequent 
Cycle until return to baseline. 
Bronchoscopy is 
recommended*. 
Prescribe corticosteroids if 
infective origin is ruled out. 
Taper as medically indicated. 
Discontinue treatment. 
*A bronchoscopy with biopsy and/or bronchoalveolar lavage is recommended. 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 34 of 56 
 
5.3.2 Management of Hepatitis reactivation 
In cancer patients with hepatitis B, whether carriers or in chronic state, use of antivirals 
during anticancer therapy has been shown to reduce the risk of hepatitis B virus (HBV) 
reactivation and associated HBV morbidity and mortality (Loomba et al. 2008). 
 
Monitoring and prophylactic treatment for hepatitis B reactivation 
Table 3-2 provides details of monitoring and prophylactic therapy according to the 
baseline results of viral load and serologic markers testing. 
 
Table 3-2 
Action to be taken for positive baseline hepatitis B results 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBs Ab 
+ or - 
+ or - 
+ 
and no prior 
HBV 
vaccination 
+ or - 
- 
or + with 
prior HBV 
vaccination 
HBc Ab 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendation 
Prophylaxis treatment should be 
started 1-2 weeks prior to first 
dose of study drug 
Monitor HBV-DNA approximately 
every 4 weeks 
No prophylaxis 
Monitor HBV-DNA 
approximately every 4 weeks 
No specific 
action 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of 
study drug. 
For patients who have already received study drug prior to the approval of the 
amendment, the same process should be followed at the patient's next visit. The first 
HBV-DNA result would be regarded as baseline. 
For hepatitis B reactivation, definition and management guidelines, see Table 3-3 
Guidelines for management of hepatitis B. 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 35 of 56 
 
Table 3-3 
Guidelines for management of hepatitis B 
HBV reactivation  (with or without clinical signs and symptoms)* 
For patients with baseline results:  
Positive HBV-DNA 
OR 
positive HBsAg 
-------------------------------------- 
reactivation is defined as:   
[Increase of 1 log in HBV-DNA relative to 
baseline HBV-DNA value OR new 
appearance of measurable HBV-DNA] 
AND 
ALT elevation x 5 ULN 
Treat: Start a second antiviral  
AND 
Interrupt study drug administration until resolution:  
 ≤ grade 1 ALT (or baseline ALT, if > grade 1) and 
 ≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days study drug should be re-started at 
one dose lower, if available. If the patient is already receiving the lowest 
dose of study drug according to the protocol, the patient should restart at 
the same dose after resolution. Both antiviral therapies should continue at 
least 4 weeks after last dose of study drug.  
If resolution occurs > 28 days Patients should discontinue study drug but 
continue both antiviral therapies at least 4 weeks after last dose of study 
drug. 
For patients with baseline results:  
Negative HBV-DNA and HBsAg  
AND  
[Positive HBs Ab (with no prior history of 
vaccination against HBV), OR positive 
HBc Ab]  
------------------------------------- 
reactivation is defined as: 
New appearance of measurable HBV-
DNA 
Treat : Start first antiviral medication  
AND 
Interrupt study drug administration until resolution:  
  ≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days study drug should be re-started at 
one dose lower, if available. If the patient is already receiving the lowest 
dose of study drug according to the protocol, the patient should restart at 
the same dose after resolution. Antiviral therapy should continue at least 4 
weeks after last dose of study drug.  
If resolution occurs > 28 days Patients should discontinue study drug but 
continue antiviral therapy at least 4 weeks after last dose of study drug. 
* All reactivations of hepatitis B are to be recorded as grade 3 (CTCAE v 3.0 Metabolic Laboratory/Other: Viral Re-
activation), unless considered life threatening by the investigator; in which case they should be recorded as grade 4 
(CTCAE v 3.0 Metabolic Laboratory/Other: Viral Re-activation). Date of viral reactivation is the date on which both 
DNA and ALT criteria were met (e.g. for a patient who was HBV-DNA positive on 01-JAN-10 and whose ALT reached 
≥ 5 × ULN on 01-APR-10, the date of viral reactivation is 01-APR-10). 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 36 of 56 
 
5.3.3 Monitoring for hepatitis C 
The following two categories of patients should be monitored every 4 weeks for HCV 
reactivation: 
 Patients with detectable HCV RNA-PCR test at baseline. 
 Patients known to have a history of HCV infection, despite a negative viral load test 
at baseline (including those that were treated and are considered ‘cured’) 
For definition of hepatitis C reactivation and the management guidelines, see Table 3-4 Guidelines for 
management of hepatitis C. 
Table 3-4 Guidelines for management of hepatitis C 
HCV reactivation* 
For patients with baseline results:  
Detectable HCV-RNA,  
------------------------------------------ 
reactivation is defined as: ALT elevation x 5 ULN  
Discontinue study drug 
For patients with baseline results: 
Knowledge of past hepatitis C infection with no detectable HCV-RNA, 
------------------------------------------- 
reactivation is defined as: New appearance of detectable HCV-RNA  
Discontinue study drug 
* All reactivations of hepatitis C are to be recorded as grade 3 (CTCAE v3.0 Metabolic Laboratory/Other: 
Viral Re-activation), unless considered life threatening by the investigator; in which case they should be 
recorded as grade 4 (CTCAE v 3.0 Metabolic Laboratory/Other: Viral Re-activation).  
 
5.3.4 Concomitant therapy 
 
Lipid-lowering drugs  
Increased lipid levels are a known adverse effect of treatment with both RAD001 and 
aromatase inhibitors. In case of hyperlipidemia (≥grade 1 hypercholesterolemia with or 
without hypertriglyceridemia), in addition to dietary advice to patients, an HMG-CoA 
reductase inhibitor such as atorvastatin, pravastatin or fluvastatin may be associated 
with study treatment. 
 It is highly recommended that patients positive HBV-DNA or HBsAg are treated 
prophylactically with an antiviral for 1-2 weeks prior to receiving study drug (see 
Section 3.2).  
 The antiviral treatment should continue throughout the entire study period and for at 
least 4 weeks after the last dose of study drug.  
 Patients on antiviral prophylaxis treatment or positive HBV antibodies should be 
tested for HBV-DNA according to study visit schedule.  

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 37 of 56 
 
 Oral contraceptives in preclinical and clinical data have shown everolimus to have 
CYP3A4 inhibitory activity rather than induction activity, induction of metabolism of 
contraceptive hormones by everolimus is unlikely. Consequently, administration of 
everolimus should not reduce the efficacy of oral contraceptives. 
 Patients will be provided a list of all drugs/substances to avoid when entered on the 
study (Appendix E). 
 
5.3.5 INDUCERS & INHIBITORS OF CYP3A4 AND/OR PgP and OTHER 
RELEVANT DRUG INTERACTIONS 
Table 3-5 Inducers/Inhibitors of CYP3A4 and/or PgP 
Inhibitors of CYP3A4 and/or PgP 
Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) or P-
glycoprotein (PgP) should be avoided. 
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or PgP inhibitors 
should be used with caution.  If patient requires co-administration of moderate CYP3A4 inhibitors or 
PgP inhibitors, reduce the dose of everolimus to half the currently used dose e.g., 10mg daily would be 
reduced to 5mg daily. Additional dose reductions to every other day may be required to manage 
toxicities. If the inhibitor is discontinued the everolimus dose should be returned to the dose used prior 
to initiation of the moderate CYP3A4/PgP inhibitor. 
Seville orange, star fruit, grapefruit and their juices affect P450 and PgP activity. Concomitant use 
should be avoided. 
Inducers of CYP3A4 and/or PgP 
Avoid the use of strong CYP3A4 inducers. If patient requires co-administration of strong CYP3A4 
inducers (i.e., phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s wort), an 
increase in the dose of everolimus up to twice the currently used daily dose should be considered, 
using 5mg increments. Enzyme induction usually occurs within 7-10 days, therefore everolimus dose 
should be increased by one increment 7 days after the start of the inducer therapy.  If no safety 
concerns are seen within the next 7 days, the dose can be increased again one additional increment up 
to a maximum of twice the daily dose used prior to initiation of the strong CYP3A4 inducer.   
This dose adjustment of everolimus is intended to achieve similar AUC to the range observed without 
inducers.  However, there are no clinical data with this dose adjustment in patients receiving strong 
CYP3A4 inducers.  If the strong inducer is discontinued the everolimus dose should be returned to the 
dose used prior to initiation of the strong CYP3A4/PgP inducer. 
 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 38 of 56 
 
Table 3-6 
Clinically relevant drug interactions: substrates, inducers, and inhibitors of isoenzyme CYP3A 
 
SUBSTRATES 
Antibiotics: 
Clarithromycin, erythromycin, 
telithromycin 
Calcium channel blockers: 
Amlodipine, diltiazem, felodipine, lercanidipine, nifedipine, 
nisoldipine, nitrendipine, verapamil 
Anti-arrhythmics: 
Quinidine 
HMG CoA reductase inhibitors: 
Cerivastatin, lovastatin, simvastatin 
Benzodiazepines: 
Alprazolam, diazepam, midazolam, 
triazolam 
Steroid 6beta-OH: 
estradiol, hydrocortisone, progesterone, testosterone 
Immune modulators: 
Cyclosporine, tacrolimus (FK506) 
Miscellaneous: 
Alfentanil, aprepitant, aripirazole, buspirone,  cafergot, 
caffeine, cilostazol, cocaine, codeine-N-demethylation, 
dapsone, dexamethasone, dextromethorphan, docetaxel 
domperidone, eplerenone, fentanyl, finasteride, 
Gleevec/imatinib, haloperidol, irinotecan, LAAM, lidocaine, 
methadone, nateglinide, ondansetron, pimozide, 
propranolol, quetiapine, quinine, risperidone, salmeterol, 
sildenafil, sirolimus, sorafenib, sunitinib, tamoxifen, taxol, 
terfenadine, torisel, trazodone, vincristine, zaleplon, 
ziprasidone, zolpidem 
HIV Antivirals: 
Indinavir, nelfinavir, ritonavir, saquinavir 
Prokinetic: 
Cisapride 
Antihistamines: 
Astemizole, chlorpheniramine, terfenadine 
INDUCERS 
Barbiturates, carbamazepine, glucocorticoids, modafinil, oxcarbazepine, phenobarbital, phenytoin, 
pioglitazone, rifabutin, rifampin, St. John’s wort, troglitazone, efavirenz, nevirapine 
INHIBITORS 
Strong inhibitors:  
indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, 
telithromycin, Posaconazole (Krishna et al, 2009) 
Moderate inhibitors:  
aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil,  
Weak inhibitors: 
Cimetidine, Seville orange (Malhotra et al, 2001) 
Unclassified as per the Indiana University DDI listing: 
Ciprofloxacin, delaviridine, troleandamycin, mibefradil, amiodarone, chloramphenicol, 
diethyldithiocarbamate, fluvoxamine, starfruit, gestodene, imatinib, mifepristone, norfloxacin, 
norfluoxetine, voriconazole*, 
Based on http://medicine.iupui.edu/clinpharm/ddis/table.asp as of December 01, 2009 
 * Voriconazole (unclassified as per the Indiana University DDI table) 
Strong inhibitor according to the following reference: 
(http://www.nature.com/clpt/journal/v80/n5/pdf/clpt2006438a.pdf) 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 39 of 56 
 
Table 3-7  Clinically relevant drug interactions mediated by PgP 
PgP Substrates 
PgP Inhibitors in vivo 
PgP Inducers 
digoxin, fexofenadine,  indinavir, 
vincristine, colchicine, topotecan, 
paclitaxel 
amiodarone, azithromycin, captopril, 
carvedilol, clarithromycin, conivaptan, 
cyclosporine, diltiazem, elacridar, 
erythromycin, felodipine, (GF120918), 
itraconazole, ketocoanzole, lopinavir, 
(LY335979), mibefradil, nifedipine, 
nitrendipine, (PSC833), quinidine, 
ranolazine, ritonavir, talinolol, 
valspodar, verapamil 
rifampin, St John’s 
wort 
 
Seville orange, star fruit, grapefruit and their juices affect P450 and PgP activity. Concomitant use 
should be avoided 
 
No chronic treatment with systemic steroids (at a dose equivalent of greater than 20 mg prednisone 
per day) or other immunosuppressive agents. Topical or inhaled corticosteroids are allowed. 
 
The use of live vaccines and close contact with those who have received live vaccines should be 
avoided during treatment with everolimus. Examples of live vaccines include intranasal influenza, 
measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines. 
Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no 
interaction with everolimus is expected. However, drug-drug interaction studies between 
macrolide antibiotics and warfarin have produced mixed outcomes and the disparity in 
these findings has led to the conclusion that multiple factors may alter the clearance of 
warfarin. The coadministration of everolimus and oral anticoagulants is possible but 
should be subject to verification of coagulation (INR) once steady state is reached (after 
one week’s treatment). 
Examples are provided in Table 3-5 (CYP3A4 inhibitors/inducers) and Table 3-6 (Drug 
interactions mediated by P-glycoprotein). A comprehensive list of cytochrome P450 
isoenzymes and CYP3A4 inhibitors, inducers, and substrates can be found at 
http://medicine.iupui.edu/flockhart.  
Patients will be provided a list of all drugs/substances to avoid when entered on the 
study (Appendix E). 
 
5.4 
Treatment compliance  
Novartis will distribute agents direct to sites under individually negotiated contracts. M. 
D. Anderson Cancer Center (MDACC) will collect and manage regulatory and monitor 
/audit sites.  RAD001 and letrozole will be dispensed from the sites investigational 
pharmacy. Patients will be provided with an adequate supply (1 cycle plus 1 week) of 
letrozole plus RAD001 for self-administration at home. Patients are requested to bring 
their unused medication, including the empty blister packs, to the clinic at each visit. 
Compliance should be verified by a patient pill diary (Appendix G) and counting the 
number of tablets consumed between visits.  
Records of study medication used, dosages administered, and intervals between visits 
will be kept during the study, during site visits and at the completion of the trial. Patients 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 40 of 56 
 
will be asked to return all unused medication at the end of treatment. All unused 
medication will be returned to the investigational pharmacy. 
The site must maintain an overall drug accountability log for the study, as well as 
individual accountability records (pill diaries) for each patient. The dose, amount 
dispensed, amount received, and amount unused must be recorded in the source 
documents for each patient. To avoid waste, leftover medications at the end of each 
cycle may be used in the subsequent cycle.  
5.5 
Supportive Care Guidelines/Concomitant Medications 
5.5.1 Growth Factors: Routine prophylactic use of growth factors is not 
permitted. However, therapeutic use in patients with serious hematologic 
complications such as sepsis may be considered at the investigator's 
discretion. 
 
5.5.2 Antiemetics: The use of antiemetics will be left to the investigator's 
discretion. 
 
5.5.3 Other Concomitant Medications: In general, concomitant medications 
and therapies deemed necessary for the supportive care and safety of the 
patient are allowed, provided their use is documented in the patient 
record. The administration of any other anticancer agents including 
chemotherapy and biologic agents is NOT permitted. Similarly, the use of 
other concurrent investigational drugs is not allowed. 
 
5.6  
Drug Information 
 
5.6.1 Physical, Chemical and Pharmaceutical Properties of Letrozole 
 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 41 of 56 
 
5.6.2 Physical, Chemical and Pharmaceutical Properties of Everolimus 
 
 
 
 
6 STUDY PROCEDURES 
 
Patients will be seen by a physician at the start of treatment and then prior to initiating 
subsequent cycles, i.e., every four weeks. In order to more precisely determine time of 
progression, the investigator is encouraged to obtain radiologic assessments earlier if 
there is a strong clinical suspicion of progression of disease to either confirm or refute 
the clinical impression. Adverse events will be discussed in detail with each patient and 
assessed on a continuing basis. 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 42 of 56 
 
6.1 
Schedule of Assessments 
Assessments 
Screening / 
baseline 
Weekly 
Every 
cycle 
Every 2nd / 
3rd cycled 
End of 
treatment j 
Follow-uph 
Medical history 
Xa 
 
 
 
 
 
Physical examination 
Xb,c 
 
Xc 
 
X 
X 
Vital signs 
Xb 
 
X 
 
X 
X 
Zubrod Performance Status 
Xb 
 
Xb 
 
X 
X 
Weight 
Xb 
 
X 
 
X 
X 
CBC with differential and platelets 
Xb 
 
X 
 
X 
 
Hepatitis screening/monitoring 
Xl,n 
 
Xm,o 
 
 
 
Serum chemistries (Mg+, SGPT, total 
bilirubin, BUN, serum creatinine/creatinine 
clearance) and electrolytes, glucose 
Xb,p 
 
X 
 
X 
 
Lipid panel (Triglycerides, LDL, HDL) 
Xb 
 
X 
 
X 
 
Tumor staging (baseline tumor 
measurements) 
Xa,e 
 
 
 
 
 
Chest x-ray 
Xa 
 
 
Xi 
Xi 
 
CT/MRI of chest, abdomen and pelvis and/or 
appropriate imaging 
Xa,e 
 
 
Xf 
Xf 
X 
Toxicity 
Xa 
Xg 
X 
 
X 
X 
Tumor response 
 
 
 
X 
 
 
Serum estradiolk 
Xa 
 
 
 
 
 
Medication compliance/pill count 
 
 
Xq 
 
 
 
a 
Within 4 weeks prior to Step 2 of study registration (treatment assignment) 
b Within 7 days of initiation of therapy 
c 
Pelvic exam every cycle if disease is in the pelvis. Otherwise, pelvic exam is done at baseline, after 2 cycles, and then every 3rd 
cycle thereafter. 
d Obtained after the first two cycles (approximately 8 weeks), after four cycles (approximately 16 weeks) for confirmation, then 
every three cycles (approximately 12 weeks) thereafter. 
e CT/MRI of chest only in patients with chest disease. 
f 
Using the same imaging technique used during the initial evaluation. 
g 
Toxicity will be assessed on an ongoing basis. 
h Follow-up time interval at the physician’s discretion. Follow up begins after the patient stops study medication. 
i 
Only in patients with chest disease 
j 
Within 4 weeks of the last dose of study drug. 
k 
Documentation of a serum estradiol < 10 pg/mL is required only for patients in whom hysterectomy was performed 
premenopausally and in whom bilateral oophorectomy was not completed. Estradiol is not required for women known to be 
menopausal or surgically castrated. 
l 
Hepatitis B Virus testing: Prior to randomization (or starting study drug in non-randomized trials), the categories of patients 
listed in Section 3.2 should be tested for hepatitis B serologic markers and viral load: HBV-DNA HBsAg, HBc Ab, and HBs Ab.  
m HBV DNA monitoring should be done depending on results from serologic markers and viral load as listed in Table 3-3. 
n Hepatitis C Virus testing: Patients with hepatitis C risk factors and additional patients at the discretion of the investigator 
should be tested for HCV RNA-PCR test at baseline. For a list of hepatitis C risk factors, refer to Table 3-2. Follow-up testing will 
be performed, as per the visit schedule, only if the patient has a history or is positive at baseline, or both. 
o Patients with detectable HCV RNA-PCR (determined at baseline) and Patients known to have a history of HCV infection, 
despite a negative viral load test at baseline (including those that were treated and arae considered “cured”) should be 
monitored every 4 weeks for HCV reactivation 
p Creatine clearance: Patients must have an adequate renal function of >50cc/min as documented by the Cockcroft Gault 
formula: 
 
 
 
 
 
(140 – age) x (weight kg) 
 
Estimated GFR  =   72 x serum Creatinine  (non-IDMS)  x 0.85 (female) 
q Patients are requested to bring their unused medication, including the empty blister packs, to the clinic at each visit. 
Compliance should be verified by a patient pill diary (Appendix G) and counting the number of tablets consumed between 
visits. 

MDACC Protocol # 2009-0059 
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6.2 
Screening/Baseline 
To be completed within four weeks prior to Step 2 of study registration 
(treatment assignment): 
1. Medical history including list of current medications and dosing schedules, 
history of previous therapies for current disease; and any residual toxicity 
from prior therapies should be recorded by using the grading schema in 
CTCAE, v3.0.  
2. Zubrod performance status. 
3. Baseline tumor measurements  
4. Chest x-ray 
5. CT/MRI of chest, abdomen and pelvis and/or appropriate imaging. Chest 
imaging (only in patients with chest disease) 
6. Hepatitis screening 
 
To be completed within seven days of initiation of therapy. Therapy must 
be initiated within 10 calendar days after Step 2 of registration (treatment 
assignment): 
1. Physical exam including pelvic exam 
2. Weight 
3. Vital signs (blood pressure, pulse, respiratory rate, temperature) 
4. Zubrod performance status 
5. Complete blood count with leukocyte differential and platelet count 
6. Serum chemistries (magnesium, SGPT, total bilirubin, BUN, serum creatinine, 
glucose and electrolytes). 
7. Lipid panel (Triglycerides, LDL, HDL) 
 
6.3 Treatment Evaluations To be obtained every cycle (4 weeks): 
1. Weight 
2. Complete blood count, serum chemistries (magnesium, SGPT, total bilirubin, 
BUN, serum creatinine), glucose and electrolytes. 
3. Lipid panel (Triglycerides, LDL, HDL) 
4. Vital Signs (blood pressure, pulse, respiratory rate, temperature) 
5. Physical exam including pelvic exam every cycle if disease is in the pelvis. 
Otherwise pelvic exam is performed at baseline, after 2 cycles (8 weeks), and 
then every 3 cycles (12 weeks) thereafter.  
6. Zubrod performance status  

MDACC Protocol # 2009-0059 
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Page 44 of 56 
 
7. Assessment of treatment related toxicities 
8. Hepatitis monitoring, if indicated 
9. Medication compliance, pill count 
 
To be obtained after the first 2 cycles (8 weeks): 
1. Evaluation of measurable tumor 
2. Physical exam (including pelvic exam) 
3. CT/MRI scan of chest, abdomen and pelvis and/or appropriate imaging (the 
same imaging technique used during the initial evaluation will be performed). 
Chest imaging (only in patients with chest disease) 
4. Assessment of treatment related toxicities 
 
After this first evaluation, patients with progressive disease will be taken off 
study. To be assigned a status of PR or CR according to RECIST 1.1, tumor 
measurements must be confirmed by repeat studies (i.e., evaluation of 
measurable tumor, physical exam, and imaging) that should be performed no 
less than 4 weeks after the criteria for disease control are first met. To be 
assigned a status SD, tumor measurements must be confirmed by repeat studies 
(i.e., evaluation of measurable tumor, physical exam, and imaging) that should 
be performed no less than 8 weeks after the criteria for disease control are first 
met. 
 
After these confirmatory studies, to be obtained every 3 cycles (12 weeks): 
1. Pelvic exam 
2. CT/MRI scan and/or appropriate imaging (the same imaging technique used 
during the initial evaluation will be performed) 
3. Chest imaging (only in patients with chest disease) 
 
 
6.4 
End of Treatment: To be obtained at the end of treatment: 
1. Physical exam including pelvic exam 
2. Vital signs 
3. Zubrod performance status 
4. Weight 
5. Complete blood count with differential and platelets, serum chemistries 
(magnesium, SGPT, total bilirubin, BUN, serum creatinine, glucose and 
electrolytes. 
6. Lipid panel (Triglycerides, LDL, HDL) 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 45 of 56 
 
7. CT/MRI scan of chest, abdomen and pelvis and/or appropriate imaging (the 
same imaging technique used during the initial evaluation will be performed). 
Chest imaging (only in patients with chest disease) 
8. Assessment of treatment related toxicities 
9. Medication compliance/pill count and return of unused medication 
 
6.5 
Follow-up 
Follow-up will be at the discretion of the patient’s primary physician.  However, 
follow-up data will be due to M. D. Anderson OMCR every 6 months. 
 
To be obtained during follow-up visits: 
 Physical exam including pelvic exam 
 Vital signs (blood pressure, pulse, respiratory rate, temperature, weight) 
 Performance status 
 CT/MRI scan of chest, abdomen and pelvis and/or appropriate imaging (the 
same imaging technique used during the initial evaluation will be performed). 
Chest imaging (only in patients with chest disease). The frequency of imaging 
will be determined by the physician. 
 Toxicity assessment 
6.6 
Correlative Studies 
 
When available, we will collect paraffin embedded tumors from the original tumor 
at the time of hysterectomy, pretreatment biopsy, and post-treatment biopsy. We 
will evaluate the immunohistochemical expression of PTEN, mTOR, AKT, 
p70S6K, and E4-BP1 using commercially available antibodies.  We will also 
evaluate the difference in expression of these proteins between the primary 
tumors and the recurrences (pre- and post- treatment) in the same patients to 
determine if there are any alterations of the expression of these biomarkers 
during the progression of disease.  Paraffin blocks will be requested from all 
study participants (both responders and non-responders).  If paraffin blocks are 
not available, at least 5 slides each (pre- and post-treatment) will be requested.  
Pre-treatment samples will be sequenced to analyze the mutational status of K-
Ras as this may also be a marker of response.       

MDACC Protocol # 2009-0059 
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7 
Efficacy and Safety Assessments – RECIST 1.1 
 
7.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response after 
the first 2 cycles (8 weeks).  In addition to a baseline scan, confirmatory scans 
should also be obtained after the next two cycles (8 weeks) following initial 
documentation of objective response. 
 
Response and progression will be evaluated in this study using the new 
international criteria proposed by the revised Response Evaluation Criteria in 
Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  
Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used 
in the RECIST criteria. 
 
7.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the 
time of their first treatment with Letrozole (Evirolimus) and RAD001. 
 
Evaluable for objective response.  Only those patients who have 
measurable disease present at baseline, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered 
evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions 
present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for non-
target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
7.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm 
with calipers by clinical exam.  All tumor measurements must be recorded 
in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might 
or might not be considered measurable. Tumors within a previously 

MDACC Protocol # 2009-0059 
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irradiated field will be designated as “non-target” lesions, unless 
progression is documented or a biopsy is obtained to confirm persistence 
at least 90 days following completion of radiation therapy. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 
5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including 
small lesions (longest diameter <10 mm or pathological lymph nodes with 
≥ 10 to <15 mm short axis), are considered non-measurable disease.  
Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-
measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions (neither 
measurable nor non-measurable) since they are, by definition, simple 
cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion which can be measured reproducibly should be 
selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters.  If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum.  The baseline sum 
diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be 

MDACC Protocol # 2009-0059 
Revised April 28, 2020 
Page 48 of 56 
 
identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
 
7.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a 
ruler or calipers.  All baseline evaluations should be performed as closely 
as possible to the beginning of treatment and never more than 4 weeks 
before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used 
to characterize each identified and reported lesion at baseline and during 
follow-up. Imaging-based evaluation is preferred to evaluation by clinical 
examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when 
they are superficial (e.g., skin nodules and palpable lymph nodes) and 10 
mm diameter as assessed using calipers (e.g., skin nodules).  In the case 
of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  However, 
CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, 
and temporal resolution; however, there are many image acquisition 
variables involved in MRI, which greatly impact image quality, lesion 
conspicuity, and measurement.  Furthermore, the availability of MRI is 
variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the 
modality used at follow-up should be the same as was used at baseline 
and the lesions should be measured/assessed on the same pulse 
sequence.  It is beyond the scope of the RECIST guidelines to prescribe 
specific MRI pulse sequence parameters for all scanners, body parts, and 

MDACC Protocol # 2009-0059 
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diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to 
prior scans.  Body 
scans should be performed with breath-hold scanning techniques, if 
possible. 
 
 
7.1.4 Response Criteria 
 
 
7.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to 
<10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference 
the baseline sum diameters 
 
Progressive Disease (PD): At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference 
the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  
In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also 
considered progressions). 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while 
on study 
 
7.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 
mm short axis) 
 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 

MDACC Protocol # 2009-0059 
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Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level 
above the normal limits 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status 
change, not a single lesion increase.     
 
 
Although a clear progression of “non-target” 
lesions only is exceptional, the opinion of the 
treating physician should prevail in such 
circumstances, and the progression status 
should be confirmed at a later time by the 
review panel (or Principal Investigator). 
 
7.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started).  The patient's best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 

MDACC Protocol # 2009-0059 
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For Patients with Measurable Disease (i.e., Target Disease) 
 
Target Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 

MDACC Protocol # 2009-0059 
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7.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is 
measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is 
objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of 
the treatment until the criteria for progression are met, taking as reference 
the smallest measurements recorded since the treatment started, 
including the baseline measurements.  
 
Patients achieving a complete response, once confirmed, are permitted to stop 
study medication.  Subsequent follow-up will be at the discretion of the treating 
physician. 
 
7.1.6 Other efficacy parameters 
 
Duration of disease control, time to disease progression, and survival will 
be evaluated. 
 
7.1.7 Safety assessments 
 
Safety assessments will consist of monitoring and recording all adverse 
events and serious adverse events, the regular monitoring of hematology, 
blood chemistry and urine values, regular measurement of vital signs and 
the performance of physical examinations. 
7.1.7.1 
Adverse events 
Adverse events will be recorded and collected in the in 
accordance with the Adverse Event Recording Guidelines 
(Described in the Data Quality Management Plan (DQMP) 
Appendix L. 
 
8 
STUDY MONITORING 
Study Monitoring procedures are described in the Data Quality Management Plan 
(DQMP) Appendix L. 

MDACC Protocol # 2009-0059 
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9 
DATA MANAGEMENT 
9.1 
Registration: MDACC will serve as the primary site for this study.  All 
patients enrolled in the study from each of the participating sites will be 
registered in the Clinical Oncology Research System (CORe) at MDACC 
following procedures described in section 5.1.  Patient data will be 
collected and entered in the MDACC’s Protocol Data Monitoring System 
(PDMS). 
 
9.2  
Confidentiality Procedures: 
All pathology specimens, evaluations forms, reports and other records will 
be identified in a manner designed to maintain patient confidentiality. All 
records will be kept in a secure storage area with limited access. Clinical 
information will not be released without the written permission of the 
patient or the patient’s guardian, except as necessary for monitoring by 
the OMCR or its representative, regulatory authorities, or the IRB.  
 
The investigators and all employees and co-workers involved with this 
study shall not disclose or use for any purpose, other than performance of 
the study, any data, records or other unpublished, confidential information 
disclosed to those individuals for the purpose of the study.   No patient 
identifiers will be used when analyzing the data or reporting the results. 
 
9.3  
Data Safety and Monitoring Committee: The MDACC Data Safety and 
Monitoring Committee will monitor the overall conduct of the study. 
 

MDACC Protocol # 2009-0059 
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10 
STATISTICAL METHODOLOGY 
 
This is a phase II activity trial. We will accrue a minimum of 10 patients and a maximum 
of 35 evaluable patients at a rate of 2 patients per month. We estimate 7 patients will be 
inevaluable and thus need to be replaced. Therefore our total number of patients will not 
exceed 42. The primary outcome for this trial is the objective response or stable disease 
rate (CR + PR + SD), which is evaluated within approximately 8 weeks of treatment. A 
confirmatory evaluation will be made no sooner than 4 weeks from this event (8 weeks, 
if SD). Once a response category is confirmed, evaluation for objective responses will 
be made every 12 weeks as outlined in Sections 6 and 7.1.3. Our target objective 
response or stable disease rate is 20%. We will monitor the objective response or stable 
disease rate as patients accrue and are evaluated following the example of Thall and 
Simon.[17] We will stop the trial if we have evidence that the target objective response 
or stable disease rate cannot be met. 
 
We will stop the trial early if P(objective response or stable disease rate ≥ 20% | data 
from the trial) < 0.10. That is, given the outcomes from the patients who have already 
been evaluated, if we determine that there is less than a 10% chance that the objective 
response or stable disease rate is 20% or more, we will stop the trial. This decision rule 
gives the following stopping rule. We assume a uniform prior distribution for the rate of 
objective response or stable disease. Stop the trial if: [# of patients with objective 
response or stable disease / # of patients evaluated] < 1/10, 2/17, 3/24, 4/31. 
 
The operating characteristics of this study design are shown in the following table. 
 
Operating Characteristics of Monitoring Rule 
Rate of  
CR + PR + SD 
Probability of  
Stopping Early 
P25 
P50 
P75 
0.05 
0.956 
10 
10 
17 
0.10 
0.725 
10 
17 
35 
0.15 
0.436 
17 
35 
35 
0.20 
0.220 
35 
35 
35 
0.25 
0.097 
35 
35 
35 
 
We will estimate the rate OF CR + PR + SD with a 90% credible interval once the study 
is complete. If we complete the study with 11 patients with treatment success (CR or PR 
or SD) among 35 patients total (31%), then our 90% credible interval for the success 
rate would be 20.5 to 45.5%. 
 
We will also estimate the overall survival and progression free survival for patients on 
study with the product-limit estimator of Kaplan and Meier (1958). [18] 
 
10.1 Definition of Populations for Analyses 
Patients who are removed from the study during the first course because 
of progression are considered evaluable for efficacy only if progression 
can be documented per RECIST 1.1 criteria. Patients who come off 

MDACC Protocol # 2009-0059 
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treatment for reasons other than progression (and prior to establishing 
response) are evaluable for toxicity only. 
 
10.2 Efficacy Analyses 
 
10.2.1 Definitions of Endpoints 
Survival: The observed length of life from study entry (1st 
treatment) to death or, for living patients, date of last contact. 
Time to tumor progression: The time from date of initial treatment  
Progression-free survival: The observed time from study entry 
(1st treatment) to date of tumor progression, date of death, or, for 
patients alive without tumor progression, date of last follow-up. 
 
 
10.3 Safety Analyses 
 
All eligible patients who receive therapy on this study will be considered 
evaluable for safety. Patients who are removed from the study during the first 
course because of progression, serious drug related adverse events, or for other 
reasons (e.g. patient request or non-drug related toxicity) will also be evaluable 
for safety. 
 
Descriptive statistics and tabulations will be used to summarize adverse events 
and laboratory data. Transition tables will be used to describe changes in 
laboratory values from baseline to follow-up.  
 
11 
Special safety-related procedures 
 
11.1 Instructions for rapid notification of serious adverse events 
The principle investigator has the obligation to report all serious adverse 
events per M. D. Anderson Cancer Center policy to the IRB, and Novartis 
Pharmaceuticals Clinical Safety and Epidemiology Department (CS&E).  
Procedures for reporting Serious Adverse Event’s are described in the 
Data Quality Management Plan (DQMP) (Appendix L). 
In addition, any serious adverse event occurring in a patient after 
providing informed consent, while receiving study drug, and until four 
weeks after stopping study drug must be reported by FAX (888-299-4565) 
to Novartis Pharmaceuticals CS&E Department within 24 hours of learning 
of its occurrence, even if it is not felt to be drug related (Appendix H). The 
OMCR will forward SAE’s to Novartis. 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), 
all serious adverse experiences will be forwarded to the product 
manufacturer by the investigator. 

MDACC Protocol # 2009-0059 
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12 
REFERENCES 
 
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Shumsky AG, Stuart GC, Brasher PM, et al: An evaluation of routine follow-up of 
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Thigpen JT, Blessing JA, DiSaia PJ, et al: A randomized comparison of 
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study. J Clin Oncol 12:1408-14, 1994 
6. 
Thigpen JT, Blessing JA, Lagasse LD, et al: Phase II trial of cisplatin as second-
line chemotherapy in patients with advanced or recurrent endometrial carcinoma. 
A Gynecologic Oncology Group study. Am J Clin Oncol 7:253-6, 1984 
7. 
Thigpen JT, Blessing JA, Homesley H, et al: Phase II trial of cisplatin as first-line 
chemotherapy in patients with advanced or recurrent endometrial carcinoma: a 
Gynecologic Oncology Group Study. Gynecol Oncol 33:68-70, 1989 
8. 
Burke TW, Munkarah A, Kavanagh JJ, et al: Treatment of advanced or recurrent 
endometrial carcinoma with single-agent carboplatin. Gynecol Oncol 51:397-400, 
1993 
9. 
Thigpen J: Phase III trial of doxorubicin +/- cisplatin in advanced or recurrent 
endomterial carcinoma:  a Gynecologic Oncology Group (GOG) study. Proc Am 
Soc Clin Oncol 12:261, 1993 
10. 
Muggia FM, Blessing JA, Sorosky J, et al: Phase II trial of the pegylated 
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