Clinical trial NCT01797120
Conditions: Metastatic Breast Cancer
Keywords: Post-Menopausal Patients Hormone-Receptor Positive Resistant to Aromatase Inhibitor Therapy Fulvestrant Faslodex mTOR Inhibitor Everolimus RAD001 Afinitor
Sponsor: PrECOG, LLC.
Start date: 2013-05-31; Completion date: 2017-09-12
Enrollment: 131 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Post-menopausal women with hormone-receptor positive (HR+) metastatic breast cancer resistant to aromatase inhibitor (AI) therapy will be randomized to receive Fulvestrant (Faslodex) with Everolimus or Fulvestrant (Faslodex) with a placebo (no active ingredients).

Fulvestrant has demonstrated activity when used as first, second, or third line endocrine therapy, making it an attractive therapy for combination with other agents. In addition, it is commonly reserved for use following disease progression on AI therapy.

Everolimus is an orally administered drug that blocks a signaling pathway called "mTOR". "mTOR" acts as a regulator for many processes in the body, including cell growth. Blocking this pathway may have an effect on cell growth.

The combination of a novel class of agents (mTOR inhibitors) and an established standard treatment for metastatic HR+ breast cancer may potentially increase the clinical benefit by targeting multiple different biological pathways.

Detailed description:
Breast cancer is the most commonly diagnosed malignancy in women worldwide. In the United States, an estimated 230,480 new cases of invasive breast cancer were diagnosed in 2011, with 39,520 breast cancer deaths. In 40-80% of women with node-positive disease at diagnosis, their breast cancer will recur. When distant metastases occur, median survival is 18 to 36 months from time of recurrence. Among the 60-70% of women with HR+ breast cancer, 40-60% of them will benefit from endocrine therapy. Endocrine therapy has shown to yield similar survival rates in hormone-sensitive disease as compared to chemotherapy; although response rates are lower and responses develop more slowly. Endocrine therapy is considerably less toxic than chemotherapy, and is therefore the preferred treatment option for patients with HR+ disease.

Endocrine therapy represents the foundation of treatment for HR+ metastatic and locally advanced breast cancer. Multiple compounds in varying classes exist, and those most widely used include the selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and the selective estrogen receptor down-regulators (SERDs). Although the utility of these drugs is well established, as many as 50% of women with HR+ breast cancer will fail to respond to endocrine treatment. Moreover, those who do respond will inevitably develop acquired resistance.

Fulvestrant is the first drug which acts as a pure estrogen receptor (ER) antagonist without known agonist effects. It competitively binds to the ERs with an approximately 100 times greater affinity than that of tamoxifen. Fulvestrant promotes the degradation of ERs and subsequently prevents ER-mediated gene transcription.

Everolimus (RAD001) is an oral derivative of rapamycin that is an m-TOR inhibitor. At cellular and molecular levels, everolimus acts as a signal transduction inhibitor. Everolimus selectively inhibits mTOR (mammalian target of rapamycin); a key and highly conserved serine-threonine kinase which is present in all cells and is a central regulator of protein synthesis and ultimately cell growth, cell proliferation, angiogenesis and cell survival. mTOR is the only currently known target of everolimus.

In oncology, everolimus has been in clinical development since 2002 for patients with various hematologic and non-hematologic malignancies as a single agent or in combination with antitumor agents, including cytotoxic chemotherapeutic agents, targeted therapies, antibodies and hormonal agents.

Patients will be randomized (1:1) to receive everolimus or placebo with fulvestrant after consideration of stratification factors of performance status (0 vs. 1), measurable disease (yes vs. no), and prior chemotherapy for metastatic disease (yes vs. no).

Patients will be evaluated for disease response every 12 weeks, and treated until disease progression or unacceptable toxicity or withdrawal of consent for a maximum of 12 cycles (48 weeks).

Patients with no evidence of progressive disease who remain on study after completing 12 cycles are unblinded and continue to receive fulvestrant alone (if originally randomized to placebo) or in combination with everolimus (if originally randomized to everolimus) at the same dose and schedule. Patients will continue to be evaluated for disease response every 12 weeks and continue until disease progression or unacceptable toxicity.

Arms: arm 1: Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus everolimus daily x 12 cycles. arm 2: Fulvestrant Day 1 \& 15 of Cycle 1, then Day 1 of all subsequent cycles (every 28 days for 12 cycles) plus placebo daily x 12 cycles.
Interventions: intervention 1: Fulvestrant intervention 2: Everolimus intervention 3: Placebo
Intervention descriptions: intervention 1: Fulvestrant 500 mg Day 1 \& 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles).

If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. intervention 2: Everolimus 10 mg (2 tablets) daily x 12 cycles.

If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity. intervention 3: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.

Protocol documents:
Prot_000.pdf: 
PrECOG Protocol Number: PrE0102 
Confidential 
Date: 1/22/2014 
 
PrECOG PROTOCOL NUMBER: PrE0102 
Randomized, Double-Blind, Placebo-Controlled Phase II Trial of 
Fulvestrant (Faslodex) plus Everolimus in Post-Menopausal Patients 
with Hormone-Receptor Positive Metastatic Breast Cancer Resistant 
to Aromatase Inhibitor Therapy 
STUDY CHAIR: 
Noah Kornblum, MD 
STUDY CO-CHAIR: 
Joseph A. Sparano, MD 
MEDICAL MONITOR: 
Katherine M. Smith, MD 
STUDY STATISTICIAN: 
Judi Manola, MS 
PrECOG STUDY CONTACT: 
Carolyn Andrews, RN 
(Internal Use Only) Novartis Ref. ID Number: CRAD001JU596T 
IND #:  
Exempt 
Version Number:  
Version 2.0 
Version Date:  
January 22, 2014 
 
 
Release/Revision History 
Version 1.0: December 19, 2012 
Released to sites 
Version 2.0: January 22, 2014 
Released to sites 
 
 
This protocol contains information that is confidential and proprietary 
 
 


PrECOG Protocol Number: PrE0102 
Confidential 
Date: 1/22/2014 
2 
Revision History 
Version 1.0 
12/19/2012 
Released to sites 
THE FOLLOWING AMENDMENT WAS MADE TO VERSION 1.0 OF THE PROTOCOL 
Version 2.0 
1/22/2014 
Released to sites 
Was: 
MEDICAL MONITOR: Deborah Campbell, MD 
Is: 
MEDICAL MONITOR: Katherine M. Smith, MD 
Was: 
Is: 
MEDICAL MONITOR 
MEDICAL MONITOR 
Deborah Campbell, MD 
Katherine M. Smith, MD 
PrECOG, LLC 
PrECOG, LLC 
1818 Market Street, Suite 1100 
1000 Continental Drive 
Philadelphia, PA 19103 
Suite 200 
8:30 AM - 5 PM Eastern Time Zone 
King of Prussia, PA 19406 
Phone: 610-354-0404 
8:30 AM - 5 PM Eastern Time Zone 
After 5 PM Eastern Time Zone 
Phone: 610-354-0404 
Phone: 484-574-2367 
After 5 PM Eastern Time Zone 
Email: dcamppbell@precogllc.org 
Phone: 484-574-2367 
SAE Fax: 888-801-8795 
Email: ksmith@precogllc.org 
 
SAE Fax: 888-801-8795 
Brief Protocol Synopsis- Patient Population 
Was: 
• 
Patients must be Aromatase Inhibitor (AI) resistant, defined as: 
o 
relapsed while receiving adjuvant therapy with an aromatase inhibitor (anastrozole, letrozole, or 
exemestane) or, 
o 
progressive disease while receiving an aromatase inhibitor for metastatic disease. 
Is: 
• 
Patients must be Aromatase Inhibitor (AI) resistant, defined as: 
o 
relapsed while receiving adjuvant therapy with an aromatase inhibitor (anastrozole, letrozole, or 
exemestane) or, 
o 
progressive disease while receiving an aromatase inhibitor for metastatic disease. 
Note: Patients may have received an endocrine agent (e.g., Tamoxifen) between the time of 
progression on an AI and registration. 


PrECOG Protocol Number: PrE0102 
Confidential 
Date: 1/22/2014 
3 
3.1 Eligibility Criteria- Inclusion 
Was: 
7. Patients must be Aromatase Inhibitor (AI) resistant, defined as: 
• 
relapsed while receiving adjuvant therapy with an aromatase inhibitor (anastrozole, letrozole, or 
exemestane) or, 
• 
progressive disease while receiving an aromatase inhibitor for metastatic disease. 
Is: 
7. Patients must be Aromatase Inhibitor (AI) resistant, defined as: 
• 
relapsed while receiving adjuvant therapy with an aromatase inhibitor (anastrozole, letrozole, or 
exemestane) or, 
• 
progressive disease while receiving an aromatase inhibitor for metastatic disease. 
Note: Patients may have received an endocrine agent (e.g., Tamoxifen) between the time of 
progression on an AI and registration. 
3.1 Eligibility Criteria- Inclusion 
Was: 
8. Patients who have received one prior dose of fulvestrant within 28 days of randomization are eligible 
so long as they meet other eligibility criteria. 
• 
patients previously treated with two or more prior doses of fulvestrant are not eligible. 
Is: 
8. Patients who have received one prior cycle (dose on day 1 and day 15) of fulvestrant within 28 days 
of randomization are eligible so long as they meet other eligibility criteria. 
• 
patients previously treated with two or more prior cycles of fulvestrant are not eligible 
3.1 Eligibility Criteria- Exclusion 
Was: 
3. Patients must not be receiving any concomitant anticancer treatment or have received anticancer 
treatment within 4 weeks of randomization (including chemotherapy, radiation therapy, antibody based 
therapy, etc.), with the following exceptions: 
• 
Bisphosphonates or Zometa for bone metastases 
• 
a GnRH analog is permitted if the patient had progressive disease on a GnRH analog plus a 
SERM or an AI; the GnRH analog may continue but the SERM or AI must be discontinued. 
Is: 
3. Patients must not be receiving any concomitant anticancer treatment or have received anticancer 
treatment within 4 weeks of randomization (including chemotherapy, radiation therapy, antibody based 
therapy, etc.), with the following exceptions: 
• 
Bisphosphonates, Zometa or Xgeva for bone metastases 
• 
Hormonal therapy (e.g., AI, Tamoxifen) 
• 
a GnRH analog is permitted if the patient had progressive disease on a GnRH analog plus a 
SERM or an AI; the GnRH analog may continue but the SERM or AI must be discontinued. 


PrECOG Protocol Number: PrE0102 
Confidential 
Date: 1/22/2014 
4 
5.2.1 Fulvestrant (Arm A and Arm B)- Induction Phase 
Was: 
Cycle 1 (28 day cycle) 
Patients will receive fulvestrant 500 mg IM (two-250 mg injections each dose) on day 1 and 15. 
Note: Cycle 1 is the only time fulvestrant is given on day 15. 
Is: 
Cycle 1 (28 day cycle) 
Patients will receive fulvestrant 500 mg IM (two-250 mg injections each dose) on day 1 and 15. 
Note: Cycle 1 is the only time fulvestrant is given on day 15. If patient previously received one cycle 
of fulvestrant (day 1 and day 15) prior to study entry as permitted in Inclusion Criteria #8, 
patient should receive fulvestrant 500 mg on day 1 only. 
5.2.2 Everolimus or Placebo (Arm A and Arm B) 
Was: 
• 
PrECOG, or their designee, will be responsible for blinding, drug randomization, and management of 
the electronic interactive web registration (IWR) system. Both tablets will be blinded and identified by 
pack number only. The IWR system will assign the proper pack to the patient based on the patient 
randomization. Conditions for study drug will be described on the medication label. 
Is: 
• 
PrECOG, or their designee, will be responsible for blinding, drug randomization, and management of 
the electronic interactive web registration (IWR) system. Both tablets will be blinded and identified by 
kit number only. The IWR system will assign the proper kit to the patient based on the patient 
randomization. Conditions for study drug will be described on the medication label. 
5.3.1 Dose Modifications General Guidelines for Everolimus/Placebo 
Table 5-1 Non-Hematological Criteria for Dose-Modification in Case of Suspected Everolimus or Placebo 
Related Adverse Events and Re-Initiation of Everolimus or Placebo Treatment 
Was: 
AST or ALT elevation 
Grade 4 (>20x ULN)* 
Recurrence of grade 4 after dose reduction 
or toxicity requiring everolimus interruption 
for >28 days 
Interrupt everolimus administration until resolution to 
≤ grade 1 (or ≤ grade 2 if baseline values were 
within the range of grade 2). If resolution occurs ≤ 7 
days, everolimus should be re-started at one dose 
level lower. If resolution takes >7 days, discontinue 
everolimus. 
Discontinue everolimus. 
Is: 
AST or ALT elevation 
Grade 4 (>20x ULN)* 
Interrupt everolimus administration until resolution to 
≤ grade 1 (or ≤ grade 2 if baseline values were 
within the range of grade 2). If resolution occurs ≤ 7 
days, everolimus should be re-started at one dose 
level lower. If resolution takes >7 days, discontinue 
everolimus. 
 


PrECOG Protocol Number: PrE0102 
Confidential 
Date: 1/22/2014 
5 
5.3.1 Dose Modifications General Guidelines for Everolimus/Placebo 
Table 5-1 Non-Hematological Criteria for Dose-Modification in Case of Suspected Everolimus or Placebo 
Related Adverse Events and Re-Initiation of Everolimus or Placebo Treatment 
Was: 
Intolerable Grade 2 mucositis 
(see Section 5.3.2.6) 
OR 
Grade 3 AE, except 
hyperglycemia or  
hypertriglyceridemia or 
hypercholesterolemia 
(see Section 5.3.2.8) 
Interrupt everolimus administration until resolution to ≤ grade 1 or 
baseline grade/value. 
If resolution occurs within ≤ 7 days, everolimus should be re-started at 
the dose level prior to interruption. 
If resolution takes >7 days, or if event recurs within 28 days, hold 
everolimus until recovery to ≤ grade 1 or baseline grade/value and 
reintroduce everolimus at one dose level lower, if available. 
Patients will be withdrawn from the study if they fail to recover to ≤ 
grade 1 or baseline grade/value within 28 days. 
Is: 
Intolerable Grade 2 mucositis 
(see Section 5.3.2.5) 
Interrupt everolimus administration until resolution to ≤ grade 1 or 
baseline grade/value. 
If resolution occurs within ≤ 7 days, everolimus should be re-started at 
the dose level prior to interruption. 
If resolution takes >7 days, or if event recurs within 28 days, hold 
everolimus until recovery to ≤ grade 1 or baseline grade/ value and 
reintroduce everolimus at one dose level lower, if available. 
Patients will be withdrawn from the study if they fail to recover to ≤ 
grade 1 or baseline grade/value within 21 days. 
Grade 3 AE, except: 
hyperglycemia or 
hypertriglyceridemia or 
hypercholesterolemia 
(see Section 5.3.2.7) 
Interrupt everolimus administration until resolution to ≤ grade 1 
or baseline grade/value. 
Reintroduce everolimus at one dose level lower, if available. 
Patients will be withdrawn from the study if they fail to recover to 
≤ grade 1 or baseline grade/value within 21 days. 
 
5.3.1 Dose Modifications General Guidelines for Everolimus/Placebo 
Table 5-1 Non-Hematological Criteria for Dose-Modification in Case of Suspected Everolimus or Placebo 
Related Adverse Events and Re-Initiation of Everolimus or Placebo Treatment 
Was: 
Recurrence of intolerable Grade 2 
mucositis or Grade 3 event after dose 
reduction 
Reduce dose to the next lower dose level, if available. The 
lowest possible dose level of everolimus is 2.5 mg daily. 
Below this level, everolimus must be discontinued. 
Any non-hematologic toxicity requiring 
everolimus interruption for >28 days 
Discontinue everolimus. 
 


PrECOG Protocol Number: PrE0102 
Confidential 
Date: 1/22/2014 
6 
5.3.1 Dose Modifications General Guidelines for Everolimus/Placebo 
Table 5-1 Non-Hematological Criteria for Dose-Modification in Case of Suspected Everolimus or Placebo 
Related Adverse Events and Re-Initiation of Everolimus or Placebo Treatment 
Is: 
Recurrence of intolerable Grade 2 
mucositis or Grade 3 event after dose 
reduction 
Reduce dose to the next lower dose level, if available. The 
lowest possible dose level of everolimus is 5 mg every 
other day. Below this level, everolimus must be 
discontinued. 
Any non-hematologic toxicity requiring 
everolimus interruption for >21 days 
Discontinue everolimus. 
 
5.3.1 Dose Modifications General Guidelines for Everolimus/Placebo 
Table 5-2 Hematological Criteria for Dose-Modification in Case of Suspected Everolimus or Placebo 
Related Adverse Events and Re-Initiation of Everolimus or Placebo Treatment 
Was: 
Recurrence of Grade 3 toxicity after 
dose reduction 
Reduce dose to the next lower dose level, if available. The 
lowest possible dose level of everolimus is 5 mg every other 
day (2.5 mg daily). Below this level, everolimus must be 
discontinued. 
Any 
hematologic 
toxicity 
requiring 
everolimus interruption for >28 days 
Discontinue everolimus. 
Is: 
Recurrence of Grade 3 toxicity after 
dose reduction 
Reduce dose to the next lower dose level, if available. The 
lowest possible dose level of everolimus is 5 mg every other 
day. Below this level, everolimus must be discontinued. 
Any 
hematologic 
toxicity 
requiring 
everolimus interruption for >21 days 
Discontinue everolimus. 
 
Removed: 
5.3.2.1 Hepatic Impairment Dose Modifications 
• 
Mild hepatic impairment (Child-Pugh A) – the recommended dose is 7.5 mg daily. 
• 
Moderate hepatic impairment (Child-Pugh B) – the recommended dose is 2.5 mg daily. 
• 
Severe hepatic impairment (Child-Pugh C) – not recommended. If the desired benefit 
outweighs the risk, a dose of 2.5 mg daily must not be exceeded. 
• 
Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes 
during treatment. 
Everolimus is not recommended for patients with hepatic impairment who require doses 
below 2.5 every other day. 


PrECOG Protocol Number: PrE0102 
Confidential 
Date: 1/22/2014 
7 
5.3.2.2 Monitoring and Prophylactic Treatment for Hepatitis B Reactivation 
Table 5-4 Guidelines for Management for Hepatitis B 
Was: 
For patients with baseline 
results: 
Positive HBV-DNA 
OR 
Positive HBsAg 
-------------------------------------- 
Reactivation is defined as: 
Increase of 1 log in HBV-
DNA relative to baseline 
HBV-DNA value OR new 
appearance of measurable 
HBV-DNA 
Treat: Start a second antiviral 
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. 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. 
Is: 
For patients with baseline 
results: 
Positive HBV-DNA 
OR 
Positive HBsAg 
-------------------------------------- 
Reactivation is defined as: 
Increase of 1 log in HBV-
DNA relative to baseline 
HBV-DNA value OR new 
appearance of measurable 
HBV-DNA 
Treat: Start a second antiviral 
AND 
Interrupt study drug administration until resolution: 
≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 21 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 >21 days, patients should discontinue study drug 
but continue both antiviral therapies at least 4 weeks after last dose of 
study drug. 
 


PrECOG Protocol Number: PrE0102 
Confidential 
Date: 1/22/2014 
8 
5.3.2.2 Monitoring and Prophylactic Treatment for Hepatitis B Reactivation 
Table 5-4 Guidelines for Management for Hepatitis B 
Was: 
For patients with baseline results: 
Negative HBV-DNA and HBsAg 
AND 
Positive HBsAb (with no prior 
history of vaccination against 
HBV), OR positive HBcAb 
------------------------------------- 
Reactivation is defined as: 
New appearance of measurable 
HBV-DNA 
Treat: Start first antiviral medication 
AND 
Interrupt 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. 
Is: 
For patients with baseline results: 
Negative HBV-DNA and HBsAg 
AND 
Positive HBsAb (with no prior 
history of vaccination against 
HBV), OR positive HBcAb 
------------------------------------- 
Reactivation is defined as: 
New appearance of measurable 
HBV-DNA 
Treat: Start first antiviral medication 
AND 
Interrupt study drug administration until resolution: 
≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 21 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 >21 days, patients should discontinue study 
drug but continue antiviral therapy at least 4 weeks after last 
dose of study drug. 
 
5.3.2.5 Management of Stomatitis/Oral Mucositis/Mouth Ulcers 
Added: 
Suggested prophylactic treatment for prevention of stomatitis/mucositis is listed below: 
a) Use 15 mL baking soda/salt mouth rinse QID (swish and spit). Mix 1/3 teaspoon baking soda 
and 1/3 teaspoon of salt in 1 quart of water (refrigeration is not needed); do not eat or drink 
anything for 10 minutes after rinsing. 
b) Use 10 mL prescribed “miracle mouth wash’’ QID (swish and spit). For 16-ounce recipe: 320 mL 
Benadryl solution, 2 g tetracycline powder, 80 mg hydrocortisone, and 40 mL nystatin 
suspension, quantity sufficient with water. Wait 10-15 minutes after the baking soda/salt rinse 
before using “miracle mouthwash’’.55 


PrECOG Protocol Number: PrE0102 
Confidential 
Date: 1/22/2014 
9 
5.3.2.5 Management of Stomatitis/Oral Mucositis/Mouth Ulcers 
Was: 
1. For mild toxicity (Grade 1), use conservative measures such as non-alcoholic mouth wash or salt 
water (0.9%) mouth wash several times a day until resolution. 
2. For more severe toxicity (Grade 2 in which case patients have pain but are able to maintain adequate 
oral alimentation, or Grade 3 in which case patients cannot maintain adequate oral alimentation), the 
suggested treatments are topical analgesic mouth treatments (e.g., local anesthetics such as 
benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol) with or without topical 
corticosteroids, such as triamcinolone oral paste 0.1% (Kenalog in Orabase®). 
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen mouth ulcers. 
It is preferable to avoid these agents. 
Is: 
1. For mild toxicity (Grade 1), use conservative measures as noted above, baking soda/salt mouth 
rinse and “miracle mouth wash”. 
2. For more severe toxicity (Grade 2 in which case patients have pain but are able to maintain adequate 
oral alimentation, or Grade 3 in which case patients cannot maintain adequate oral alimentation), the 
suggested treatments are: 
In addition to baking soda/salt mouth rinse and “miracle mouth wash” above, topical analgesic 
mouth treatments (e.g., local anesthetics such as benzocaine, butyl aminobenzoate, tetracaine 
hydrochloride, menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral 
paste 0.1% (Kenalog in Orabase®) or Periogard® oral rinse. 
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen mouth ulcers. 
It is preferable to avoid these agents. Alcohol–containing rinses and tooth paste with sodium 
lauryl sulfate should also be avoided. Avoid acidic, spicy, hard, or crunchy foods, and 
consume foods that are tepid rather than hot. 55 
5.3.2.8 Management of Non-Infectious Pneumonitis 
Table 5-6 Management of Non-Infectious Pneumonitis 
Was: 
Worst Grade 
Pneumonitis 
Everolimus Dose Adjustment 
Grade 2 
Rule out infection and consider interruption of everolimus until symptoms improve to 
Grade ≤ 1. 
Re-initiate everolimus at one dose level lower.  
Discontinue everolimus if failure to recover within ≤ 28 days. 
Grade 3 
Rule out infection and interrupt everolimus until symptoms improve to Grade ≤ 1. 
Consider re-initiating everolimus at one dose level lower. 
Discontinue everolimus if failure to recover within ≤ 28 days. 
 


PrECOG Protocol Number: PrE0102 
Confidential 
Date: 1/22/2014 
10 
5.3.2.8 Management of Non-Infectious Pneumonitis 
Table 5-6 Management of Non-Infectious Pneumonitis 
Is: 
Worst Grade 
Pneumonitis 
Everolimus Dose Adjustment 
Grade 2 
Rule out infection and consider interruption of everolimus until symptoms improve to 
Grade ≤ 1. 
Re-initiate everolimus at one dose level lower.  
Discontinue everolimus if failure to recover within ≤ 21 days. 
Grade 3 
Rule out infection and interrupt everolimus until symptoms improve to Grade ≤ 1. 
Consider re-initiating everolimus at one dose level lower. 
Discontinue everolimus if failure to recover within ≤ 21 days. 
 
5.3.4 Prohibited Therapies and Restrictions 
Was: 
• 
No anticancer agents other than the study medication should be given to patients, with the following 
exceptions: 
o 
Bisphosphonates or Zometa for bone metastases 
o 
a GnRH analog is permitted if the patient had progressive disease on a GnRH analog plus a 
SERM or an AI; the GnRH analog may continue but the SERM or AI must be discontinued. 
Is: 
• 
No anticancer agents other than the study medication should be given to patients, with the following 
exceptions: 
o 
Bisphosphonates, Zometa or Xgeva for bone metastases 
o 
a GnRH analog is permitted if the patient had progressive disease on a GnRH analog plus a 
SERM or an AI; the GnRH analog may continue but the SERM or AI must be discontinued. 
5.3.4 Prohibited Therapies and Restrictions 
Added: 
• 
Concurrent radiation therapy is prohibited, however palliative radiotherapy may be considered 
on a case by case basis after discussion with the Study Chair. 
5.3.5.1 Inhibitors of CYPA34 and/or PgP 
Was: 
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or PgP inhibitors 
should be used with caution. If a patient requires co-administration of moderate CYP3A4 inhibitors or PgP 
inhibitors, reduce the dose of everolimus to 2.5 mg 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 after a washout period 
of 2-3 days. 


PrECOG Protocol Number: PrE0102 
Confidential 
Date: 1/22/2014 
11 
5.3.5.1 Inhibitors of CYPA34 and/or PgP 
Is: 
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or PgP inhibitors 
should be used with caution. If a patient requires co-administration of moderate CYP3A4 inhibitors or PgP 
inhibitors, reduce the dose of everolimus to 5 mg every other day. Additional dose reductions to every 
other day may be required to manage toxicities. If the inhibitor is discontinued, the everolimus dose should 
be returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor after a washout 
period of 2-3 days. 
5.3.5.2 Inducers of CYPA34 and/or PgP 
Was: 
Avoid the use of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, 
phenobarbital, St. John’s Wort). If a patient requires co-administration of strong CYP3A4 inducers, an 
increase in the dose of everolimus up to twice the currently used daily dose should be considered, 5 mg 
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. 
Is: 
Avoid the use of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, 
phenobarbital, St. John’s Wort). If a patient requires co-administration of strong CYP3A4 inducers, an 
increase in the dose of everolimus up to twice the currently used daily dose should be considered, 5 mg 
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. The choice to adjust the dose 
of everolimus in a patient requiring co-administration of strong CYP3A4 inducers will be done at 
the discretion of the treating investigator. 
7.0 Study Parameters- Study Table 
Was: 
Serum Creatinine, Electrolytes (K, Na, Cl, CO2), Ca, BUN, Bicarbonate, 
Albumin, Total Protein, Phosphorus, AST (SGOT), ALT (SGPT), Alkaline 
Phosphatase, Total Bilirubin, Magnesium, Uric Acid. 
Is: 
Serum Creatinine, Electrolytes (K, Na, Cl, CO2), Ca, BUN, Albumin, Total 
Protein, Phosphorus, AST (SGOT), ALT (SGPT), Alkaline Phosphatase, 
Total Bilirubin, Magnesium, Uric Acid. 
 
7.0 Study Parameters- Study Table 
Was: 
HBV DNA, HCV RNA-PCR 
Is: 
HBV DNA 
HCV RNA-PCR 
 


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7.0 Study Parameters- Footnotes 
Was: 
c: ≤ 72 hour window allowed prior to D1 of each subsequent cycle after the first cycle for scheduled 
therapy/tests/visits. Delay due to holidays, weekends, bad weather or other unforeseen circumstances will 
be permitted. 
e: ≤ 72 hours prior to Cycle 2 Day 1 then approximately every 12 weeks during treatment (and more 
frequently as clinically indicated), and at end of treatment. 
Is: 
c: +/- 72 hour window allowed prior to D1 of each subsequent cycle after the first cycle for scheduled 
therapy/tests/visits. Delay due to holidays, weekends, bad weather or other unforeseen circumstances will 
be permitted. 
e: +/- 72 hours prior to Cycle 2 Day 1 then approximately every 12 weeks during treatment (and more 
frequently as clinically indicated), and at end of treatment. 
7.0 Study Parameters- Footnotes 
Was: 
f: All patients should be screened for hepatitis risk factors and any past illnesses of hepatitis B and 
hepatitis C infection. It is highly recommended that patients positive HBV-DNA or HBsAg are treated 
prophylactically with an antiviral (e.g., Lamivudine) for 1-2 weeks prior to receiving study drug (see Table 
5-3). The antiviral treatment should continue throughout the entire study period and for at least 4 weeks 
after the last dose of everolimus. Patients with viral hepatitis C risk factors should be screened for 
HCV RNA-PCR. Patients on antiviral prophylaxis treatment or positive HBV antibodies should be 
tested for HBV-DNA ≤ 7 days prior to the start of C1D1 and ≤ 72 hrs prior to D1 of each subsequent 
cycle to monitor for reactivation. See Table 5-4 for reactivation instructions. Patients with positive 
HCV RNA-PCR results at screening and/or a history of past infection (even if treated and 
considered ‘cured’) should have HCV RNA-PCR testing performed on ≤ 7 days prior to the start of 
C1D1 and ≤ 72 hrs prior to D1 of each subsequent cycle to monitor for flare. Everolimus must be 
discontinued if HCV flare is confirmed according to the guidance in Table 5-5. 
Is: 
f: All patients should be screened for hepatitis risk factors and any past illnesses of hepatitis B and 
hepatitis C infection (see Section 7.1.1). All patients with a positive medical history per Section 7.1.1 
need hepatitis testing as noted on above table. It is highly recommended that patients positive for 
HBV-DNA or HBsAg or HBsAb are treated prophylactically with an antiviral (e.g., Lamivudine) for 1-2 
weeks prior to receiving study drug (see Table 5-3). The antiviral treatment should continue throughout the 
entire study period and for at least 4 weeks after the last dose of everolimus. 
g: Patients on antiviral prophylaxis treatment or positive HBV antibodies should be tested for HBV-
DNA ≤ 7 days prior to the start of C1D1 and +/- 72 hrs prior to D1 of each subsequent cycle to 
monitor for reactivation. See Table 5-4 for reactivation instructions. 
h: Patients with positive HCV RNA-PCR results at screening and/or a history of past infection 
(even if treated and considered ‘cured’) should have HCV RNA-PCR testing performed on ≤ 7 days 
prior to the start of C1D1 and +/- 72 hrs prior to D1 of each subsequent cycle to monitor for flare. 
Everolimus must be discontinued if HCV flare is confirmed according to the guidance in Table 5-5. 


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7.0 Study Parameters- Footnote 
Was: 
g: Tumor measurements may be made using physical examination, CT Scans or MRI. Tumor 
assessments will be performed every 12 weeks, +/- week (every 3 months) with first assessment within 
2 weeks prior to Cycle 4 treatment. Imaging will include chest and abdomen. Bone Scans and Brain 
CT/MRI may be performed as clinically indicated. Scans do not have to be repeated once disease 
progression is documented. 
Is: 
i: Tumor measurements may be made using physical examination, CT Scans or MRI. Tumor assessments 
will be performed every 12 weeks, +/- 1 week (every 3 months). Imaging will include chest and abdomen. 
Bone Scans and Brain CT/MRI may be performed as clinically indicated. Scans do not have to be 
repeated once disease progression is documented. 
7.0 Study Parameters- Footnote 
Was: 
* Day 1 of each cycle is defined as the day in which fulvestrant is given, including the first fulvestrant 
dose, third fulvestrant dose, and every dose thereafter (the second fulvestrant dose is given on day 15 
of the first cycle only). 
Is: 
* Cycle 1, Day 1 is defined as the first day on which fulvestrant is given in combination with 
placebo/everolimus (the second fulvestrant dose is given on day 15 of the first cycle only). Day 1 of each 
additional cycle is defined as the day in which fulvestrant is given in combination with 
everolimus/placebo. 
7.1.1 Pre-Study 
Was: 
• 
Serum Creatinine, Electrolytes (K, Na, Cl, CO2), Ca, BUN, Bicarbonate, Albumin, Total Protein, 
Phosphorus, AST (SGOT), ALT (SGPT), Alkaline Phosphatase, Total Bilirubin, Magnesium and Uric 
Acid 
Is: 
• 
Serum Creatinine, Electrolytes (K, Na, Cl, CO2), Ca, BUN, Albumin, Total Protein, Phosphorus, AST 
(SGOT), ALT (SGPT), Alkaline Phosphatase, Total Bilirubin, Magnesium and Uric Acid 
7.1.2 Induction Phase (fulvestrant + everolimus/placebo) 
Was: 
Day 1 of each cycle is defined as the day in which fulvestrant is given, including the first fulvestrant dose, 
third fulvestrant dose, and every dose thereafter (the second fulvestrant doses is given on day 15 of the 
first cycle only). 
Is: 
Day 1 of each cycle is defined as the day in which fulvestrant is given, including the first fulvestrant dose, 
third fulvestrant dose, and every dose thereafter (the second fulvestrant doses is given on day 15 of the 
first cycle only). Note: If patient previously received one cycle of fulvestrant (day 1 and day 15) prior 
to study entry as permitted in Inclusion Criteria #8, patient should receive fulvestrant 500 mg on 
day 1 only. 


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7.1.2.1 Within 7 Days of Cycle 1 Day 1 and 7.1.2.2 Cycle 1 Day 15 
Was: 
• 
Serum Creatinine, Electrolytes (K, Na, Cl, CO2), Ca, BUN, Bicarbonate, Albumin, Total Protein, 
Phosphorus, AST (SGOT), ALT (SGPT), Alkaline Phosphatase, Total Bilirubin, Magnesium and Uric 
Acid 
Is: 
• 
Serum Creatinine, Electrolytes (K, Na, Cl, CO2), Ca, BUN, Albumin, Total Protein, Phosphorus, AST 
(SGOT), ALT (SGPT), Alkaline Phosphatase, Total Bilirubin, Magnesium and Uric Acid 
Was: 
7.1.2.3 Within 72 Hours of Cycle 2 (and each subsequent cycle) Day 1 
• 
Serum Creatinine, Electrolytes (K, Na, Cl, CO2), Ca, BUN, Bicarbonate, Albumin, Total Protein, 
Phosphorus, AST (SGOT), ALT (SGPT), Alkaline Phosphatase, Total Bilirubin, Magnesium and Uric 
Acid 
• 
Fasting Glucose (≤ 72 hours of Cycle 2 Day 1, then every 12 weeks during treatment, and more 
frequently as clinically indicated) 
• 
Fasting Serum Lipid Profile (triglycerides, total cholesterol, HDL and LDL) (≤ 72 hours of Cycle 2 Day 
1, then every 12 weeks during treatment, and more frequently as clinically indicated) 
Is: 
7.1.2.3 Cycle 2 (and each subsequent cycle) Day 1 
• 
Serum Creatinine, Electrolytes (K, Na, Cl, CO2), Ca, BUN, Albumin, Total Protein, Phosphorus, AST 
(SGOT), ALT (SGPT), Alkaline Phosphatase, Total Bilirubin, Magnesium and Uric Acid 
• 
Fasting Glucose (Cycle 2 Day 1, then every 12 weeks during treatment, and more frequently as 
clinically indicated) 
• 
Fasting Serum Lipid Profile (triglycerides, total cholesterol, HDL and LDL) (Cycle 2 Day 1, then every 
12 weeks during treatment, and more frequently as clinically indicated) 
7.1.3 End of Induction Phase <OR> End of Treatment 
Was: 
• 
Serum Creatinine, Electrolytes (K, Na, Cl, CO2), Ca, BUN, Bicarbonate, Albumin, Total Protein, 
Phosphorus, AST (SGOT), ALT (SGPT), Alkaline Phosphatase, Total Bilirubin, Magnesium and Uric 
Acid 
Is: 
Serum Creatinine, Electrolytes (K, Na, Cl, CO2), Ca, BUN, Albumin, Total Protein, Phosphorus, AST 
(SGOT), ALT (SGPT), Alkaline Phosphatase, Total Bilirubin, Magnesium and Uric Acid 
8.1.2 Storage Requirements/Stability 
Was: 
Everolimus should not be stored at temperatures above 25°C. 
Is: 
Everolimus should be stored at room temperature between 20°C to 25°C (68°F to 77°F). 


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8.1.3 4 Special Instructions for Unblinding 
Was: 
If a participant is in a life-threatening situation in which knowledge of the treatment is crucial to care AND 
the Medical Monitor cannot be reached immediately, the investigator may unblind the participant 
without prior approval and must then immediately notify the Medical Monitor and submit a detailed 
report detailing the unblinding event. Report information will include but is not limited to: 
Is: 
If a participant is in a life-threatening situation in which knowledge of the treatment is crucial to care AND 
the Medical Monitor cannot be reached immediately, the PM should be contacted to facilitate the 
unblinding process. A report including the unblinding details will be generated after the patient 
has been unblinded and will be sent to the site for documentation (refer to Study Reference 
Manual for Unblinding Process). Report information will include but is not limited to: 
9.1 Primary Efficacy Endpoint 
Was: 
The primary efficacy endpoint is progression-free survival (PFS). PFS is defined as the time from 
randomization to documented disease progression or death. Based on results from the CONFIRM trial, 
median PFS among patients with AI-resistant disease on fulvestrant alone is 5.4 months. AI resistant 
disease is defined as: patients who have either relapsed while receiving adjuvant therapy with an 
aromatase inhibitor (anastrozole, letrozole, or exemestane) or have progressive disease while receiving 
an aromatase inhibitor for metastatic disease. (Patients previously treated with two or more prior doses of 
fulvestrant are not eligible. Patients who have received one prior dose of fulvestrant within 28 days of 
randomization are eligible so long as they meet other eligibility criteria). Randomization will be 1:1, 
stratified for balancing purposes using ECOG performance status (0 vs. 1), presence of measurable 
disease (yes vs. no), and prior chemotherapy (yes vs. no). 
Is: 
The primary efficacy endpoint is progression-free survival (PFS). PFS is defined as the time from 
randomization to documented disease progression or death. Based on results from the CONFIRM trial, 
median PFS among patients with AI-resistant disease on fulvestrant alone is 5.4 months. AI resistant 
disease is defined as: patients who have either relapsed while receiving adjuvant therapy with an 
aromatase inhibitor (anastrozole, letrozole, or exemestane) or have progressive disease while receiving 
an aromatase inhibitor for metastatic disease. (Patients previously treated with two or more prior cycles of 
fulvestrant are not eligible. Patients who have received one prior cycle (day 1 and day 15) of fulvestrant 
within 28 days of randomization are eligible so long as they meet other eligibility criteria). Randomization 
will be 1:1, stratified for balancing purposes using ECOG performance status (0 vs. 1), presence of 
measurable disease (yes vs. no), and prior chemotherapy (yes vs. no). 
9.1 Primary Efficacy Endpoint 
Removed: 
If median PFS among patients treated with fulvestrant alone is 20 weeks (4.6 months), there will be 
acceptable power (86%) to detect a hazard ratio of 0.62, corresponding to a median PFS of 7.4 
months if distributions are exponential. Full information of 104 events would be required for this 
analysis. 


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13.0 Appendix A: Eligibility Checklist 
Inclusion Criteria 
Was: 
Patients must have had relapse while receiving adjuvant therapy with an aromatase inhibitor 
(anastrozole, letrozole, or exemestane), OR progressive disease while receiving an aromatase inhibitor 
for metastatic disease. Patients previously treated with two or more prior doses of fulvestrant are not 
eligible. Patients who have received one prior dose of fulvestrant within 28 days of randomization are 
eligible as long as they meet other eligibility criteria. 
Is: 
Patients must have had relapse while receiving adjuvant therapy with an aromatase inhibitor 
(anastrozole, letrozole, or exemestane), OR progressive disease while receiving an aromatase inhibitor 
for metastatic disease. Note: Patients may have received an endocrine agent (e.g., Tamoxifen) 
between the time of progression on an AI and registration. 
Patients previously treated with two or more prior cycles of fulvestrant are not eligible. Patients who 
have received one prior cycle (dose on day 1 and day 15) of fulvestrant within 28 days of 
randomization are eligible as long as they meet other eligibility criteria. 
 
13.0 Appendix A: Eligibility Checklist 
Exclusion Criteria 
Was: 
Patients must not be receiving any concomitant anticancer treatment or have received anticancer 
treatment within 4 weeks of randomization (including chemotherapy, radiation therapy, antibody based 
therapy, e.g.), with the following exceptions: 
• 
Bisphosphonates or Zometa for bone metastases 
• 
a GnRH analog is permitted if the patient had progressive disease on a GnRH analog plus a 
SERM or an AI; the GnRH analog may continue but the SERM or AI must be discontinued. 
Is: 
Patients must not be receiving any concomitant anticancer treatment or have received anticancer 
treatment within 4 weeks of randomization (including chemotherapy, radiation therapy, antibody based 
therapy, e.g.), with the following exceptions: 
• Bisphosphonates, Zometa or Xgeva for bone metastases 
• Hormonal therapy (e.g., AI, Tamoxifen) 
• a GnRH analog is permitted if the patient had progressive disease on a GnRH analog plus a 
SERM or an AI; the GnRH analog may continue but the SERM or AI must be discontinued. 
 
Section 19. References 
Added: 
55. Divers J, RN BSN, Texas Oncology. Management of Stomatitis Associated with mTOR 
Inhibitors in Hormone Receptor-Positive HER2-Negative Advanced Breast Cancer: Clinical 
Experiences from a Single Center. Presented at the 38th Annual Oncology Nurses’ Society 
Congress, April 25-28, 2013. Novartis Internal Communication. 


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Section 20 Investigator’s Statement 
Was: 
Version 1.0 dated 12/19/2012 
Is: 
Version 2.0 dated 1/22/2014 
 


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Medical Monitor Contact Information 
Katherine M. Smith, MD 
PrECOG, LLC 
1000 Continental Drive 
Suite 200 
King of Prussia, PA 19406 
8:30 AM – 5 PM Eastern Time Zone  
Phone: 610-354-0404 
After 5 PM Eastern Time Zone  
Phone: 484-574-2367 
Email: ksmith@precogllc.org 
SAE Fax: 888-801-8795 
PrECOG Study Contact 
Carolyn Andrews, RN 
PrECOG, LLC 
1818 Market Street, Suite 1100 
Philadelphia, PA  19103 
9 AM – 5 PM Eastern Time Zone  
Phone: 215-789-7001 
Email: candrews@precogllc.org 
 


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BRIEF PROTOCOL SYNOPSIS 
(This section is provided as a brief summary and is not a substitution for referring to the 
full protocol details. See protocol document sections for complete details.) 
Schema 
 
 
 
 
 
 
 
 
 
This is a Phase II study. 25 sites will be activated. 130 patients will be enrolled. There will be a balanced 
1:1 randomization of everolimus:placebo (e.g., for every patient randomized to receive everolimus, one 
patient will be randomized to receive placebo). 
Patients will be treated for a maximum of 12 cycles with fulvestrant plus everolimus/placebo during the 
Induction Phase. Induction treatment continues until there is evidence of progressive disease or 
unacceptable toxicity for a maximum of 12 cycles (see Section 5.6). Patients with no evidence of 
progressive disease who remain on study after completing 12 cycles of the Induction Phase are 
unblinded and proceed to the Continuation Phase. Patients in the Continuation Phase should continue to 
receive fulvestrant alone (if originally randomized to placebo) or in combination with everolimus (if 
originally randomized to everolimus) until disease progression or unacceptable toxicity. Patients in both 
the Induction and Continuation Phases should have tumor measurements performed every 12 weeks 
(+/- 1 week). 
Patient Population 
• 
Patients must be postmenopausal and have stage IV disease or inoperable locally advanced 
disease. 
• 
Patients must have ER and/or PR-positive disease as determined by their local pathology or 
reference laboratory by ASCO-CAP criteria. Tumors must be HER-2/neu negative or 
equivocal by standard ICH/FISH or ICH/CISH methodologies by ASCO-CAP criteria. 
• 
Patients must be Aromatase Inhibitor (AI) resistant, defined as: 
o 
relapsed while receiving adjuvant therapy with an aromatase inhibitor (anastrozole, 
letrozole, or exemestane) or, 
o 
progressive disease while receiving an aromatase inhibitor for metastatic disease. 
Note: Patients may have received an endocrine agent (e.g., Tamoxifen) between the time of 
progression on an AI and registration. 
.
 
Stratify:  
 
PS (0 vs 1) 
 
Measurable 
Disease  
(yes or no) 
 
Prior Chemo 
vs No Prior 
Chemo 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
Arm A: Induction Phase 
fulvestrant 500 mg IM (two- 250 mg injections each 
dose) day 1 & 15 of cycle 1, then 500 mg IM (two- 250 
mg injections) day 1 of all subsequent cycles (every 28 
days for 12 cycles) plus 
everolimus 10 mg (two- 5 mg tablets) PO QD  
x 12 cycles 
Arm B: Induction Phase 
fulvestrant 500 mg IM (two- 250 mg injections each 
dose) day 1 & 15 of cycle 1, then 500 mg IM (two- 250 
mg injections) day 1 of all subsequent cycles (every 28 
days for 12 cycles) plus  
placebo 2 tablets PO QD  
x 12 cycles 
Continuation Phase: 
If no evidence of disease 
progression after 12 cycles, 
unblind 
and 
continue 
fulvestrant 500 mg IM day 1 of 
every cycle (every 28 days) 
alone (if originally randomized 
to placebo) or with everolimus 
(if originally randomized to 
everolimus) 
until 
disease 
progression or unacceptable 
toxicity. 


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Table of Contents 
1 
Introduction ...................................................................................... 23 
1.1 
Background and Rationale ...................................................................... 23 
1.2 
Breast Cancer ........................................................................................... 24 
1.3 
Endocrine Therapy for Breast Cancer .................................................... 24 
1.3.1 
Fulvestrant for Post Menopausal Women with Breast Cancer ...........................24 
1.3.2 
Fulvestrant for Aromatase Inhibitor (AI) Resistant Disease ...............................25 
1.3.3 
Rationale for Fulvestrant for this Trial ..................................................................26 
1.4 
Everolimus (RAD001) ............................................................................... 27 
1.4.1 
mTOR Pathway and Mechanism of Action ............................................................27 
1.4.2 
Pre-Clinical Safety ...................................................................................................30 
1.4.3 
Clinical Experience ..................................................................................................31 
1.5 
Rationale and Study Design .................................................................... 35 
2 
Objectives ........................................................................................ 37 
2.1 
Primary Objective ..................................................................................... 37 
2.2 
Secondary Objectives .............................................................................. 37 
3 
Selection of Patients ....................................................................... 38 
3.1 
Eligibility Criteria ...................................................................................... 38 
4 
Randomization Procedures ............................................................ 42 
4.1 
Ethics ........................................................................................................ 42 
4.2 
Regulatory Requirements ........................................................................ 42 
4.3 
Patient Randomization ............................................................................. 42 
5 
Treatment Plan ................................................................................. 44 
5.1 
Administration Schedule ......................................................................... 44 
5.2 
Dosing and Administration ...................................................................... 44 
5.2.1 
Fulvestrant (Arm A and Arm B) ..............................................................................44 
5.2.2 
Everolimus or Placebo (Arm A and Arm B) ..........................................................45 
5.3 
Dose Modifications and Toxicity Management ...................................... 46 
5.3.1 
Dose Modifications General Guidelines for Everolimus/ Placebo ......................46 
5.3.2 
Common Adverse Events Associated with Everolimus ......................................49 
5.3.3 
Concomitant Therapies ...........................................................................................56 
5.3.4 
Prohibited Therapies and Restrictions ..................................................................57 


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5.3.5 
Administration of Everolimus and CYP3A4 Inhibitors/ Inducers .......................58 
5.4 
Supportive Care........................................................................................ 59 
5.5 
Duration of Therapy ................................................................................. 59 
5.6 
Withdrawal of Patients from Study ......................................................... 60 
6 
Measurement of Effect .................................................................... 61 
6.1 
Antitumor Effect- Solid Tumors .............................................................. 61 
6.1.1 
Definitions ................................................................................................................61 
6.1.2 
Disease Parameters .................................................................................................61 
6.1.3 
Methods for Evaluation of Measurable Disease ...................................................62 
6.1.4 
Response Criteria ....................................................................................................64 
6.1.5 
Duration of Response .............................................................................................68 
6.1.6 
Progression-Free Survival ......................................................................................68 
7 
Study Parameters ............................................................................ 69 
7.1 
Procedures by Visit .................................................................................. 72 
7.1.1 
Pre-Study ..................................................................................................................72 
7.1.2 
Induction Phase (fulvestrant + everolimus/placebo) ...........................................73 
7.1.3 
End of Induction Phase <OR> End of Treatment .................................................76 
7.1.4 
Continuation Phase (fulvestrant +/- everolimus) ..................................................77 
7.1.5 
Follow-Up Off-Therapy ............................................................................................77 
8 
Drug Formulation and Procurement .............................................. 78 
8.1 
Everolimus ................................................................................................ 78 
8.1.1 
Packaging and Labeling ..........................................................................................78 
8.1.2 
Storage Requirements/Stability .............................................................................78 
8.1.3 
Handling, Dispensing and Administration ............................................................78 
8.1.4 
Side Effects ..............................................................................................................80 
8.1.5 
Investigational Product Records at Investigational Site(s) .................................80 
8.1.6 
Return and Destruction of Investigational Product .............................................81 
8.2 
Fulvestrant (Faslodex) ........................................................................... 81 
8.2.1 
Packaging and Labeling ..........................................................................................81 
8.2.2 
Handling and Dispensing ........................................................................................82 
8.2.3 
Side Effects ..............................................................................................................83 
9 
Statistical Considerations .............................................................. 84 
9.1 
Primary Efficacy Endpoint ....................................................................... 84 


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9.2 
Safety Analyses ........................................................................................ 84 
9.3 
Analyses of Other Secondary Endpoints ............................................... 85 
10 
Adverse Event Reporting ................................................................ 86 
10.1 
Collection of Safety Information ............................................................. 86 
10.2 
Handling of Serious Adverse Events (SAEs) ......................................... 87 
10.2.1 
SAE Definitions ........................................................................................................87 
10.2.2 
SAE Reporting Requirements ................................................................................87 
10.3 
Reporting of Second Primary Cancers ................................................... 88 
11 
Administrative .................................................................................. 89 
11.1 
Protocol Compliance ............................................................................... 89 
11.2 
Institutional Review Board ...................................................................... 89 
11.3 
Informed Consent Procedures ................................................................ 89 
11.4 
Safety Communication ............................................................................. 90 
11.5 
Monitoring ................................................................................................. 90 
11.6 
Study Records .......................................................................................... 91 
11.7 
Electronic Case Report Form (eCRF) Information ................................. 91 
11.8 
Records Retention ................................................................................... 91 
12 
Glossary of Terms and List of Abbreviations ............................... 93 
13 
Appendix A: Eligibility Checklist .................................................... 98 
14 
Appendix B: ECOG Performance Status Scale ........................... 103 
15 
Appendix C: Medications that can Inhibit/Induce CYP3A4 
and PgP .......................................................................................... 104 
16 
Appendix D: New York Heart Association (NYHA) Cardiac 
Classification of Functional Capacity and Objective 
Assessment ................................................................................... 106 
17 
Appendix E: CTEP Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0 .......................................... 107 
18 
Appendix F: Patient Pill Diary ....................................................... 108 
19 
References ..................................................................................... 110 
20 
Investigator’s Statement ............................................................... 115 
 


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1 
Introduction 
1.1 Background and Rationale 
Endocrine therapy represents the foundation of treatment for hormone-receptor 
positive metastatic and locally advanced breast cancer. Multiple compounds in 
varying classes exist, and those most widely used include the selective estrogen 
receptor modulators (SERMs), aromatase inhibitors (AIs), and the selective estrogen 
receptor down-regulators (SERDs). Although the utility of these drugs is well 
established, as many as 50% of women with hormone-receptor positive breast cancer 
will fail to respond to endocrine treatment (de novo resistance). Moreover, those who 
do respond will inevitably develop acquired resistance.1 Resistance to endocrine 
therapy remains a serious clinical challenge. 
Basic scientific research into the mechanisms surrounding endocrine therapy 
resistance has been particularly intense in recent years. Advances in this area of 
investigation are driving the development of novel treatments and therapeutic 
strategies. For example, various signal transduction pathways, when activated, have 
been demonstrated to allow breast cancer cells to escape the effect of endocrine 
therapy. The Protein Kinase B (Akt/PKB), a downstream target in the PI3 kinase 
signaling pathway appears to play a vital role in drug resistance.2 Several studies 
identify a close association between aberrant Akt signaling and tamoxifen resistance.3 
High levels of Akt activity confer resistance to the aromatase inhibitor letrozole and 
the selective estrogen receptor down-regulator fulvestrant.4 This Akt-induced 
resistance does not appear to be secondary to failure of these agents to inhibit the 
estrogen receptor α activity, but instead may lead to altered cell cycle and apoptotic 
response.5 Clinically, Akt/PKB activation in breast cancer appears to predict an 
inferior outcome among patients treated with endocrine therapy.6 
mTOR, mammalian target of rapamycin, is a cytoplasmic protein kinase that acts as a 
central regulator of many biological processes involved in cellular proliferation, 
angiogenesis and metabolism. mTOR is a key protein involved in control and 
regulation of the cell’s translational machinery through multiple mechanisms including 
by directly activating or inhibiting ribosomal activity.7 mTOR is a key intracellular point 
of convergence for a number of cellular signaling pathways, including Akt/PKB.8 
mTOR lies downstream to Akt/PKB, and targeted inhibition of this protein has 
emerged as an important therapeutic strategy in clinical oncology. Inhibition of mTOR 
activity has been shown to restore tamoxifen response in breast cancer cells with 
aberrant Akt activity.9 
Everolimus is an orally bioavailable inhibitor of the mTOR pathway. Combination 
treatment with everolimus and either letrozole or fulvestrant has been shown to 
reverse Akt-mediated endocrine therapy resistance and restore responsiveness to 
anti-estrogens in preclinical studies.5 These observations formed the rationale leading 
to the Phase I clinical trial evaluating the combination of everolimus and letrozole in 
women previously treated with letrozole ≥ 4 months without objective response (e.g., 
stable or progressive disease). Eighteen postmenopausal female patients with 
advanced HR+ breast cancer were treated with letrozole 2.5 mg/day and everolimus 
at 5 mg/day (cohort 1) or 10 mg/day (cohort 2).10 Overall the combination was well 
tolerated and toxicities were manageable and consistent with that expected for 


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24 
everolimus monotherapy. The results suggest antitumor activity for this combination 
without Pharmacokinetic (PK) interactions. 
This study will examine the efficacy and tolerability of the combination of fulvestrant 
and everolimus for the treatment of postmenopausal metastatic breast cancer 
resistant to an aromatase inhibitor. 
1.2 Breast Cancer 
Breast cancer is the most commonly diagnosed malignancy in women worldwide. In 
the United States, an estimated 230,480 new cases of invasive breast cancer were 
diagnosed in 2011, with 39,520 breast cancer deaths.11 Despite the recent advances 
in breast cancer therapy, 40-80% of women with node-positive disease and up to 
30% of women with node-negative disease at diagnosis will relapse. When distant 
metastases occur, the prognosis remains poor with a median survival of 18 to 36 
months from time of recurrence. Among the 60-70% of women with hormone-receptor 
positive breast cancer, 40-60% of them will benefit from endocrine therapy. Endocrine 
therapy has shown to yield similar survival rates in hormone-sensitive disease as 
compared to chemotherapy; although response rates are lower and responses 
develop more slowly. Endocrine therapy is considerably less toxic than 
chemotherapy, and is therefore the preferred treatment option for patients with 
hormone-receptor (HR)-positive disease.12,13 Chemotherapy is generally indicated in 
HR-negative disease, in cases unresponsive to endocrine therapy, or when extensive 
metastases require rapid tumor response.14 
1.3 Endocrine Therapy for Breast Cancer 
Several endocrine therapies are available for the treatment of metastatic breast 
cancer in postmenopausal women, including selective estrogen-receptor modulators 
(SERMs), aromatase inhibitors (AIs), progestins, androgens, and most recently the 
selective estrogen receptor downregulators (SERDs- e.g., fulvestrant). Tamoxifen 
was generally regarded as a standard option in HR-positive disease for adjuvant 
therapy, and for first-line therapy of metastatic disease in postmenopausal women. 
Within the past decade, however, the AIs (letrozole, anastrozole, exemestane) have 
supplanted tamoxifen as the preferred choice for adjuvant therapy and metastatic 
disease in postmenopausal women.15,16 There is therefore a need to develop more 
effective endocrine therapies for patients with AI-resistant disease, and to enhance 
the effectiveness of existing endocrine therapies that have demonstrated efficacy in 
AI-resistant disease. 
1.3.1 
Fulvestrant for Post Menopausal Women with Breast Cancer 
Fulvestrant (Faslodex®, AstraZeneca Pharmaceuticals LP, Wilmington, DE) has 
several unique characteristics. It is the first drug which acts as a pure estrogen 
receptor (ER) antagonist without known agonist effects. It competitively binds to the 
ERs with an approximately 100 times greater affinity than that of tamoxifen. 
Fulvestrant promotes the degradation of ERs and subsequently prevents ER-
mediated gene transcription. Two studies that led to the approval of fulvestrant were 
performed in postmenopausal women with HR-positive metastatic breast cancer who 
had progressive disease after tamoxifen therapy. These trials compared fulvestrant 


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(250 mg IM injection monthly) with anastrozole (1 mg PO daily) (Table 1-0).17,18 The 
primary endpoint for both studies was time to disease progression (TTP), which was 
similar between the two treatment arms (5.4 versus 3.4 months in the North American 
trial, and 5.5 versus 5.1 months in the European trial). Secondary endpoints were 
also comparable. The response rate for fulvestrant was 17-20% (versus 15.7-17.5% 
for anastrozole), Clinical Benefit Rate (CBR) was 42-45% (versus 36-45% for 
anastrozole), median duration of response was 15-19 months (versus 11-15 months 
for anastrozole), and median time to disease progression (TTP) was 5.5 months 
(versus 3.4-5.1 months for anastrozole). Further subgroups analyses confirm the 
clinical activity of fulvestrant in both visceral and non-visceral metastatic disease as 
compared with anastrozole.19 These trials led to the approval of Faslodex® 
(fulvestrant) Injection for “…the treatment of hormone-receptor positive metastatic 
breast cancer in postmenopausal women with disease progression following 
antiestrogen therapy”. 
Table 1-0 
Phase III Studies Comparing Fulvestrant and Anastrozole after Tamoxifen-
Failure in Postmenopausal Women with HR-Positive Metastatic Breast Cancer 
 
North American Trial18 
European Trial19 
Treatment Group: 
Fulvestrant 
Anastrozole 
Fulvestrant 
Anastrozole 
No. of Patients: 
206 
194 
222 
229 
Overall RR (%): 
17.5 
4.9 
12.6 
17.5 
3.6 
13.9 
20.7 
4.5 
16.2 
15.7 
1.7 
14.0 
    CR (%): 
    PR (%): 
Clinical Benefit Rate (%): 
42.2 
24.8 
36.1 
18.6 
44.6 
23.9 
45.0 
29.3 
    SD for more than 24 weeks (%): 
Median TTP (months): 
5.4 
3.4 
5.5 
5.1 
Median Duration of Response 
(months): 
19.0 
10.8 
15.0 
14.5 
Withdrawal Rate (%): 
2.5 
2.6 
3.2 
1.3 
Fulvestrant has also been compared with tamoxifen as first line therapy in a Phase III 
trial that included 587 postmenopausal women with HR-positive metastatic breast 
cancer, but proved to be no more effective than tamoxifen in this setting.20 When 
comparing fulvestrant with tamoxifen, the objective response rate (34% versus 32%) 
and clinical benefit rate (57% versus 62%) were similar. 
1.3.2 
Fulvestrant for Aromatase Inhibitor (AI) Resistant Disease 
Several trials have evaluated the role of fulvestrant in AI-resistant disease, as 
summarized in Table 1-1. 


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Table 1-1 
Phase II or III Trial of Fulvestrant in AI-Resistant Disease 
Reference 
Treatment 
No. 
RR 
CBR 
Median TTP 
Ingle, 200621 
Fulvestrant 
77 
14% 
25% 
3.0 mo.  
Perey, 200722 
Fulvestrant 
20 
5% 
37% 
3.5 mo. 
Chia, 200823 
Fulvestrant 
Exemestane 
270 
270 
7% 
7% 
23% 
19% 
3.7 mo. 
3.7 mo.  
The Clinical Benefit Rate (CBR) for patients with AI-resistant disease is approximately 
20-30%, and median TTP is approximately 3.5 months. In the EFECT trial reported by 
Chia et al, patients who had progressive disease after treatment with a non-steroidal 
AI (anastrozole, letrozole) were randomized to fulvestrant or the steroidal aromatase 
inhibitor exemestane. In contrast to most other trials that utilized a single 250 mg 
monthly dose based upon the original pharmacokinetic studies,23 patients in the 
EFECT trial received a 500 mg loading dose on day 1, then 250 mg on day 15 and 28 
(then every 4 weeks thereafter) based upon recent evidence that this dose/schedule 
may more rapidly achieve therapeutic blood levels. There was no significant 
difference in CBR between the two treatment arms. Nevertheless, the EFECT trial 
confirmed the effectiveness of fulvestrant previously reported in other smaller trials of 
fulvestrant in AI-resistant disease. 
Previous trials had demonstrated that a dose of 125 mg was less effective than the 
250 mg monthly dose.16,20 Based upon evidence that dosing schedules higher than 
the 250 mg monthly dose may produce greater clinical benefit, several trials 
evaluated alternative dosing schedules (similar to that used in the EFECT trial), 
including FINDER I (NCT00305448), FINDER II (NCT00313170), and CONFIRM 
(NCT00099437). 
1.3.3 
Rationale for Fulvestrant for this Trial 
Fulvestrant has demonstrated activity when used as first, second, or third line 
endocrine therapy, making it an attractive therapy for combination with other agents. 
In addition, it is commonly reserved for use following disease progression on AI 
therapy. The loading dose schedule employed in the EFECT trial will be used in this 
study taking advantage of the known dose-response effect observed for fulvestrant, 
the more rapid achievement of therapeutic blood levels, the extensive efficacy and 
safety experience with this schedule, and because it appears to be emerging as the 
preferred schedule for fulvestrant based upon the results of ongoing and recently 
completed clinical trials. 
The recently reported CONFIRM trial compared fulvestrant dosing of 250 mg every 
28 days (the previously FDA-approved dose) with 500 mg on days 1, 14, 28 and 
every 28 days thereafter (the current FDA-approved dose).24 The study demonstrated 
that the higher dose was more effective. Median time to progression (TTP) was 6.5 
months with the higher dose compared with 5.5 months with the lower dose (HR 0.8, 
p=0.006). The CBR was 45%, with the high dose as compared to 39.6% with the low 
dose arm (odds ratio 1.28, p=0.10). In the subgroup of patients who had 


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relapsed/progressed on an aromatase inhibitor (the population targeted in this study), 
median TTP was 5.4 months with the high-dose arm, and 4.1 months on the standard 
arm (with CBRs of 36% and 32% respectively). We will therefore use the high-dose 
regimen as utilized in the CONFIRM trial.24 
1.4 Everolimus (RAD001) 
Everolimus (RAD001) is a novel oral derivative of rapamycin that is an m-TOR 
inhibitor. 
Everolimus has been in clinical development since 1996 as an immunosuppressant in 
solid organ transplantation. Everolimus is approved in Europe and other global 
markets (trade name: Certican®) for cardiac and renal transplantation, and in the 
United States (trade name: Zortress®) for the prevention of organ rejection of kidney 
transplantation.  
Everolimus was developed in oncology as Afinitor® and was approved for advanced 
renal cell carcinoma (RCC) in 2009. In 2010, Afinitor® received United States (US) 
approval for patients with subependymal giant cell astrocytoma (SEGA) associated 
with tuberous sclerosis (TS). Everolimus is also available as Votubia® in the 
European Union (EU) for patients with SEGA associated with TS. Afinitor® was 
approved for “progressive pancreatic neuroendocrine tumor (PNET) in patients with 
unresectable, locally advanced, or metastatic disease” in 2011 in various countries, 
including the US and Europe. 
In 2012 Afinitor® received approval for the treatment of postmenopausal women with 
advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ 
BC) in combination with exemestane, after failure of treatment with letrozole or 
anastrozole. Furthermore in 2012, Afinitor® received approval for the treatment of 
patients with Tuberous Sclerosis Complex (TSC) who have renal angiomyolipoma not 
requiring immediate surgery. 
Everolimus is being investigated as an anticancer agent based on its potential to act: 
• 
Directly on the tumor cells by inhibiting tumor cell growth and proliferation. 
• 
Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via 
potent inhibition of tumor cell HIF-1 activity, VEGF production and VEGF-induced 
proliferation of endothelial cells). The role of angiogenesis in the maintenance of 
solid tumor growth is well established, and the mTOR pathway has been 
implicated in the regulation of tumor production of proangiogenic factors as well 
as modulation of VEGFR signaling in endothelial cells. 
At weekly and daily schedules and at various doses explored, everolimus is generally 
well tolerated. The most frequent adverse events (rash, mucositis, fatigue and 
headache) associated with everolimus therapy are manageable. Non-infectious 
pneumonitis has been reported with mTOR inhibitors but is commonly low-grade and 
reversible. 
1.4.1 
mTOR Pathway and Mechanism of Action 
At cellular and molecular levels, everolimus acts as a signal transduction inhibitor. 
Everolimus selectively inhibits mTOR (mammalian target of rapamycin), specifically 


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targeting the mTOR-raptor signal transduction complex. mTOR is a key and highly 
conserved serine-threonine kinase which is present in all cells and is a central 
regulator of protein synthesis and ultimately cell growth, cell proliferation, 
angiogenesis and cell survival. mTOR is the only currently known target of 
everolimus.25 
mTOR is downstream of PI3K/AKT pathway, a pathway known to be dysregulated in 
a wide spectrum of human cancers (e.g. through loss/mutation of the PTEN negative 
regulator; through PI3K mutation/amplification; through AKT/PKB overexpression/ 
overactivation; through modulation of TSC1/TSC2 tumor suppressors). In addition, 
activation of the PI3K/AKT/mTOR pathway is associated with worsening prognosis 
through increased aggressiveness, resistance to treatment and progression. 
The main known functions of mTOR include the following:7,25 
• 
mTOR functions as a sensor of mitogens, growth factors and energy, and nutrient 
levels, facilitating cell-cycle progression from G1 to S phase in appropriate growth 
conditions. 
• 
The PI3K-mTOR pathway itself is frequently activated in many human cancers, 
and oncogenic transformation may sensitize tumor cells to mTOR inhibitors. 
• 
Through inactivating eukaryotic initiation factor 4E binding proteins (4E-BP1) and 
activating the 40S ribosomal S6 kinases (e.g., p70S6K1), mTOR regulates protein 
translation, including the HIF-1 proteins. Inhibition of mTOR is expected to lead to 
decreased expression of HIF-1. 
• 
The activation of mTOR pathway is involved in the production of pro-angiogenic 
factors (i.e., VEGF) and inhibition of endothelial cell growth and proliferation. 
• 
The regulation of mTOR signaling is complex and involves positive regulators, 
such as AKT that phosphorylate and inactivate negative regulators such as the 
Tuberous Sclerosis Complex (TSC1/TSC2). 
mTOR is represented by two structurally and functionally distinct multiprotein 
signaling complexes, mTORC1 (mTOR complex 1, rapamycin sensitive) and 
mTORC2 (mTOR complex 2, rapamycin insensitive).26 
mTORC1 is mainly activated via the PI3 kinase pathway through AKT (also known as 
PKB, protein kinase B) and the tuberous sclerosis complex (TSC1/TSC2).7 Activated 
AKT phosphorylates TSC2, which leads to the dissociation of TSC1/TSC2 complex, 
thus inhibiting the ability of TSC2 to act as a GTPase activating protein. This allows 
Rheb, a small G-protein, to remain in a GTP bound state and to activate mTORC1. 
AKT can also activate mTORC1 by PRAS40 phosphorylation, thereby relieving the 
PRAS40-mediated inhibition of mTORC1.27,28 
mTORC2 (mTOR complex 2) is activated through a currently unknown mechanism, 
possibly by receptor tyrosine kinase (RTK) signaling.27 It has been suggested that 
mTORC2 phosphorylates and activates a different pool of AKT that is not upstream of 
mTORC1. PHLPP phosphatase plays a role of a negative regulator. mTORC2 is 
rapamycin insensitive and is required for the organization of the actin cytoskeleton.26 
mTORC1-mediated signaling is subject to modulation by the macrocyclic lactone 
rapamycin and its derivatives, such as everolimus. Once these agents bind to the 12 
kDa cytosolic FK506-binding protein immunophilin FKBP12, the resulting rapamycin-
FKBP12 complexes bind to a specific site near the catalytic domain of mTORC1 and 


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inhibit phosphorylation of mTOR substrates. As a consequence, downstream 
signaling events involved in regulation of the G1 to S-phase transition are inhibited. 
This mechanism is thought to be responsible for the immunosuppressive effects of 
rapamycin as well as its putative antineoplastic activity.29 As many cancers are 
characterized by dysregulation of G1 transit (for example, overexpression of cyclin or 
cyclin-dependent kinases), inhibition of mTOR becomes an intriguing target for 
inducing cytostasis.7 
1.4.1.1 
Preclinical Studies 
Everolimus acts as an inhibitor of cytokine and growth-factor-dependent proliferation 
of cells. The only currently known target of everolimus is mTOR, a key regulatory 
protein affecting cell growth.25 Everolimus exerts its activity through high affinity 
interaction with an intracellular receptor protein, the immunophilin FKBP12. The 
FKBP12/everolimus complex subsequently interacts with the mTOR protein kinase, 
inhibiting downstream signaling events involved in regulation of the G1 to S-phase 
transition. 
The main known functions of mTOR include: 
• 
Function as a sensor of mitogens, growth factors, energy and nutrient levels, 
facilitating cell-cycle progression from G1 - S phase in appropriate growth 
conditions. 
• 
Regulation of protein synthesis important for tumor cell proliferation and 
angiogenesis through inactivating eukaryotic initiation factor 4E binding proteins 
and activating the 40S ribosomal S6 kinases (e.g. p70S6K1). For example, 
activation of the mTOR pathway leads to a) increased production of pro-
angiogenic factors (e.g. VEGF) in tumors b) tumor, endothelial and smooth 
muscle cell growth and proliferation. 
The PI3K-mTOR pathway itself is frequently activated in many human cancers, and 
oncogenic transformation may sensitize tumor cells to mTOR inhibitors. The 
regulation of mTOR signaling is complex and involves positive regulators such as 
AKT that phosphorylate and inactivate negative regulators such as the Tuberous 
Sclerosis Complex (TSC1/TSC2). In summary, mTOR has pleiotropic functions; 
hence, the activities of everolimus may vary depending upon cell type. 
The mTOR inhibitory activities presumably contribute to the anti-proliferative activity 
of everolimus against tumor cell lines. However, everolimus may also exert an 
antitumor effect through the inhibition of angiogenesis. Indeed, both rapamycin and 
everolimus potently inhibit proliferation of endothelial cells and have antiangiogenic 
activity in vivo.30,31 Exactly which molecular determinants predict responsiveness of 
tumor cells to everolimus is still unclear. Currently, the activation status of the 
PI3K/AKT/mTOR/p70 S6K pathway may be indicative of responsiveness to 
rapamycins. For example, pre-clinically, loss of PTEN or constitutive/hyper-activation 
of AKT has been suggested to sensitize tumors to the effects of inhibition of 
mTOR.25,31 Also, clinically, it has been suggested that high p70S6K activation in 
baseline Glioblastoma Multiforme (GBM) tumor samples may predict a patient 
population more likely to derive benefit from mTOR inhibition.32 


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Everolimus is a highly specific inhibitor of mTOR, which is afforded by high-affinity 
binding to the protein FKBP-12 (IC50 of 5.3 nM) similar to that of rapamycin. Similar 
potency of rapamycin and everolimus was also demonstrated at forming the mTOR/ 
FKBP-12 tertiary complex in vitro. Specificity was demonstrated by a lack of inhibitory 
activity against 10 other protein kinases at concentrations up to 10 μM. 
The anti-proliferative effects of everolimus were investigated in a mixed panel of 48 
different tumor cell lines (including breast, colon, epidermoid, glioblastoma, lung, 
melanoma, prostate and renal). The majority of tumor cell lines were highly sensitive 
to the anti-proliferative effects of everolimus while a few others appeared intrinsically 
insensitive, or ‘resistant’ (IC50 range 0.2 to 4125 nM).33 The median IC50 value of the 
48 cell lines was 0.5 nM. Similar findings have been observed for rapamycin.34 
Everolimus was also shown to have activity in human pancreatic neuroendocrine 
cells, where induction of apoptosis was reported,35 as well as in acute myeloid 
leukemia cells,36 mantle cell lymphoma cells37, adult T-cell leukemia cells38, diffuse 
large B cell lymphoma cells,39 pancreatic tumor cells,40 ovarian cancer cells,31,41 and 
hepatocellular carcinoma cells.42 
Everolimus was also evaluated in a clonogenic assay using cells derived from 81 
patient derived tumor xenografts never cultured in vitro (11 human tumor types with 3 
to 24 tumors each: bladder, colon, gastric, Non-Small Cell Lung Cancer (NSCLC), 
Small Cell Lung Cancer (SCLC), breast, ovary, pancreatic, renal, melanoma, and 
pleuramesothelioma). Everolimus inhibited colony formation in a concentration-
dependent manner (mean IC50: 175 nM). In addition, normal hematopoetic stem cells 
were found to be relatively insensitive to everolimus, with an IC50 about 15 fold higher 
than the tumor lines. 
Everolimus was effective and well tolerated against subcutaneous (s.c.) tumors 
established from a variety of tumor cell lines of diverse histotypes (NSCLC, 
pancreatic, colon, melanoma, epidermoid), including a PgP170-overexpressing, multi-
drug resistant tumor line. Typically, the antitumor activity of everolimus was that of 
reduction of tumor growth rates rather than producing regressions or stable disease 
although, in the case of A549 and NCI-H596 lung and ARJ42 pancreatic tumors, 
regressions could be obtained. These effects occurred within the dose range of 2.5 to 
10 mg/kg, P.O., once per day. The change in tumor volume of the treated mice 
divided by the change in tumor volume of control mice (T/C) typically ranged from 
approximately 15 to 50% at optimal doses. A marked loss of antitumor activity 
occurred when tumor-bearing mice were treated with everolimus once per week, but 
improved moderately with twice per week dosing. Antitumor activity of everolimus has 
also been demonstrated in mouse models of ovarian,31 breast,43,44 and 
gastrointestinal stromal tumors.45 
1.4.2 
Pre-Clinical Safety 
In safety pharmacology studies, everolimus was devoid of relevant effects on vital 
organ functions including the cardiovascular, respiratory and nervous systems. 
Everolimus had no effects on QT interval. Furthermore, everolimus showed no 
antigenic potential. Although everolimus passes the blood-brain barrier, there was no 
indication of relevant changes in the behavior of rodents, even after single oral doses 
up to 2000 mg/kg or after repeated administration at up to 40 mg/kg/day. 


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The preclinical safety profile of everolimus was assessed in mice, rats, minipigs, 
monkeys, and rabbits. The major target organs were male and female reproductive 
systems (testicular tubular degeneration, reduced sperm content in epididymides and 
uterine atrophy) in several species; lungs (increased alveolar macrophages) in rats 
and mice; and eyes (lenticular anterior suture line opacities) in rats only. Minor kidney 
changes were seen in the rat (exacerbation of age-related lipofuscin in tubular 
epithelium, increases in hydronephrosis) and mouse (exacerbation of background 
lesions). There was no indication of kidney toxicity in monkeys or minipigs. 
Genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of 
clastogenic or mutagenic activity. Administration of everolimus for up to 2 years did 
not indicate any oncogenic potential in mice and rats up to the highest doses, 
corresponding respectively to 4.2 and 0.2 times the estimated clinical exposure. In 
reproduction studies, everolimus was toxic to the conceptus in rats and rabbits, and 
was considered potentially teratogenic in rats. It is therefore recommended that 
women of childbearing potential should use effective contraceptive measures during 
the entire treatment period and for 8 weeks thereafter. 
More pre-clinical information is provided in the Investigator’s Brochure. 
1.4.3 
Clinical Experience 
1.4.3.1 
Everolimus Pharmacokinetics 
Everolimus is rapidly absorbed with a median tmax of 1-2 hours. The steady-state 
AUC0-τ is dose-proportional over the dose range between 5 to 70 mg in the weekly 
regimen and 5 and 10 mg in the daily regimen. Steady-state was achieved within two 
weeks with the daily dosing regimen. Cmax is dose-proportional between 5 and 10 mg 
for both the weekly and daily regimens. At doses of 20 mg/week and higher, the 
increase in Cmax is less than dose proportional. In healthy subjects, high fat meals 
reduced systemic exposure to everolimus 10 mg (as measured by Area Under the 
Concentration Time-Curve (AUC)) by 22% and the peak plasma concentration Cmax 
by 54%. Light fat meals reduced AUC by 32% and Cmax by 42%. Food, however, had 
no apparent effect on the post absorption phase concentration-time profile. 
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the 
range of 5 to 5,000 ng/mL, is 17% to 73%. The amount of everolimus confined to the 
plasma is approximately 20% at blood concentrations observed in cancer patients 
given everolimus 10 mg/day. Plasma protein binding is approximately 74% both in 
healthy subjects and in patients with moderate hepatic impairment. 
Everolimus is a substrate of CYP3A4 and a substrate and moderate inhibitor of PgP. 
Following oral administration, everolimus is the main circulating component in human 
blood and is considered to contribute the majority of the overall pharmacologic 
activity. No specific excretion studies have been undertaken in cancer patients; 
however, data available from the transplantation setting found the drug to be mainly 
eliminated through the feces. There was a significant correlation between AUC0-τ and 
pre-dose trough concentration at steady-state on the daily regimen. The mean 
elimination half-life of everolimus is approximately 30 hours. 
Appendix C lists examples of clinically relevant CYP3A4 inhibitors and inducers. 


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Please refer to Section 5.3.5 for more information on the concomitant use of CYP3A4 
inhibitors/inducers and other medications. 
More information on everolimus pharmacokinetics is provided in the Investigator’s 
Brochure. 
1.4.3.2 
Everolimus Pharmacodynamic Studies 
Pharmacokinetic/pharmacodynamic modeling based on inhibition of the biomarker 
p70S6 kinase 1 [S6K1] in peripheral blood mononuclear cells [PBMC]) suggests that 
5-10 mg daily should be an adequate dose to produce a high-degree of sustained 
target inhibition ([Study C2101]/[Study 2102]).46 Molecular changes in tumor were 
evaluated through serial biopsy before and during treatment. Biopsy on treatment 
took place in week 4 (pharmacokinetic steady-state). All patients underwent a 24-
hour post-dose biopsy. Patients following the weekly regimen had a further biopsy on 
Day 4 or 5 of the same week. Molecular activity was measured by 
immunohistochemistry. In the absence of a reliable technique for measuring mTOR 
phosphorylation, the phosphorylation status of downstream markers S6 and eIF4G, 
for which reliable antibodies exist, was selected as reflecting the immediate 
pharmacodynamic effect of everolimus. Also measured were changes in the 
phosphorylation status of upstream AKT and the proliferation index Ki67. Fifty-five 
patients were treated and the results revealed a dose and schedule dependent 
inhibition of the mTOR pathway with a near complete inhibition of pS6 and pelF-4G at 
the 10 mg/day and 50 mg/wk schedules. In addition, pAKT was upregulated in 50% of 
the treated tumors. In the daily schedule, there was a correlation between everolimus 
plasma trough concentrations and inhibition of peIF4G and p4E-BP1. There was 
good concordance of mTOR pathway inhibition between skin and tumor. [Study 
C2107].47 
More information on everolimus pharmacodynamics is provided in the Investigator’s 
Brochure (IB). 
1.4.3.3 
Clinical Experience with Everolimus 
Everolimus has been in clinical development since 1996 as an immunosuppressant in 
solid organ transplantation and was approved in Europe in 2003 under the trade 
name Certican®, for the prevention of organ rejection in patients with renal and 
cardiac transplantation. It is also approved in the United States (trade name: 
Zortress®) for the prevention of organ rejection of kidney transplantation. Additional 
non-oncologic indications currently being explored are wet age-related macular 
degeneration (AMD) and autosomal dominant polycystic kidney disease (ADPKD). 
Clinical experience of everolimus in the transplant indication is summarized in a 
separate Investigator’s Brochure. 
In oncology, everolimus has been in clinical development since 2002 for patients with 
various hematologic and non-hematologic malignancies as a single agent or in 
combination with antitumor agents. Please note that safety pharmacology and 
toxicology studies as well as some human pharmacology studies which have been 
conducted in support of the transplant indication, are described in the oncology IB 
due to the relevance of these data for the oncology indication. Malignancies that are 
currently being evaluated in Novartis sponsored studies include the following: 


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metastatic renal cell carcinoma (mRCC), breast cancer, gastroenteropancreatic 
neuroendocrine tumors (GEP-NET), mantle cell lymphoma and diffuse large B cell 
lymphoma (DLBCL), hepatocellular cancer (HCC), gastric cancer, and lung cancer. In 
addition, treatment of patients with Tuberous Sclerosis Complex (TSC) associated 
subependymal giant cell astrocytoma (SEGA) and Angiomyolypoma is also being 
evaluated. Colorectal cancer (CRC) is no longer being evaluated. 
Everolimus 2.5 mg, 5 mg and 10 mg tablets were approved under the trade name 
Afinitor® for patients with advanced renal cell carcinoma in the US, EU and several 
other countries and is undergoing registration in other regions worldwide. Recent 
approval was granted in the US for the treatment of patients with subependymal giant 
cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) who require 
therapeutic intervention but are not candidates for curative surgical resection. 
Phase I dose escalating studies, exploratory Phase I/II studies with everolimus as 
single agent or in combination with other anti-cancer agents, Phase II/III studies of 
everolimus in indications, and Phase III double-blind studies are contributing to the 
extensive database. 
Approximately 18,730 cancer patients have been treated with everolimus as of 30-
Sep-2011: 
• 
9,528 patients in Novartis-sponsored clinical trials 
• 
2,559 patients in the individual patient supply program 
• 
6,638 in investigator-sponsored studies. 
• 
In addition, healthy volunteer subjects have participated in the clinical 
pharmacology studies as described in Section 1.4.3.1. 
As of 30-Sep-2011, there are a total of 11 Phase III trials ongoing in the indications 
mRCC (1), advanced NET (2), breast cancer (3), TSC (2), DLBCL (1), gastric cancer 
(1) and HCC (1). 
Recent approvals of everolimus (Afinitor®) were based upon a Phase III, international, 
multicenter randomized, double-blind, placebo-controlled study [C2240] in patients 
with metastatic renal cell carcinoma (mRCC) whose disease had progressed despite 
prior treatment with VEGFR-TKI (vascular endothelial growth factor receptor tyrosine 
kinase inhibitor) therapy. Progression-free survival (PFS) assessed via a blinded, 
independent central review, was the primary endpoint. Secondary endpoints included 
safety and objective tumor response. 
In the pivotal, Phase III study [C2240], which included patients with advanced renal 
cell carcinoma, the most common adverse reactions (incidence ≥ 10%) were 
stomatitis, rash, fatigue, asthenia, diarrhea, anorexia, nausea, mucosal inflammation, 
vomiting, pneumonitis, cough, peripheral edema, infections, dry skin, epistaxis, 
pruritus, and dyspnea. The most common grade 3-4 adverse reactions (incidence ≥ 
2%) were infections, stomatitis, fatigue, and pneumonitis. Non-infectious pneumonitis 
is a class effect of rapamycin derivatives, including everolimus and some of these 
cases have been severe and on rare occasions, fatal outcomes have been observed. 
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 


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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. 
The most common laboratory abnormalities (incidence ≥ 50%) were anemia, 
hypercholesterolemia, 
hypertriglyceridemia, 
hyperglycemia, 
lymphopenia, 
and 
increased creatinine. The most common grade 3/4 laboratory abnormalities 
(incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and 
hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection 
(0.7%), and acute renal failure (0.4%) were observed on the everolimus arm. The 
rates of treatment-emergent adverse reactions resulting in permanent discontinuation 
were 7% and 0% for the everolimus and placebo treatment groups, respectively. 
Safety data from study [C2240] are described in detail in Section 1.4.3.3. 
Overall, safety data available from completed, controlled and uncontrolled studies are 
consistent with the aforementioned findings of the Phase III trial. Everolimus is 
generally well tolerated at weekly and daily dose schedules. The safety profile is 
characterized by manageable adverse events (AEs). These AEs are generally 
reversible and non-cumulative. 
Further detailed information regarding everolimus clinical development, safety and 
efficacy is provided in the Investigator’s Brochure. 
1.4.3.4 
Clinical Experience with Everolimus in Metastatic Breast Cancer 
Resistant to Non-Steroidal Aromatase Inhibitors 
Based on data indicating that resistance to endocrine therapy in breast cancer is 
associated with activation of the mammalian target of rapamycin (mTOR) intracellular 
signaling pathway, a Phase 3, randomized trial (BOLERO2) compared the steroidal 
aromatase inhibitor exemestane (25 mg PO daily) plus either everolimus (10 mg PO 
daily) or a placebo (randomly assigned in a 2:1 ratio) in 724 patients with HR-positive 
advanced breast cancer who had recurrence or progression while receiving previous 
therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat 
advanced disease (or both). The primary end point was progression-free survival. 
Secondary end points included survival, response rate, and safety. A preplanned 
interim analysis was performed by an independent data and safety monitoring 
committee after 359 progression-free survival events were observed. Baseline 
characteristics were well balanced between the two study groups. The median age 
was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive 
disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), 
fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse 
events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the 
placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), 
hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At 
the interim analysis, median progression-free survival was 6.9 months with 
everolimus plus exemestane and 2.8 months with placebo plus exemestane, 
according to assessments by local investigators (hazard ratio for progression or 
death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). Median 
progression-free survival was 10.6 months and 4.1 months, respectively, according to 
central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001). The study 
met its pre-specified endpoint, which led to FDA approval of everolimus in 


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combination with exemestane for this indication in the U.S. on July 20, 2012.48  
Overall survival results were immature at the time of the interim analysis, with a total 
of 83 deaths: 10.7% of patients in the combination-therapy group and 13.0% of those 
in the exemestane-alone group died. Patients and investigators continue to be 
unaware of study assignments and will remain so until survival results are mature for 
analysis.49  
1.5 Rationale and Study Design 
We hypothesize more complete blockade of the ER-signaling pathway may be 
achieved with selective estrogen receptor downregulator fulvestrant (given at a high 
dose) than may be achieved with the steroidal AI exemestane, and that this will result 
in either comparable or greater effectiveness for the fulvestrant-everolimus 
combination than the exemestane-everolimus combination. This is supported by 
preclinical data demonstrating that fulvestrant is particularly effective when combined 
with agents targeting the PI3K-AKT-m-TOR pathway in tumors that have undergone 
long-term estrogen deprivation, as is the case for patients who have acquired 
resistance to AI therapy.50 
We therefore propose to study the efficacy of fulvestrant in combination with 
everolimus for the treatment of post-menopausal HR-positive metastatic breast 
cancer in women who have progressed after treatment with an aromatase inhibitor. 
The combination of a novel class of agents (mTOR inhibitors) and an established 
standard treatment for metastatic HR-positive breast cancer may potentially increase 
the clinical benefit by targeting multiple different biological pathways. 
This is a randomized, double-blind, placebo controlled Phase II study. It is expected 
that 130 patients will be accrued at 25 centers within the US. Patients will be 
randomized (1:1) to receive everolimus or placebo after consideration of stratification 
factors of performance status (0 vs.1), measurable disease (with or without non-
measurable) vs. non-measurable disease, and prior chemotherapy for metastatic 
disease vs. no prior chemotherapy. 
Induction Phase: 
Treatment during the Induction Phase includes: 
Fulvestrant 500 mg IM (two-250 mg injections per dose) on day 1 & 15 of Cycle 1, 
then 500 mg IM (two-250 mg injections) on day 1 of all subsequent cycles (every 28 
days) plus everolimus 10 mg (two- 5 mg tablets) PO daily 
OR 
Fulvestrant 500 mg IM (two-250 mg injections per dose) on day 1 & 15 of Cycle 1, 
then 500 mg IM (two-250 mg injections) on day 1 of all subsequent cycles (every 28 
days) plus placebo two tablets PO daily 
Patients will be evaluated for disease response every 12 weeks (every 3 treatment 
cycles), +/- 1 week, and treated until disease progression, unacceptable toxicity or for 
a total of up to 12 cycles. 
 
 


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Continuation Phase: 
Patients with no evidence of progressive disease who remain on study after 
completing Cycle 12 will be unblinded and proceed to the Continuation Phase. 
Patients in the Continuation Phase should continue to receive fulvestrant alone (if 
originally randomized to placebo) or in combination with everolimus (if originally 
randomized to everolimus) at the same dose and schedule. Patients will continue to 
be evaluated for disease response every 12 weeks (every 3 treatment cycles), +/- 1 
week, and may continue treatment until disease progression or unacceptable toxicity. 
All patients will be followed for 30 days for toxicity after the last dose of study therapy 
(fulvestrant and/or everolimus/placebo) or until recovery from all toxicity (to ≤ grade 1) 
attributed to study therapy, whichever is longer (or if >grade 1, event must be 
permanent and stable). 


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2 
Objectives 
2.1 Primary Objective 
To assess progression-free survival in post-menopausal patients with hormone-
receptor positive metastatic breast cancer that is resistant to aromatase inhibitor 
therapy treated with fulvestrant and everolimus compared to fulvestrant alone. 
2.2 Secondary Objectives 
To describe the safety profile, objective response rate, time to progression and 
overall survival in this patient population. 


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3 
Selection of Patients 
3.1 Eligibility Criteria 
Each of the criteria in the following section must be met in order for a patient to be 
considered eligible for this study. 
PrECOG will not grant any exceptions or waivers to protocol eligibility criteria.  
In calculating pre-treatment days of tests and measurements, the day a test or 
measurement is done is considered Day 0. Therefore, if a test is done on a 
Monday, the Monday four weeks later would be considered Day 28. 
Note:  All questions regarding eligibility should be directed to the PrECOG Study 
Contact in study materials. Questions will be further discussed with the medical leads 
for the trial as deemed appropriate (e.g., medical monitor, study chair). 
Investigator sites may use the eligibility checklist (see Appendix A: Eligibility 
Checklist) which will be provided as a separate study document, as documentation 
that eligibility criteria were verified. If used, it should be reviewed, signed, and dated 
prior to patient randomization by the treating physician, and all required elements of 
source documentation must be found in the patient record (e.g. scans, consent, 
pathology). 
Inclusion Criteria: 
1. Must be willing to sign a protocol-specific informed consent. 
2. Patients must be 18 years of age or older. 
3. Patients must have an ECOG Performance Status 0 or 1 (see Appendix B: 
ECOG Performance Status Scale). 
4. Patients must have histologically or cytologically confirmed adenocarcinoma 
of the breast. 
5. Patients must have stage IV disease or inoperable locally advanced disease. 
6. Patients must have ER and/or PR-positive disease as determined by their 
local pathology or reference laboratory by ASCO-CAP criteria.51 Tumors must 
be HER-2/neu negative or equivocal by standard ICH/FISH or ICH/CISH 
methodologies by ASCO-CAP criteria.52 
7. Patients must be Aromatase Inhibitor (AI) resistant, defined as: 
• 
relapsed while receiving adjuvant therapy with an aromatase inhibitor 
(anastrozole, letrozole, or exemestane) or, 
• 
progressive disease while receiving an aromatase inhibitor for metastatic 
disease. 
Note: Patients may have received an endocrine agent (e.g., Tamoxifen) 
between the time of progression on an AI and registration. 
 


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8. Patients who have received one prior cycle (dose on day 1 and day 15) of 
fulvestrant within 28 days of randomization are eligible so long as they meet 
other eligibility criteria. 
• 
patients previously treated with two or more prior cycles of fulvestrant are 
not eligible. 
9. Patients must be female and postmenopausal, defined as: 
• 
a history of at least 12 months without spontaneous menstrual bleeding or, 
• 
prior bilateral salpingo-oophorectomy, with or without hysterectomy or, 
• 
age ≥ 55 years with a prior hysterectomy with or without oophorectomy or,  
• 
age <55 years with a prior hysterectomy without oophorectomy or 
unknown status, with a documented FSH level in postmenopausal range 
within 4 weeks of randomization or,  
• 
receiving a gonadotropin releasing hormone analog (GnRH) to suppress 
ovarian function (e.g., goserelin 3.6 mg q 4 weeks). 
10. Patients may have received up to one prior systemic chemotherapy regimen 
for metastatic disease. 
11. Adequate organ function, as evidenced by ALL the following obtained within 4 
weeks of randomization*: 
• 
total white blood cell count (leukocytes, WBC) ≥ 3.0 x 109/L, absolute 
neutrophil count (ANC) ≥ 1.5 x 109/L and platelet count ≥ 100 x 109/L 
• 
hemoglobin ≥ 9 g/dL 
• 
serum bilirubin ≤ 1.5 x ULN  
• 
AST or ALT ≤ 2.5 x ULN (≤ 5 x ULN in patients with liver metastases) 
• 
serum creatinine ≤ 1.5 x ULN 
• 
serum albumin ≥ 3 g/dL 
• 
fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting 
triglycerides ≤ 2.5 x ULN. Note: In case one or both of these thresholds 
are exceeded, the patient can only be included after initiation of 
appropriate lipid lowering medication. 
• 
PT with INR ≤ 1.5 (Anticoagulation is allowed if target INR ≤ 1.5 on a 
stable dose of warfarin or on a stable dose of LMW heparin for >2 weeks 
at time of randomization.) 
*Please see study table in Section 7.0 for labs that may need to be repeated 
within ≤ 7 days of Cycle 1 Day 1 (C1D1). 
12. Patients may have measurable disease, non-measurable disease (e.g., bone 
only metastases), or both per RECIST Version 1.1 Criteria. 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 are not considered measurable. 


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13. Patients with basal cell or squamous cell carcinoma of the skin or carcinoma 
in situ of the cervix within the past five years must have been treated with 
curative intent. Patients with a history of prior malignancy are eligible provided 
they were treated with curative intent and have been free of disease for >3 
years. 
Exclusion Criteria: 
1. Patients who have had any major surgery or significant traumatic injury within 
4 weeks of randomization, or have not recovered from the side effects of any 
major surgery (defined as requiring general anesthesia) or patients that may 
require major surgery during the course of the study are not eligible. 
(Placement of vascular access device will not be considered major surgery.) 
2. Patients may not be receiving any other investigational agents or have 
received any investigational agent within 4 weeks of randomization. 
3. Patients must not be receiving any concomitant anticancer treatment or have 
received anticancer treatment within 4 weeks of randomization (including 
chemotherapy, radiation therapy, antibody based therapy, etc.), with the 
following exceptions: 
• 
Bisphosphonates, Zometa or Xgeva for bone metastases 
• 
Hormonal therapy (e.g., AI, Tamoxifen) 
• 
a GnRH analog is permitted if the patient had progressive disease on a 
GnRH analog plus a SERM or an AI; the GnRH analog may continue but 
the SERM or AI must be discontinued. 
4. Patients must not have received prior treatment with an mTOR inhibitor 
(sirolimus, temsirolimus, everolimus). 
5. Patients must not be receiving chronic, systemic treatment with corticosteroids 
or another immunosuppressive agent greater than or equal to 5 mg 
prednisone or its equivalent daily. Topical or inhaled corticosteroids are 
allowed. 
6. Patients must not receive immunization with attenuated live vaccines within 
one week of randomization or during the study period. 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. 
7. Patients must not have current or a prior history of brain metastases or 
leptomeningeal disease. Patients must not have rapidly progressive, life-
threatening metastases. This includes patients with extensive hepatic 
involvement (>50% of the liver involved) and symptomatic lymphangitic 
metastases. 
8. Patients must not have a known hypersensitivity/history of allergic reactions 
attributed to compounds of similar chemical or biologic composition to 
everolimus (or other rapamycins such as sirolimus, temsirolimus) or 
fulvestrant. 


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9. Since everolimus may cause bone marrow suppression, patients with 
congenital or acquired immune deficiency at increased risk of infection are not 
eligible. This includes patients being treated with chronic immunosuppressive 
agents (including greater than or equal to 5 mg prednisone or its equivalent 
daily), and patients with known HIV seropositivity. 
10. Patients must not have any impairment of gastrointestinal function or 
gastrointestinal disease that may significantly alter the absorption of 
everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome or small bowel resection). 
11. Patients must not have an active, bleeding diathesis. 
12. Patients must not have a history of any condition or uncontrolled intercurrent 
illness including, but not limited to, ongoing or active infection or psychiatric 
illness/social situations that in the opinion of the local investigator might 
interfere with or limit the patient’s ability to comply with the protocol or pose 
additional or unacceptable risk to the patient. 
13. Patients must not have any severe and/or uncontrolled medical conditions or 
other conditions that could affect their participation in the study such as: 
• 
Symptomatic congestive heart failure of New York Heart Association Class 
III or IV (see Appendix D) 
• 
Unstable angina pectoris, myocardial infarction within 6 months of 
randomization, serious uncontrolled cardiac arrhythmia or any other 
clinically significant cardiac disease 
• 
History of symptomatic pulmonary disease or non-malignant pulmonary 
disease (e.g. COPD) requiring treatment. Such patients would be eligible if 
PFTs performed within 8 weeks of treatment noted a DLCO greater than 
50%. 
• 
Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN 
(Note: Optimal glycemic control should be achieved before starting trial 
therapy.) 
• 
Active (acute or chronic) or uncontrolled severe infections 
• 
Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh 
Class C). 
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. (see 
Section 7.1.1 for additional details). 


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4 
Randomization Procedures 
4.1 Ethics 
This study will be conducted in accordance with the ethical principles that have their 
origin in the current Declaration of Helsinki and will be consistent with applicable US 
regulatory requirements and International Conference on Harmonization Good 
Clinical Practice (ICH GCP). 
The study will be conducted in compliance with the protocol. The protocol and any 
amendments and the patient informed consent will receive Institutional Review Board 
(IRB) approval prior to initiation of the study. 
Freely given written informed consent must be obtained from every patient or their 
legally acceptable representative prior to clinical trial participation, including informed 
consent for any screening procedures conducted to establish patient eligibility for the 
trial. 
Study personnel involved in conducting this trial will be qualified by education, 
training, and experience to perform their respective task(s). This trial will not use the 
services of investigators or study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure, 
debarment). Investigators are responsible for the conduct of the study at their study 
site. 
4.2 Regulatory Requirements 
Before a site may enter patients, protocol-specific regulatory and other documents 
must be submitted to PrECOG as noted in study materials. Detailed information 
regarding document submission and control is provided to each site in separate study 
materials. 
Once all required documents are received, reviewed and approved by PrECOG or 
their representative, a Study Reference Manual (SRM) will be forwarded to the site. 
Any changes to site regulatory documents must be submitted by the investigator to 
the responsible party in a timely manner. Initial study drug shipment will not occur 
until the regulatory packet is complete. No patients will begin protocol therapy without 
formal randomization as per the process below. 
4.3 Patient Randomization 
Patients must meet all of the eligibility requirements listed in Section 3 prior to 
randomization. Treatment must begin ≤ 7 working days from randomization. 
An eligibility checklist has been appended as an example to the protocol and a usable 
version is available in separate study materials provided to the site. A confirmation of 
eligibility assessment by the investigator/site will be performed during the 
randomization process. 
Information regarding stratification factors (performance status, measurable disease 
and prior chemotherapy) must be available at the time of randomization. 


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Once it is determined that a patient meets all eligibility requirements, the patient will 
be randomized to the study by site personnel using an electronic interactive web 
registration (IWR) system. Full information regarding registration and randomization 
procedures and guidelines can be found in the SRM provided to your site. All 
correspondence regarding patient randomization must be kept in the study records. 
 


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5 
Treatment Plan 
5.1 Administration Schedule 
Note: 1 cycle = 28 days. 
Patients must begin treatment within 7 working days of randomization. 
Disease evaluations will occur after every 12 weeks, +/- 1 week (which corresponds 
to every 3 treatment cycles) and patients will be treated until disease progression, 
unacceptable toxicity or for a total duration of 12 cycles (Induction Phase). Patients 
with no evidence of progressive disease who remain on study after completing 12 
cycles will be unblinded and proceed to the Continuation Phase. Patients in the 
Continuation Phase should continue to receive fulvestrant alone (if originally 
randomized to placebo) or in combination with everolimus (if originally randomized to 
everolimus) at the same dose and schedule. Disease evaluations will continue to 
occur after every 12 weeks (every 3 treatment cycles), +/- 1 week, and patients may 
continue treatment until disease progression is documented or unacceptable toxicity. 
All patients will be followed for 30 days for toxicity after the last dose of study therapy 
(fulvestrant and/or everolimus/placebo) or until recovery from all toxicity (to ≤ grade 1) 
attributed to study therapy, whichever is longer (or if >grade 1, event must be 
permanent and stable). 
See Sections 8.1 and 8.2 for information on study drug procurement, storage, 
preparation, handling and destruction information. 
5.2 Dosing and Administration 
5.2.1 
Fulvestrant (Arm A and Arm B) 
Induction Phase: 
Cycle 1 (28 day cycle) 
Patients will receive fulvestrant 500 mg IM (two-250 mg injections each dose) 
on day 1 and 15. 
Note: Cycle 1 is the only time fulvestrant is given on day 15. If patient 
previously received one cycle of fulvestrant (day 1 and day 15) prior to study 
entry as permitted in Inclusion Criteria #8, patient should receive fulvestrant 500 
mg on day 1 only. 
Cycle 2, and thereafter (28 day cycles) 
Patients will receive fulvestrant 500 mg IM (two-250 mg injections) on day 1 of 
all subsequent cycles for a maximum of 12 cycles. 
Continuation Phase: 
Patients with no evidence of disease progression after completing 12 cycles are 
unblinded and continue fulvestrant alone (if originally randomized to placebo) or in 
combination with everolimus (if originally randomized to everolimus) at the same dose 
and schedule until progression of disease or unacceptable toxicity. 


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Fulvestrant will be obtained from commercial pharmacy stock. 
5.2.2 
Everolimus or Placebo (Arm A and Arm B) 
• 
The study drug everolimus/placebo will be self-administered (by the patients 
themselves). The local investigator will instruct the patient to take the study drug 
exactly as specified in the protocol. Everolimus/placebo should be administered 
orally once daily, preferably in the morning, at the same time every day with or 
without food. Everolimus/placebo tablets should be swallowed whole with a glass 
of water. The tablets must not be chewed or crushed. In cases where tablets 
cannot be swallowed, the tablets should be disintegrated in water just prior to 
being taken. Approximately 30 mL (2 tablespoons) of water should be put into a 
glass. The tablets should then be added and the contents stirred gently (for a 
maximum of 7 minutes) until the tablets are disintegrated. The contents should 
then be drunk. If the patient vomits after taking the study drug, they should not 
take another tablet that day. If the patient forgets to take the medication and 
remembers by 10 PM, they may take the dose. Otherwise, skip that dose and 
begin as usual the next day. 
• 
Everolimus/placebo will be administered orally as once daily dose of 10 mg (two- 
5 mg tablets) continuously from study day 1 until progression of disease or 
unacceptable toxicity for 12 cycles. See Section 5.5 regarding duration of therapy 
(including guidelines for treatment beyond Cycle 12). 
• 
If vomiting occurs, no attempt should be made to replace the vomited dose. 
• 
All dosages prescribed and dispensed to the patient and all dose changes during 
the study must be recorded. 
• 
PrECOG, or their designee, will be responsible for blinding, drug randomization, 
and management of the electronic interactive web registration (IWR) system. Both 
tablets will be blinded and identified by kit number only. The IWR system will 
assign the proper kit to the patient based on the patient randomization. Conditions 
for study drug will be described on the medication label. 
• 
Both everolimus and placebo will be provided by Novartis. Everolimus is 
formulated as tablets for oral administration of 5 mg strength. Both placebo and 
everolimus tablets are blister-packed under aluminum foil in units of 10 tablets per 
blister card, which should be opened only at the time of administration as drug is 
both hygroscopic and light-sensitive. 
• 
Dose modifications should be made prior to dose calculation at the beginning of 
each cycle and reasons recorded in source documents and on appropriate case 
report forms. 
 
 
 
 


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5.3 Dose Modifications and Toxicity Management 
5.3.1 
Dose Modifications General Guidelines for Everolimus/ 
Placebo 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0 will be utilized for AE reporting. All appropriate treatment areas should 
have access to a copy of the CTCAE Version 4.0. A copy of the CTCAE Version 4.0 
can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
All appropriate treatment areas should have access to a copy of the CTEP CTCAE 
Version 4.0. (see Appendix E). 
Dose modifications for all drugs will be made using the general guidelines below. 
• 
All dose reductions are permanent. Fulvestrant will not be dose reduced. 
• 
Regardless of the reason for holding any study drug treatment, the maximum 
allowable length of treatment interruption is ≤ 3 weeks. If the delivery of any study 
drug due to toxicity is delayed for more than 3 weeks, that drug should be 
permanently discontinued. 
• 
No more than 2 dose reductions for everolimus/placebo will be allowed. Further 
need for dose reduction will result in discontinuation of that drug. 
• 
If dose is delayed due to toxicity, labs/toxicity should be reevaluated at least 
weekly until recovery to treatment levels, or as indicated in the dose modification 
tables. 
• 
Patients who discontinue everolimus/placebo because of suspected everolimus-
associated toxicity should continue treatment with fulvestrant alone until disease 
progression. 
• 
In unusual circumstances where fulvestrant must be discontinued prior to disease 
progression due to intolerable fulvestrant-associated toxicity, the Medical Monitor 
should be contacted. 
Table 5-0 
Everolimus or Placebo Dose Level Modification Guidelines 
 
Everolimus/Placebo 
Fulvestrant 
Starting dose 
10 mg daily 
(two- 5 mg tablets) 
500 mg 
Dose Level -1 
5 mg daily 
No reduction 
Dose Level -2 
5 mg every other day 
No reduction 


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Table 5-1 
Non-Hematological Criteria for Dose-Modification in Case of Suspected 
Everolimus or Placebo Related Adverse Events and Re-Initiation of Everolimus 
or Placebo Treatment 
Adverse Event 
Action 
Non Hematological 
 
Reactivation of HBV or HCV flare 
Please refer to Table 5-4 and Table 5-5. 
Non-Infectious Pneumonitis 
Please refer to Table 5-6. 
AST or ALT elevation 
Grade 1 (>ULN - 3.0x ULN) 
Grade 2 (>3.0 - 5.0x ULN) 
Maintain current dose level. 
AST or ALT elevation 
Grade 3 (>5.0 - 20.0 ULN)* 
Interrupt everolimus administration until resolution to ≤ grade 1 
(or ≤ grade 2 if baseline values were within the range of grade 
2). If resolution occurs ≤ 7 days, everolimus should be re-started 
at the dose level prior to interruption. 
If resolution takes >7 days, or if event recurs within 28 days, 
hold everolimus until recovery to ≤ grade 1 or baseline grade/ 
value and reintroduce everolimus at one dose level lower, if 
available. 
AST or ALT elevation 
Grade 4 (>20x ULN)* 
Interrupt everolimus administration until resolution to ≤ grade 1 
(or ≤ grade 2 if baseline values were within the range of grade 
2). If resolution occurs ≤ 7 days, everolimus should be re-started 
at one dose level lower. If resolution takes >7 days, discontinue 
everolimus. 
Intolerable Grade 2 mucositis 
(see Section 5.3.2.5) 
Interrupt everolimus administration until resolution to ≤ grade 1 
or baseline grade/value. 
If resolution occurs within ≤ 7 days, everolimus should be re-
started at the dose level prior to interruption. 
If resolution takes >7 days, or if event recurs within 28 days, 
hold everolimus until recovery to ≤ grade 1 or baseline grade/ 
value and reintroduce everolimus at one dose level lower, if 
available. 
Patients will be withdrawn from the study if they fail to recover to 
≤ grade 1 or baseline grade/value within 21 days. 
Grade 3 AE, except: 
hyperglycemia or 
hypertriglyceridemia or 
hypercholesterolemia 
(see Section 5.3.2.7) 
Interrupt everolimus administration until resolution to ≤ grade 1 
or baseline grade/value. 
Reintroduce everolimus at one dose level lower, if available. 
Patients will be withdrawn from the study if they fail to recover to 
≤ grade 1 or baseline grade/value within 21 days. 


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Any other Grade 4 
Hold everolimus until recovery to grade ≤ 1 or baseline value. 
Reintroduce everolimus at one dose level lower, if available. 
Grade 3 or 4 clinical liver failure 
(asterixis 
or 
encephalopathy/ 
coma) 
Discontinue everolimus. 
Recurrence of intolerable Grade 2 
mucositis or Grade 3 event after 
dose reduction 
Reduce dose to the next lower dose level, if available. The 
lowest possible dose level of everolimus is 5 mg every other 
day. Below this level, everolimus must be discontinued. 
Recurrence of Grade 4 after 
dose reduction 
Discontinue everolimus. 
Any 
non-hematologic 
toxicity 
requiring 
interruption 
of 
everolimus for >21 days 
Discontinue everolimus. 
* Should HCV flare be confirmed, the guidelines for flare must take precedence (Table 5-5). 
 
Table 5-2 
Hematological Criteria for Dose-Modification in Case of Suspected Everolimus 
or Placebo Related Adverse Events and Re-Initiation of Everolimus or Placebo 
Adverse Event 
Action 
Hematological 
 
Grade 2 thrombocytopenia 
(platelets <75, ≥ 50 x 109/L) 
No action. 
Grade 3 thrombocytopenia 
(platelets <50, ≥ 25 x 109/L) 
Interrupt everolimus until resolution to grade ≤1  
If resolution occurs ≤ 7 days, reintroduce everolimus at the 
dose level prior to interruption. 
If resolution occurs >7 days, or event occurs within 28 days, 
reintroduce everolimus at one dose level lower, if available. 
Grade 4 thrombocytopenia 
(platelets <25 x 109/L) 
Interrupt everolimus until recovery to grade ≤ 1. Then 
reintroduce everolimus at one dose level lower, if available. 
Grade 3 neutropenia or anemia  
(neutrophil <1, ≥ 0.5 x 109/L) 
Interrupt everolimus until resolution to grade ≤1 or baseline 
value 
If AE resolution occurs ≤ 7 days, reintroduce everolimus at 
the same dose level. 
If AE resolution occurs >7 days, or event occurs within 28 
days, reintroduce everolimus at one dose level lower, if 
available. 
 


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Grade 4 neutropenia or anemia 
Interrupt everolimus until recovery to grade ≤ 1 or baseline 
value. Reintroduce everolimus at one dose level lower, if 
available.* 
Febrile neutropenia 
Interrupt everolimus until resolution to grade ≤ 1 (or baseline 
value) and no fever. Reintroduce everolimus at one dose 
level lower, if available.* 
Recurrence of Grade 3 toxicity after 
dose reduction 
Reduce dose to the next lower dose level, if available. The 
lowest possible dose level of everolimus is 5 mg every other 
day. Below this level, everolimus must be discontinued. 
*Recurrence of Grade 4 toxicity 
(including febrile neutropenia) after 
dose reduction 
Discontinue everolimus. 
*Any hematologic toxicity requiring 
everolimus interruption for >21 
days 
Discontinue everolimus. 
5.3.2 
Common Adverse Events Associated with Everolimus 
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 dyspnea. 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, 
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. 


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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.53 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.54 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. 
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. 
The use of live vaccines and close contact with those who have received live 
vaccines should be avoided during treatment with everolimus. 
Hypophosphatemia, hypomagnesaemia, hyponatremia and hypocalcaemia have 
been reported as serious adverse reactions. Electrolytes should be monitored in 
patients treated with everolimus. 
Table 5-1 and Table 5-2 provide general recommendations for the management of 
patients, with suspected drug toxicities while on treatment with everolimus as single-
agent therapy. 
More detailed information regarding everolimus reported suspected toxicities and 
individual cases are provided in the Investigator’s Brochure. 
5.3.2.1 
Management of Hepatitis Reactivation/Flare 
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.54 
 


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5.3.2.2 
Monitoring 
and 
Prophylactic 
Treatment 
for 
Hepatitis 
B 
Reactivation 
Table 5-3 provides details of monitoring and prophylactic therapy according to the 
baseline results of viral load and serologic markers testing. 
Table 5-3 
Action to be Taken for Positive Baseline Hepatitis B Results 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBsAb 
+ or - 
+ or - 
+ 
and no prior HBV 
vaccination 
+ or - 
- 
or + with prior 
HBV vaccination 
HBcAb 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendation 
Prophylaxis treatment should be 
started 1-2 weeks prior to first dose of  
study drug 
Monitor HBV-DNA approximately 
every 4-8 weeks 
No prophylaxis 
Monitor HBV-DNA approximately 
every 3-4 weeks 
No specific 
action 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of 
study drug. 
For hepatitis B reactivation, definition and management guidelines see Table 5-4 
Guidelines for Management of Hepatitis B. 


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Table 5-4 
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 
Treat: Start a second antiviral 
AND 
Interrupt study drug administration until resolution: 
≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 21 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 >21 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 HBsAb (with no 
prior history of vaccination 
against HBV), OR positive 
HBcAb 
------------------------------------- 
Reactivation is defined as: 
New 
appearance 
of 
measurable HBV-DNA 
Treat: Start first antiviral medication 
AND 
Interrupt study drug administration until resolution: 
≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 21 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 >21 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 (CTEP CTCAE Version 
4.0 Metabolic Laboratory/Other: Viral Reactivation), unless considered life threatening 
by the investigator; in which case they should be recorded as grade 4 (CTEP CTCAE 
Version 4.0 Metabolic Laboratory/Other: Viral Reactivation). 
5.3.2.3 
Monitoring for Hepatitis C Flare 
The following two categories of patients should be monitored every 4-8 weeks for 
HCV reactivation: 
• 
Patients with detectable HCV RNA-PCR test at baseline. 


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• 
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 flare and the management guidelines, see Table 5-5 
Guidelines for Management of Hepatitis C. 
Table 5-5 
Guidelines for Management of Hepatitis C 
HCV Flare* 
For patients with baseline results: 
Detectable HCV-RNA: 
HCV Flare is defined as: 
˃2 log10 IU/mL increase in HCV-RNA 
AND 
ALT elevation ˃5x ULN or 3x baseline level, 
whichever is higher 
Discontinue study drug. 
For patients with baseline results: 
Knowledge of past hepatitis C infection 
with no detectable HCV-RNA: 
HCV Flare is defined as: 
New appearance of detectable HCV-RNA 
AND 
ALT elevation ˃5x ULN or 3x baseline level, 
whichever is higher 
Discontinue study drug. 
 
* All flares of hepatitis C are to be recorded as grade 3 (CTEP CTCAE Version 4.0. 
Metabolic Laboratory/Other: Viral Flare), unless considered life threatening by the 
investigator; in which case they should be recorded as grade 4 (CTEP CTCAE 
Version 4.0 Metabolic Laboratory/Other: Viral Flare). 
5.3.2.4 
Management of Skin Toxicity 
For patients with grade 1 toxicity, no specific supportive care is usually needed or 
indicated. Rash must be reported as an AE. Patients with grade 2 or higher toxicity 
may be treated with the following suggested supportive measures at the discretion of 
the investigator: oral minocycline, topical tetracycline, topical clindamycin, topical 
silver sulfadiazine, diphenhydramine, oral prednisolone (short course), topical 
corticosteroids, or pimecrolimus. 


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5.3.2.5 
Management of Stomatitis/Oral Mucositis/Mouth Ulcers 
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with 
gastrointestinal morbidity associated with mouth/dental infections, irritation of 
esophageal mucosa e.g. gastroesophageal reflux disease (GERD) and pre-existing 
stomatitis/mucositis must be monitored even more closely. Patients should be 
instructed to report the first onset of buccal mucosa irritation/reddening to their study 
physician immediately. 
Suggested prophylactic treatment for prevention of stomatitis/mucositis: 
a) Use 15 mL baking soda/salt mouth rinse QID (swish and spit). Mix 1/3 teaspoon 
baking soda and 1/3 teaspoon of salt in 1 quart of water (refrigeration is not 
needed); do not eat or drink anything for 10 minutes after rinsing. 
b) Use 10 mL prescribed “miracle mouth wash’’ QID (swish and spit). For 16-ounce 
recipe: 320 mL Benadryl solution, 2 g tetracycline powder, 80 mg hydrocortisone, 
and 40 mL nystatin suspension, quantity sufficient with water. Wait 10-15 minutes 
after the baking soda/salt rinse before using “miracle mouthwash’’.55 
Stomatitis/oral mucositis/mouth ulcers due to everolimus should be treated using local 
supportive care. Please note that investigators in earlier trials have described the oral 
toxicities associated with everolimus as mouth ulcers, rather than mucositis or 
stomatitis. If your examination reveals mouth ulcers rather than a more general 
inflammation of the mouth, please classify the adverse event as such. Please follow 
the paradigm below for treatment of stomatitis/oral mucositis/mouth ulcers: 
1. For mild toxicity (Grade 1), use conservative measures as noted above, baking 
soda/salt mouth rinse and “miracle mouth wash”. 
2. For more severe toxicity (Grade 2 in which case patients have pain but are able to 
maintain adequate oral alimentation, or Grade 3 in which case patients cannot 
maintain adequate oral alimentation), the suggested treatments are: 
In addition to baking soda/salt mouth rinse and “miracle mouth wash” 
above, topical analgesic mouth treatments (e.g., local anesthetics such as 
benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol) 
with or without topical corticosteroids, such as triamcinolone oral paste 0.1% 
(Kenalog in Orabase®) or Periogard® oral rinse. 
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. It is preferable to avoid these agents. Alcohol–containing 
rinses and tooth paste with sodium lauryl sulfate should also be avoided. Avoid 
acidic, spicy, hard, or crunchy foods, and consume foods that are tepid rather 
than hot.55 
4. Antifungal agents must be avoided unless a fungal infection is diagnosed. In 
particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, 
itraconazole, etc.) should be avoided in all patients due to their strong inhibition of 
everolimus metabolism, thereby leading to higher everolimus exposures. 
Therefore, topical antifungal agents are preferred if an infection is diagnosed. 
Similarly, antiviral agents such as acyclovir should be avoided unless a viral 
infection is diagnosed. 
Note: Stomatitis/oral mucositis should be appropriately graded using the functional 
grading given on the CTEP CTCAE Version 4.0. 


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5.3.2.6 
Management of Diarrhea 
Appearance of grade 1-2 diarrhea attributed to study drug toxicity may be treated with 
supportive care such as loperamide, initiated at the earliest onset (for example 4 mg 
orally followed by 2 mg orally every 2 hours until resolution of diarrhea). 
5.3.2.7 
Management of Hyperlipidemia and Hyperglycemia 
Treatment of hyperlipidemia should take into account the pre-treatment status and 
dietary habits. Grade 2 or higher hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) 
or grade 2 hypertriglyceridemia or higher (>2.5x upper normal limit) should be treated 
with a 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g. atorvastatin, 
pravastatin, fluvastatin) or appropriate triglyceride-lowering medication, in addition to 
diet. 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is 
associated with an increased risk of a rare but serious skeletal muscle toxicity 
manifested by rhabdomyolysis, markedly elevated creatine phosphokinase (CPK) 
levels and myoglobinuria, acute renal failure and sometimes death. The risk versus 
benefit of using this therapy should be determined for individual patients based on 
their risk of cardiovascular complications of hyperlipidemia. 
Hyperglycemia has been reported in 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 trial therapy. 
5.3.2.8 
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. Some of these have been severe and on rare occasions, 
a fatal outcome was observed.  
A diagnosis of non-infectious pneumonitis should be considered in patients 
presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural 
effusion, cough or dyspnea, and in whom infectious, neoplastic and other non-
medicinal causes have been excluded by means of appropriate investigations. 
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. 


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For non-infectious pneumonitis definition and management guidelines, see Table 5-6 
Management of Non-Infectious Pneumonitis. 
Table 5-6 
Management of Non-Infectious Pneumonitis 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis 
Everolimus Dose 
Adjustment 
Grade 1 
CT scans with lung windows. 
No 
specific 
therapy 
is 
required 
No dose adjustment required.  
Initiate appropriate monitoring. 
Grade 2 
CT scan with lung windows. 
Consider pulmonary function 
testing 
includes: 
spirometry, 
DLCO, 
and 
room 
air 
O2 
saturation at rest. Consider a 
bronchoscopy 
with 
biopsy 
and/or BAL. Monitoring at each 
visit until return to ≤ grade 1. 
Return 
to 
initial 
monitoring 
frequency if no recurrence. 
Symptomatic only. 
Consider 
corticosteroids 
and/or 
other 
supportive 
therapy if symptoms are 
troublesome. 
Rule out infection and consider 
interruption of everolimus until 
symptoms improve to Grade ≤ 
1. 
Re-initiate everolimus at one 
dose level lower.  
Discontinue 
everolimus 
if 
failure to recover within ≤ 21 
days. 
Grade 3 
CT scan with lung windows and 
pulmonary 
function 
testing 
includes: 
spirometry, 
DLCO, 
and room air O2 saturation at 
rest. Monitoring at each visit 
until return to ≤ grade 1. Return 
to initial monitoring frequency if 
no recurrence. Bronchoscopy 
with biopsy and/or BAL is 
recommended. 
Consider corticosteroids if 
infective origin is ruled out. 
Taper 
as 
medically 
indicated. 
Rule out infection and interrupt 
everolimus 
until 
symptoms 
improve to Grade ≤ 1. 
Consider re-initiating evero-
limus at one dose level lower.  
Discontinue 
everolimus 
if 
failure to recover within ≤ 21 
days. 
Grade 4 
CT scan with lung windows and 
required 
pulmonary 
function 
testing, if possible, includes: 
spirometry, DLCO, and room air 
O2 saturation at rest. Monitoring 
at each visit until return to ≤ 
grade 
1. 
Return 
to 
initial 
monitoring 
frequency 
if 
no 
recurrence. Bronchoscopy with 
biopsy 
and/or 
BAL 
is 
recommended if possible. 
Consider corticosteroids if 
infective origin is ruled out. 
Taper 
as 
medically 
indicated. 
Rule 
out 
infection 
and 
discontinue everolimus. 
All interruptions or changes to study drug administration must be recorded. 
It will be documented whether or not each patient completed the clinical study. If for 
any patient either study treatment or observations were discontinued the reason will 
be recorded. 
5.3.3 
Concomitant Therapies 
Patients will be instructed not to take any additional medications (including over-the-
counter products) during the course of the study without prior consultation with the 
local investigator. At each visit, the investigator will ask the patient about any new 
medications he/she is or has taken after the start of the study drug. 


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Concomitant medications/significant non-drug therapies taken ≤ 28 days prior 
to start and after start of study drug, including physical therapy and blood 
transfusions, should be reviewed. 
5.3.4 
Prohibited Therapies and Restrictions 
The following restrictions apply during the entire duration of the study: 
• 
No other investigational therapy should be given to patients. 
• 
No anticancer agents other than the study medication should be given to patients, 
with the following exceptions: 
o Bisphosphonates, Zometa, or Xgeva for bone metastases 
o a GnRH analog is permitted if the patient had progressive disease on a GnRH 
analog plus a SERM or an AI; the GnRH analog may continue but the SERM 
or AI must be discontinued. 
• 
If any other anticancer agents are required for a patient then the patient must first 
be withdrawn from the study. 
• 
Concurrent radiation therapy is prohibited, however palliative radiotherapy may be 
considered on a case by case basis after discussion with the Study Chair. 
• 
Patients must not be receiving chronic, systemic treatment with corticosteroids or 
another immunosuppressive agent greater than or equal to 5 mg prednisone or its 
equivalent daily. 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. 
• 
It is highly recommended that patients with positive HBV-DNA or HBsAg are 
treated prophylactically with an antiviral for 1-2 weeks prior to receiving study drug 
(see Table 5-3). 
• 
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. 
• 
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. 
• 
Grapefruit and other citrus juices affect P450 and PgP activity. Concomitant use 
should be avoided. 


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5.3.5 
Administration of Everolimus and CYP3A4 Inhibitors/ 
Inducers 
5.3.5.1 
Inhibitors of CYP3A4 and/or PgP 
Everolimus is metabolized by CYP3A4 in the liver and to some extent in the intestinal 
wall. 
Therefore, the following are recommended: 
Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
ritonavir) or P-glycoprotein (PgP) should be avoided. 
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) 
or PgP inhibitors should be used with caution. If a patient requires co-administration 
of moderate CYP3A4 inhibitors or PgP inhibitors, reduce the dose of everolimus to 5 
mg every other day. Additional dose reductions to every other day may be required to 
manage toxicities. If the inhibitor is discontinued, the everolimus dose should be 
returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor 
after a washout period of 2-3 days. 
Grapefruit and other citrus juices affect P450 and PgP activity. Concomitant use 
should be avoided. 
Refer to Appendix C Table 15-0 for list of medications known to induce/inhibit 
CYP3A4 and Table 15-1 for a list of medications known to inhibit PgP. 
5.3.5.2 
Inducers of CYP3A4 and/or PgP 
Avoid the use of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, 
rifabutin, phenobarbital, St. John’s Wort). If a patient requires co-administration of 
strong CYP3A4 inducers, an increase in the dose of everolimus up to twice the 
currently used daily dose should be considered, 5 mg 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. The choice to adjust the dose of everolimus in a patient 
requiring co-administration of strong CYP3A4 inducers will be done at the discretion 
of the treating investigator. 
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. Refer to Appendix C Table 15-0 for list 
of medications known to induce CYP3A4 and Table 15-1 for a list of medications 
known to induce PgP. 
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 


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clearance of warfarin. The co-administration 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). 
A comprehensive list of cytochrome P450 isoenzymes and CYP3A4 inhibitors, 
inducers, and substrates can be found at: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. 
This 
website 
is 
continually 
revised and should be checked frequently for updates. 
5.4 Supportive Care 
All supportive measures consistent with optimal patient care will be given throughout 
the study. 
The clinical tolerance of the patient, the overall tumor response, and the medical 
judgment of the investigator will determine if it is in the patient’s best interest to 
continue or discontinue treatment. If treatment is discontinued due to any toxicity, the 
patient must be followed to monitor duration of toxicity, response and time to 
progression or survival and initiation of any new systemic therapy. 
5.5 Duration of Therapy 
CR, PR, or SD patients will continue therapy per their induction arm randomized 
assignments until evidence of progressive disease, unacceptable toxicity occurs, or 
for a total of 12 cycles (Induction Phase). Patients with no evidence of progressive 
disease who remain on study after completing 12 cycles will be unblinded and 
proceed to the Continuation Phase. Patients in the Continuation Phase should 
continue to receive fulvestrant alone (if originally randomized to placebo) or in 
combination with everolimus (if originally randomized to everolimus) at the same dose 
and schedule until disease progression or unacceptable toxicity.  
Protocol therapy will be discontinued for progressive disease at any time. Patients are 
free to halt therapy at their request. Treatment may be discontinued if intercurrent co-
morbidities occur, which, in the opinion of the treating physician, would preclude safe 
administration of study drugs. 
Patients who discontinue everolimus/placebo because of suspected everolimus-
associated toxicity should continue treatment with fulvestrant alone until disease 
progression. In unusual circumstances where fulvestrant must be discontinued prior 
to disease progression due to intolerable fulvestrant-associated toxicity, the medical 
monitor should be contacted. All patients who have discontinued protocol therapy will 
be followed for survival and for progression if protocol therapy was discontinued 
because of toxicity or for other reasons. All surviving patients who have discontinued 
induction protocol therapy (fulvestrant and everolimus/placebo) for any reason will be 
followed for 30 days for study drug related (fulvestrant and/or everolimus/placebo) 
toxicities to ≤ grade 1 (or if >grade 1, event must be permanent and stable). 
 
 


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5.6 Withdrawal of Patients from Study 
Patients MUST be discontinued from study therapy AND be withdrawn from the study 
for the following reasons: 
• 
Withdrawal of the patient’s consent (patient’s decision to withdraw for any reason) 
• 
Termination of the study by PrECOG 
• 
Any clinical adverse event, laboratory abnormality or intercurrent illness which, in 
the opinion of the investigator, indicates that continued participation in the study is 
not in the best interest of the subject 
• 
Inability to comply with protocol 
• 
Discretion of the investigator 
• 
Disease progression (patient will continued to be followed for survival) 
All subjects who discontinue treatment should comply with protocol specified follow-
up procedures as outlined in Section 7.1.5. 
If a subject is withdrawn before completing the study, the reason for withdrawal must 
be entered on the appropriate case report form. 


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6 
Measurement of Effect 
6.1 Antitumor Effect- Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response every 12 
weeks, +/- 1 week. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than four weeks before 
randomization. 
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).56 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. 
6.1.1 
Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their 
first treatment with fulvestrant and everolimus/placebo. All patients will be followed for 
30 days for toxicity after the last dose of study therapy (fulvestrant and/or 
everolimus/placebo) or until recovery from all toxicity (to ≤ grade 1) attributed to study 
therapy, whichever is longer (or if >grade 1, event must be permanent and stable). 
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. 
6.1.2 
Disease Parameters 
Measurable lesions: are defined as those that can be accurately measured in at least 
one dimension (longest diameter in the plane of measurement) is to be recorded with 
a minimum size of: 
• 
≥ 20 mm by chest x-ray (if clearly defined and surrounded by aerated lung) 
• 
≥ 10 mm with CT scan (irrespective of scanner type) and MRI (no less than 
double the slice thickness and a minimum of 10 mm) 
• 
≥ 10 mm with calipers by clinical exam when superficial 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 


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Note: Tumor lesions that are situated in a previously irradiated area, or in an area 
subjected to other loco-regional therapy, are usually not considered measurable 
unless there has been demonstrated progression in the lesion. 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis (perpendicular to longest diameter) 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 lesions: all other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short 
axis), are considered non-measurable disease. Leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast 
disease, and abdominal masses/organomegaly (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. 
Lytic bone lesions, with an identifiable soft tissue component, evaluated by CT or 
MRI, can be considered as measurable lesions if the soft tissue component otherwise 
meets the definition of measurability noted above. Blastic bone lesions are non-
measurable. 
6.1.3 
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 randomization. 
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. 
 
 
 


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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 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. 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements. However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring cancer 
lesions over time. Note, however, that the PET portion of the CT introduces additional 
data which may bias an investigator if it is not routinely or serially performed. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced 
in their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will 
be taken from one assessment to the next. If new lesions are identified by ultrasound 
in the course of the study, confirmation by CT or MRI is advised. If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected 
instances. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine relapse 
in trials where recurrence following complete response (CR) or surgical resection is 
an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess response. If markers 
are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. Specific guidelines for both CA-125 
response (in recurrent ovarian cancer) and PSA response (in recurrent prostate 
cancer) have been published.57-59 In addition, the Gynecologic Cancer Intergroup has 
developed CA-125 progression criteria which are to be integrated with objective 
tumor assessment for use in first-line trials in ovarian cancer.60 


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Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response 
or stable disease is mandatory to differentiate between response or stable disease 
(an effusion may be a side effect of the treatment) and progressive disease. 
FDG-PET: While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement 
CT scanning in assessment of progression (particularly possible 'new' disease). New 
lesions on the basis of FDG-PET imaging can be identified according to the following 
algorithm: 
• 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
• 
No FDG-PET at baseline and a positive FDG-PET at follow-up:  
o If the positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD. 
o If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan). 
o If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, 
this is not PD. 
• 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring. The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication. However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
6.1.4 
Response Criteria 
6.1.4.1 
Evaluation of Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and five 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 (those with the longest diameters), 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. 


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The 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 of the diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the 
disease. 
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 over the 
nadir. (Note: the appearance of one or more new lesions is also considered 
progression). 
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. (Note: a change of 20% or more that does not increase the sum of the 
diameters by 5 mm or more is coded as stable disease). 
6.1.4.2 
Evaluation of Non-Target Lesions 
All other lesions or sites of disease including any measurable lesions over and above 
the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the 
presence or absence of unequivocal progression of each should be noted throughout 
follow-up. 
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. 
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. 
When the patient also has measurable disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in the presence of SD or 
PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest “increase” in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status. The 


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designation of overall progression solely on the basis of change in non-target disease 
in the face of SD or PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the increase in overall disease 
burden should be comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in tumor burden from “trace” to 
“large”, an increase in nodal disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy. 
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). 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive Disease (PD). 
6.1.4.4 
Evaluation of Patient’s 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. 


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Table 6-0 
Patients with Measurable Disease (e.g., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
Confirmation not required 
CR 
Non-CR/Non-
PD 
No 
PR 
Confirmation not required 
CR 
Not Evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/Not 
Evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/Not 
Evaluated 
No 
SD 
Confirmation not required 
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. 
**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. 
Table 6-1 
Patients with Non-Measurable Disease (e.g., 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. 


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6.1.5 
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 PD 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. 
6.1.6 
Progression-Free Survival 
PFS is defined as the duration of time from time of randomization to time of 
progression or death, whichever occurs first. A subject who has neither progressed 
nor died will be censored on the date of last tumor assessment. 
 


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7 
Study Parameters 
TREATMENT MUST BEGIN ≤ 7 WORKING DAYS FROM RANDOMIZATION 
 
Induction Phase (fulvestrant + everolimus or placebo for a maximum of 12 cycles)  
End of 
Induction 
Phase 
<OR> 
End of 
Treatment 
Section 5.6^ 
Continuation 
Phase£ 
(until 
progression or 
unacceptable 
toxicity) 
Follow-Up Off 
Therapyo 
(every 3 
months for total 
of 3 yrs from 
date of 
randomization) 
Procedure 
Pre-Study 
Cycle 1 
Day 1* 
Cycle 1 
Day 15 
Day 1 Each 
Subsequent 
Cycle* 
Every 12 
weeks 
Eligibility Assessment 
Xa 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History & Assessment of Baseline 
Signs and Symptoms 
Xa 
 
 
 
 
 
 
 
Physical Exam 
Xa 
Xb 
X 
Xc 
 
X 
 
 
Concomitant Meds (see Appendix C) 
Xa 
Xb 
X 
Xc 
 
X 
 
 
Vital Signs (Blood Pressure, Heart Rate, 
Temperature) and Weight 
Xa 
(includes Ht) 
Xb 
X 
Xc 
 
X 
 
 
ECOG Performance Status 
Xa 
Xb 
X 
Xc 
 
X 
 
 
Adverse Events Assessments 
 
Xb 
X 
Xc 
 
Xj 
Xj 
Xj 
Imaging Scans 
Xa,i 
 
 
 
Xi 
Xi 
Xi 
Xi,m,o 
PT with INR 
Xa 
 
 
 
 
 
 
 
Urinalysis 
Xa 
 
 
 
 
 
 
 
CBC with differentials, Platelets 
Xa 
Xb 
Xd 
Xc,d 
 
Xd 
Xk 
 
Serum Creatinine, Electrolytes (K, Na, Cl, 
CO2), Ca, BUN, Albumin, Total Protein, 
Phosphorus, AST (SGOT), ALT (SGPT), 
Alkaline 
Phosphatase, 
Total 
Bilirubin, 
Magnesium, Uric Acid. 
Xa 
Xb 
X 
Xc 
 
X 
Xk 
 
Fasting Glucose 
Xa 
Xb 
 
Xe 
Xe 
Xe 
Xk 
 
Fasting serum Lipid Profile (triglycerides, 
total cholesterol, HDL and LDL) 
Xa 
Xb 
 
Xe 
Xe 
Xe 
Xk 
 


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Induction Phase (fulvestrant + everolimus or placebo for a maximum of 12 cycles)  
End of 
Induction 
Phase 
<OR> 
End of 
Treatment 
Section 5.6^ 
Continuation 
Phase£ 
(until 
progression or 
unacceptable 
toxicity) 
Follow-Up Off 
Therapyo 
(every 3 
months for total 
of 3 yrs from 
date of 
randomization) 
Procedure 
Pre-Study 
Cycle 1 
Day 1* 
Cycle 1 
Day 15 
Day 1 Each 
Subsequent 
Cycle* 
Every 12 
weeks 
HBV-DNA, HbsAg, HBsAb, HBcAb, HCV-
RNA-PCR 
Xa,f 
 
 
 
 
 
 
 
HBV DNA 
 
Xf,g 
 
Xf,g 
 
 
Xk 
 
HCV RNA-PCR 
 
Xf,h 
 
Xf,h 
 
 
Xk 
 
Study Drug Compliance (Pill Diary) 
 
 
X 
X 
 
X 
Xl 
 
PFTs with DLCO as medically indicatedn 
 
 
 
 
 
 
 
 
a: ≤ 4 weeks of randomization; if assessments required ≤ 7 days of Cycle 1 Day 1 (C1D1), they do not need to be repeated (includes labs). 
b: ≤ 7 days prior to the start of C1D1. 
c: +/- 72 hour window allowed prior to D1 of each subsequent cycle after the first cycle for scheduled therapy/tests/visits. Delay due to holidays, weekends, 
bad weather or other unforeseen circumstances will be permitted. 
d: In the event of grade 3 or 4 hematologic toxicity, CBC with differential and platelet count will be obtained every 1-3 days until there is evidence of 
hematologic recovery. 
e: +/- 72 hours prior to Cycle 2 Day 1 then approximately every 12 weeks during treatment (and more frequently as clinically indicated), and at end of 
treatment. 
f: All patients should be screened for hepatitis risk factors and any past illnesses of hepatitis B and hepatitis C infection (see Section 7.1.1). All patients with a 
positive medical history per Section 7.1.1 need hepatitis testing as noted on above table. It is highly recommended that patients positive for HBV-DNA or 
HBsAg are treated prophylactically with an antiviral (e.g., Lamivudine) for 1-2 weeks prior to receiving study drug (see Table 5-3). The antiviral treatment 
should continue throughout the entire study period and for at least 4 weeks after the last dose of everolimus. 
g: Patients on antiviral prophylaxis treatment or positive HBV antibodies should be tested for HBV-DNA ≤ 7 days prior to the start of C1D1 and +/- 72 hrs prior 
to D1 of each subsequent cycle to monitor for reactivation. See Table 5-4 for reactivation instructions. 
h: Patients with positive HCV RNA-PCR results at screening and/or a history of past infection (even if treated and considered ‘cured’) should have HCV RNA-
PCR testing performed on ≤ 7 days prior to the start of C1D1 and +/- 72 hrs prior to D1 of each subsequent cycle to monitor for flare. Everolimus must be 
discontinued if HCV flare is confirmed according to the guidance in Table 5-5. 
i: Tumor measurements may be made using physical examination, CT Scans or MRI. Tumor assessments will be performed every 12 weeks, +/- 1 week 
(every 3 months). Imaging will include chest and abdomen. Bone Scans and Brain CT/MRI may be performed as clinically indicated. Scans do not have to be 
repeated once disease progression is documented. 
j: Adverse events related to fulvestrant and/or everolimus/placebo will be followed for 30 days after the last dose of study therapy (fulvestrant and/or 
everolimus/placebo) or until ≤ grade 1 or if the grade is >1, the event must be permanent and stable. Please note- Serious adverse events >30 days after last 
dose of fulvestrant and/or everolimus/placebo are not reported unless the event may be related to everolimus/placebo. 


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k: CBC and chemistry may be used to assess ongoing toxicity but are not required in the Continuation Phase for patients who receive fulvestrant alone. 
Patients who continue fulvestrant with everolimus should periodically have CBC, chemistries, fasting glucose, fasting lipids, HBV DNA, HCV RNA-PCR per 
labeling guidelines. 
l: Study Drug Compliance (Pill Diary) for those patients who receive everolimus in the Continuation Phase. 
m: All patients including those that discontinue protocol therapy will be followed for 3 years from the time of randomization. Patients that have not progressed 
during the Induction or Continuation Phase will continue to have imaging scans completed every 12 weeks, +/- 1 week (every 3 months) until documented 
progression. 
n: PFTs with DLCO as medically indicated only, (PFTs are not otherwise required during course of study). 
o: Follow every 3 months for disease progression and survival. Initiation of any new systemic therapy will also be documented. 
 
* Cycle 1, Day 1 is defined as the first day on which fulvestrant is given in combination with placebo/everolimus (the second fulvestrant dose is given on day 15 
of the first cycle only). Day 1 of each additional cycle is defined as the day in which fulvestrant is given in combination with everolimus/placebo. 
^ End of Induction/End of Treatment should be performed within 30 days of last dose of fulvestrant. 
£ Continuation Phase: Patients in the Continuation Phase should continue to receive fulvestrant alone (if originally randomized to placebo) or in combination 
with everolimus (if originally randomized to everolimus) at the same dose and schedule (+/- 1 week window for scheduled therapy/tests/visits; delays due to 
holidays, weekends, bad weather or other unforeseen circumstances will be permitted) until disease progression or unacceptable toxicity. 
 


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7.1 Procedures by Visit 
Written informed consent must be obtained prior to any study required procedures that 
would not have been performed as part of normal patient care at the site. 
7.1.1 
Pre-Study 
Prior to randomization, patients will complete the informed consent process and have all 
required protocol assessments completed in order to assess eligibility requirements. All 
procedures and an assessment of eligibility should be documented in the patient record. 
Within ≤ 4 weeks of randomization to protocol therapy: 
• 
Medical history 
• 
Assessment of baseline signs and symptoms 
• 
Physical examination 
• 
Concomitant medication assessment (see Appendix C for list of excluded or 
medications requiring monitoring on study) 
• 
Vital signs, including blood pressure, heart rate and temperature, height and weight 
• 
Assessment of ECOG performance status 
• 
Imaging scans for complete disease assessment. Care should be taken to continue 
to use the same evaluation method during the study as used for initial evaluation. 
See Section 6 for additional details. 
• 
PT with INR 
• 
Urinalysis 
• 
CBC with differential and platelets 
• 
Serum Creatinine, Electrolytes (K, Na, Cl, CO2), Ca, BUN, Albumin, Total Protein, 
Phosphorus, AST (SGOT), ALT (SGPT), Alkaline Phosphatase, Total Bilirubin, 
Magnesium and Uric Acid 
• 
Fasting Glucose  
• 
Fasting Serum Lipid Profile (triglycerides, total cholesterol, HDL and LDL)  
A detailed assessment of hepatitis B/C medical history and risk factors must be done for 
all patients. Patients with positive hepatitis B and/or hepatitis C test results must begin a 
course of antivirals within 1-2 weeks prior to the first dose of everolimus (as outlined in 
Section 5.3.2.2 and 5.3.2.3).  
Testing for hepatitis B viral load and serologic markers: HBV-DNA, HBsAg, HBsAb, 
HBcAb and HCV RNA-PCR are required at screening for all patients in the following risk 
categories:  
o All patients who have lived in Asia, Africa, Central and South America, Eastern 
Europe, Spain, Portugal, and Greece. 
[http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-
related-to-travel/hepatitis-b.htm] 


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o Patients with any of the following risk factors: 
• 
known or suspected past hepatitis B infection 
• 
blood transfusion(s) prior to 1990 
• 
current or prior IV drug users 
• 
current or prior dialysis 
• 
household contact with hepatitis B infected patient(s) 
• 
current or prior high-risk sexual activity 
• 
body piercing or tattoos 
• 
mother known to have hepatitis B 
• 
history suggestive of hepatitis B infection, e.g., dark urine, jaundice, right 
upper quadrant pain. 
o Additional patients at the discretion of the investigator 
Testing for hepatitis C should be performed using quantitative RNA-PCR at screening for 
all patients in the following risk categories: 
o known or suspected past hepatitis C infection (including patients with past 
interferon ‘curative’ treatment) 
o blood transfusions prior to 1990 
o current or prior IV drug users 
o current or prior dialysis 
o household contact of hepatitis C infected patient(s) 
o current or prior high-risk sexual activity 
o body piercing or tattoos 
o At the discretion of the investigator, additional patients may also be tested for 
hepatitis C. 
Final determination of eligibility and randomization to therapy should be done only after 
all assessments are completed. 
7.1.2 
Induction Phase (fulvestrant + everolimus/placebo) 
Day 1 of each cycle is defined as the day in which fulvestrant is given, including the first 
fulvestrant dose, third fulvestrant dose, and every dose thereafter (the second fulvestrant 
doses is given on day 15 of the first cycle only). Note: If patient previously received one 
cycle of fulvestrant (day 1 and day 15) prior to study entry as permitted in Inclusion 
Criteria #8, patient should receive fulvestrant 500 mg on day 1 only. 
Patients will be assessed continually for toxicity and study continuation. Protocol therapy 
doses should be calculated and modified as per Section 5. Assessment of disease for 
response should be performed as per Section 6.  
One cycle in the Induction Phase is equal to 28 days. Patients are treated for a 
maximum of 12 cycles in the Induction Phase. 
7.1.2.1 
Within 7 Days of Cycle 1 Day 1 
Note: The following assessments do not have to be repeated if the pre-study 
assessments were performed within ≤ 7 days of Cycle 1 Day 1. 


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• 
Physical examination 
• 
Concomitant medication assessment (see Appendix C for list of excluded or 
medications requiring monitoring on study) 
• 
Vital signs, including blood pressure, heart rate, temperature and weight 
• 
Assessment of ECOG performance status 
• 
Adverse event assessment and dose modifications as necessary (AEs should be 
monitored continuously). AE assessment should begin after the first dose of study 
medication has been administered. 
• 
CBC with differential and platelets 
• 
Serum Creatinine, Electrolytes (K, Na, Cl, CO2), Ca, BUN, Albumin, Total Protein, 
Phosphorus, AST (SGOT), ALT (SGPT), Alkaline Phosphatase, Total Bilirubin, 
Magnesium and Uric Acid 
• 
Fasting Glucose  
• 
Fasting Serum Lipid Profile (triglycerides, total cholesterol, HDL and LDL)  
• 
Patients on antiviral prophylaxis treatment or positive HBV antibodies should be 
tested for HBV-DNA on Cycle 1 Day 1 and Day 1 of all subsequent cycles (every 28 
days) to monitor for re-activation. If re-activation is confirmed, everolimus must be 
interrupted or discontinued according to the guidance in Table 5-4. Patients with 
positive HCV RNA-PCR results at screening and/or a history of past infection (even if 
treated and considered ‘cured’) should have HCV RNA-PCR testing performed on 
Cycle 1 Day 1 and Day 1 of all subsequent cycles (every 28 days) to monitor for 
flare. Everolimus must be discontinued if HCV reactivation is confirmed according to 
the guidance in Table 5-5. 
7.1.2.2 
Cycle 1 Day 15 
• 
Physical examination 
• 
Concomitant medication assessment (see Appendix C for list of excluded or 
medications requiring monitoring on study) 
• 
Vital signs, including blood pressure, heart rate, temperature, and weight 
• 
Assessment of ECOG performance status 
• 
Adverse event assessment and dose modifications as necessary (AEs should be 
monitored continuously). (see Section 5.3 for dose modification guidelines) 
• 
CBC with differential and platelets. In the event of grade 3 or 4 hematologic toxicity, 
CBC with differentia and platelet count will be obtained every 1-3 days until there is 
evidence of hematologic recovery. 
• 
Serum Creatinine, Electrolytes (K, Na, Cl, CO2), Ca, BUN, Albumin, Total Protein, 
Phosphorus, AST (SGOT), ALT (SGPT), Alkaline Phosphatase, Total Bilirubin, 
Magnesium and Uric Acid 
• 
Study Drug Compliance (Pill Diary) for everolimus/placebo 
 


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7.1.2.3 
Cycle 2 (and each subsequent cycle) Day 1 
• 
Physical examination 
• 
Concomitant medication assessment (see Appendix C for list of excluded or 
medications requiring monitoring on study) 
• 
Vital signs, including blood pressure, heart rate, temperature and weight 
• 
Assessment of ECOG performance status 
• 
Adverse event assessment and dose modifications as necessary (AEs should be 
monitored continuously, see Section 5.3 for dose modification guidelines). 
• 
CBC with differential and platelets. In the event of grade 3 or 4 hematologic toxicity, 
CBC with differential and platelet count will be obtained every 1-3 days until there is 
evidence of hematologic recovery. 
• 
Serum Creatinine, Electrolytes (K, Na, Cl, CO2), Ca, BUN, Albumin, Total Protein, 
Phosphorus, AST (SGOT), ALT (SGPT), Alkaline Phosphatase, Total Bilirubin, 
Magnesium and Uric Acid 
• 
Fasting Glucose (Cycle 2 Day 1, then every 12 weeks during treatment, and more 
frequently as clinically indicated) 
• 
Fasting Serum Lipid Profile (triglycerides, total cholesterol, HDL and LDL) (Cycle 2 
Day 1, then every 12 weeks during treatment, and more frequently as clinically 
indicated) 
• 
Patients on antiviral prophylaxis treatment or positive HBV antibodies should be 
tested for HBV-DNA on Cycle 1 Day 1 and Day 1 of all subsequent cycles (every 28 
days) to monitor for re-activation. If re-activation is confirmed, everolimus must be 
interrupted or discontinued according to the guidance in Table 5-4. Patients with 
positive HCV RNA-PCR results at screening and/or a history of past infection (even if 
treated and considered ‘cured’) should have HCV RNA-PCR testing performed on 
Cycle 1 Day 1 and Day 1 of all subsequent cycles (every 28 days) to monitor for 
flare. Everolimus must be discontinued if HCV reactivation is confirmed according to 
the guidance in Table 5-5. 
• 
Study Drug Compliance (Pill Diary) for everolimus/placebo 
7.1.2.4 
Every 12 Weeks 
• 
Tumor evaluation every 12 weeks, +/- 1 week (every 3 months) during the Induction 
Phase. Scans should be repeated at the assigned intervals regardless of cycle or 
treatment delays. 
• 
Fasting Glucose and Fasting Serum Lipid Profile (triglycerides, total cholesterol, HDL 
and LDL) to be done every 12 weeks during Induction Phase (and more frequently 
as clinically indicated) 
 


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7.1.3 
End of Induction Phase <OR> End of Treatment 
All patients will have the following assessments completed whether they are moving into 
the Continuation Phase or no longer will be receiving treatment and are moving into 
Follow-Up Off-Therapy due to reasons noted in Sections 5.5 or 5.6. The assessments 
should be completed within 30 days of last dose of fulvestrant and before moving from 
the Induction Phase into the Continuation Phase or before moving directly into the 
Follow-Up Phase. (Note: Day 1 of the Continuation Phase should start on D29 of cycle 
12 if the assessments below are completed in order to maintain the 28 day fulvestrant 
dosing schedule). 
• 
Physical examination 
• 
Concomitant medication assessment (see Appendix C for list of excluded or 
medications requiring monitoring on study) 
• 
Vital signs, including blood pressure, heart rate, temperature and weight 
• 
Assessment of ECOG performance status 
• 
Adverse event assessment. All patients will be followed for toxicity assessment for 
30 days after the last dose of study therapy (fulvestrant and/or everolimus/placebo) 
or until resolution to ≤ grade 1 attributed to study therapy (or if >grade 1, event must 
be permanent and stable). Serious adverse events >30 days after last dose of 
fulvestrant and/or everolimus/placebo are not reported unless the event may be 
related to everolimus/placebo. 
• 
Tumor evaluation if due per every 12 weeks +/- 1 week (every 3 months) evaluation 
schedule. 
• 
CBC with differential and platelets 
• 
Serum Creatinine, Electrolytes (K, Na, Cl, CO2), Ca, BUN, Albumin, Total Protein, 
Phosphorus, AST (SGOT), ALT (SGPT), Alkaline Phosphatase, Total Bilirubin, 
Magnesium and Uric Acid 
• 
Fasting Glucose 
• 
Fasting Serum Lipid Profile (triglycerides, total cholesterol, HDL and LDL) 
• 
Study Drug Compliance (Pill Diary) for everolimus/placebo 
Patients in the Continuation Phase should continue to receive fulvestrant alone (if 
originally randomized to placebo) or in combination with everolimus (if originally 
randomized to everolimus) at the same dose and schedule until disease progression or 
unacceptable toxicity. 
Patients that are moving from the Induction Phase into Follow-Up Off Therapy should 
not receive further investigational therapies for at least 30 days after the last dose of 
study drug, if possible, in order to eliminate overlapping toxicity. 
 


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7.1.4 
Continuation Phase (fulvestrant +/- everolimus) 
Patients with no evidence of disease progression after 12 cycles of treatment (Induction 
Phase) will be unblinded and proceed to the Continuation Phase. Patients in the 
Continuation Phase should continue to receive fulvestrant alone (if originally randomized 
to placebo) or in combination with everolimus (if originally randomized to everolimus) at 
the same dose and schedule until disease progression is documented or unacceptable 
toxicity. Once progression is documented, patients will move into Follow-Up Off Therapy. 
One cycle in the Continuation Phase is equal to 28 days. Day 1 of the Continuation 
Phase should start 28 days (D29) after the last dose of fulvestrant was given during 
Cycle 12 in the Induction Phase. 
All adverse events that are related to fulvestrant and/or everolimus will be followed for 30 
days after the last dose of study therapy (fulvestrant and/or everolimus) until ≤ grade 1 
or if the grade is >1, the event must be permanent and stable. 
• 
CBC and chemistry may be used to monitor any ongoing toxicities, but are not 
required for patients that receive fulvestrant alone. 
• 
Patients who continue fulvestrant in combination with everolimus should periodically 
have CBC, chemistries, fasting glucose, fasting serum lipids, HBV DNA, and HCV 
RNA-PCR per labeling guidelines. 
• 
Study Drug Compliance (Pill Diary) for those patients who receive everolimus in the 
Continuation Phase. 
After the Continuation Phase, serious adverse events >30 days after last dose of 
fulvestrant and/or everolimus are not reported unless the event may be related to 
everolimus. 
7.1.4.1 
Every 12 Weeks 
• 
Tumor evaluation every 12 weeks, +/- 1 week (every 3 months) during the 
Continuation Phase until disease progression is documented. 
7.1.5 
Follow-Up Off-Therapy 
All patients, including those who discontinue protocol therapy, will be followed for 3 
years from the time of randomization. Patients that did not progress during the Induction 
or Continuation Phase will continue to have imaging scans completed every 3 months 
until documented progression. Patients will then be followed for survival. Initiation of any 
new systemic therapy will also be documented. Patients that have adverse events 
related to fulvestrant and/or everolimus/placebo will be followed for 30 days after the last 
dose of study therapy (fulvestrant and/or everolimus/placebo) until ≤ grade 1 or if the 
grade is >1, the event must be permanent and stable. Serious adverse events >30 days 
after last dose of fulvestrant and/or everolimus/placebo are not reported unless the event 
may be related to everolimus/placebo. 


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8 
Drug Formulation and Procurement 
8.1 Everolimus 
8.1.1 
Packaging and Labeling 
Full instructions for investigator sites and investigational pharmacies will be available in 
separate protocol-specific documents. The supply of everolimus or placebo will be 
shipped directly to the local investigator. Drug ordering procedures will be provided in 
supplemental study materials. 
8.1.1.1 
How Supplied 
Everolimus and an identically appearing placebo will be provided by Novartis. 
Everolimus is formulated as tablets for oral administration of 5 mg strength. Tablets are 
blister-packed under aluminum foil in units of 10 tablets per blister card, which should be 
opened only at the time of administration as drug is both hygroscopic and light-sensitive. 
Each 
tablet 
contains 
as 
inactive 
ingredients: 
butylhyroxytoluene/butylated 
hydroxytoluene (BHT), magnesium stearate, lactose monohydrate, hypromellose, 
crospovidone and lactose anhydrous. 
Medication labels will comply with US legal requirements and be printed in English. They 
will supply no information about the patient. The storage conditions for study drug will be 
described on the medication label. 
8.1.2 
Storage Requirements/Stability 
Everolimus should be stored at room temperature between 20°C to 25°C (68°F to 77°F). 
All investigational products must be kept in a secure place under appropriate storage 
conditions. A description of the appropriate storage and shipment conditions is specified 
on the investigational product label and investigator brochure. The stored study drug 
supplies must be accessible to authorized staff only. The storage area must also have 
adequate control of temperature in order to maintain stability and potency of study drug 
supplies. The tablets should be stored in the original pack until use. For further 
information, investigators should refer to the current Investigators Brochure (IB). 
8.1.3 
Handling, Dispensing and Administration 
8.1.3.1 
Handling 
No special precautions are necessary when handling intact tablets. Avoid contact with 
skin and eyes. Wash hands after use. The risk to health in normal handling of tablets is 
very low. Exposure to dust from crushed tablets may cause adverse health effects. 
8.1.3.2 
Dispensing 
Drug should be dispensed in original packaging. If other packaging is required by 
institutional policy, this procedure will need to be approved by PrECOG, or their 
designee, prior to proceeding. The PrECOG Site Contact should be contacted for further 


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instruction. Investigational product records should be kept as per Section 8.1.5 and 
institutional policies. 
8.1.3.3 
Administration 
Patients should be instructed to take their assigned, once-a-day oral dose of 
everolimus/placebo at the same time each morning. 
• 
Everolimus/placebo dose may be taken with or without food. 
• 
Patients should be instructed to swallow the capsules whole and not chew them. 
• 
Vomited doses should not be replaced. 
• 
If the patient forgets to take the medication and remembers by 10 PM, they may take 
the dose. Otherwise, skip that dose and begin as usual the next day. 
In cases where tablets cannot be swallowed, the tablets should be disintegrated in water 
just prior to being taken. Approximately 30 mL (2 tablespoons) of water should be put 
into a glass. The tablets should then be added and the contents stirred gently (for a 
maximum of 7 minutes) until the tablets are disintegrated. The contents should then be 
drunk. 
Patients should be given instructions on correct dosing based on study requirements 
and toxicity management (dose modifications). All changes to recommended dosing 
regimen/schedule should be documented in the patient record. Documentation of patient 
instructions for dosing changes should also be in source records. 
Patients should be instructed to record the reason for any missed doses and report to 
the investigator at the next visit. If a dose is vomited, that dose should not be replaced, 
(and recorded as a vomited dose). 
Compliance with therapy will be assessed at the beginning of each cycle. Patients will be 
given a diary (see Appendix F for an Example Patient Pill Diary) for recording of doses of 
study drug as provided by each study site. A copy of the patient diary will be provided to 
sites in study materials. 
8.1.3.4 
Special Instructions for Unblinding 
Patients on study therapy and all site study staff will remain blinded as to the assignment 
of everolimus or placebo. Patients who have not had progressive disease and remain on 
study after 12 cycles are unblinded and continue fulvestrant alone (if originally 
randomized to placebo) or in combination with everolimus (if originally randomized to 
everolimus) at the same dose and schedule in the Continuation Phase. If an emergency 
situation arises and the patient must be unblinded during the Induction Phase (Cycles 1-
12), the Medical Monitor for the study must be consulted. 
Emergency Unblinding for Patients during the Induction Phase (within Cycles 1-12): 
Unblinding is a serious action that should be restricted in order to limit potential study 
bias. The breaking of the blinding code in all cases will render the patient off-protocol. 
The Medical Monitor for the study must be involved in the decision to unblind and must 
grant approval for unblinding any individual. Requests for unblinding will only be 
considered in the event of an emergency or severe adverse reaction where identification 


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of the medication is considered important for the welfare of the patient, and the rationale 
for unblinding is applicable to the situation. All patients should be provided emergency 
medical care by the treating physician and appropriate therapies for the medical 
emergency should be initiated prior to the request for unblinding. 
For example, a Serious Adverse Event (SAE) possibly, probably or definitely related to 
the study drug occurs during the trial and the treatment of the SAE would be influenced 
by whether he/she received everolimus or placebo. Unblinding is typically not necessary 
if the medical management of the patient would not be materially altered by knowledge 
of the treatment assignment. In the event that accidental unblinding occurs, the Principal 
Investigator should report the occurrence promptly to the Medical Monitor and document 
the incident in the patient records. All unblinding will be recorded as a protocol deviation. 
If a participant is in a life-threatening situation in which knowledge of the treatment is 
crucial to care AND the Medical Monitor cannot be reached immediately, the PM should 
be contacted to facilitate the unblinding process. A report including the unblinding details 
will be generated after the patient has been unblinded and will be sent to the site for 
documentation (refer to Study Reference Manual for Unblinding Process). Report 
information will include but is not limited to: 
• 
ID number of the participant whose treatment assignment was unblinded 
• 
Date of unblinding and reconciliation of study drug in site and patient records 
• 
Reason for unblinding, including initial SAE report 
• 
Person responsible for unblinding 
• 
List of persons who are unblinded (e.g. study staff) 
8.1.4 
Side Effects 
The most common adverse reactions (incidence ≥ 10%) reported for everolimus include 
stomatitis, rash, fatigue, asthenia, diarrhea, anorexia, nausea, mucosal inflammation, 
vomiting, cough, peripheral edema, infections, dry skin, epistaxis, pruritus, and dyspnea. 
The most commonly reported grade 3-4 adverse reactions (incidence ≥ 2%) reported for 
everolimus include infections, stomatitis, fatigue, and pneumonitis. 
8.1.5 
Investigational Product Records at Investigational Site(s) 
Investigational product dispensing record/inventory logs and copies of signed packing 
lists must be maintained at the investigational site for everolimus. It is the responsibility 
of the Investigator to ensure that a current record of investigational product disposition is 
maintained at each study site where investigational product is stored and/or dispensed. 
Records must comply with applicable regulations and guidelines, and should include: 
• 
Amount received and placed in storage area. 
• 
Amount currently in storage area. 
• 
Label ID number or batch number. 
• 
Dates and initials of person responsible for each investigational product inventory 
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• 
Amount dispensed to and returned by each patient, including unique patient 
identifiers. 
• 
Amount transferred to another area for dispensing or storage. 
• 
Non-study disposition (e.g., wasted, broken). 
• 
Amount returned to manufacturer, if applicable 
• 
Amount destroyed at study site, if applicable 
8.1.6 
Return and Destruction of Investigational Product 
Investigational product should be maintained at the site for accountability purposes. 
Sites will be referred to the study pharmacy manual for instructions regarding the return 
or destruction of everolimus study drug supply (site’s drug destruction policy must be 
reviewed and approved by PrECOG before any study drug can be destroyed at a site). 
Patients will be instructed to return all blister packs (empty or partially used) to the study 
center. 
8.2 Fulvestrant (Faslodex) 
8.2.1 
Packaging and Labeling 
Fulvestrant is commercially available and approved and is indicated for the treatment of 
HR-positive metastatic breast cancer in postmenopausal women whose disease has 
returned or progressed following antiestrogen therapy. 
Investigators should review the approved Package Insert (PI) (http://www.faslodex.com/ 
faslodex-prescribing-info/index.aspx) 
for 
full 
information 
on 
storage, 
handling, 
preparation and stability. 
Fulvestrant is supplied as: 
One clear neutral glass (Type 1) barrel containing 250 mg/5 mL (50 mg/mL) Injection for 
intramuscular injection and fitted with a tamper-evident closure. NDC 0310-0720-50. 
(Note: Patients will be receiving 500 mg doses IM therefore 2 injections of 250 mg will 
be required for one dose.) 
The syringes are presented in a tray with polystyrene plunger rod and safety needles 
(SafetyGlide™) for connection to the barrel. 
Each injection contains as inactive ingredients: Alcohol, USP, Benzyl Alcohol, NF, and 
Benzyl Benzoate, USP as co-solvents, and Castor Oil, USP as a co-solvent and release 
rate modifier. 
 
 


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8.2.2 
Handling and Dispensing 
8.2.2.1 
Storage Requirements/Stability 
Refrigerate 2°-8°C (36°-46°F). To protect from light, store in the original carton until time 
of use. 
8.2.2.2 
Preparation and Administration 
Fulvestrant should be disposed of or destroyed as per written institutional policies and 
per recommendations in the current approved Package Insert. To help avoid infectious 
diseases due to accidental needle sticks, contaminated needles should not be recapped 
or removed, unless there is no alternative or that such action is required by a specific 
medical procedure. 
WARNING: - Do not autoclave safety needle before use. Hands must remain 
behind the needle at all times during use and disposal. 
Directions: 
(Source: Faslodex® Package Insert 1621903 Rev 12/11) 
• 
Remove the glass syringe barrel from tray and check that it is not damaged 
• 
Remove perforated patient record label from syringe 
• 
Peel open the safety needle outer packaging. 
• 
Break the seal of the white plastic cover on the syringe luer connector to remove the 
cover with the attached rubber tip cap (Figure 1). 
• 
Twist to lock the needle to the luer container. 
• 
Remove the needle sheath. Pull shield straight off needle to avoid damaging needle 
point. 
• 
Remove excess gas from the syringe. 
• 
Administer intramuscularly slowly in the buttock. Administer injection following 
package instruction. For user convenience, the needle ‘bevel up’ position is 
orientated to the lever arm (Figure 3). 
• 
Immediately activate needle protection device upon withdrawal from patient by 
pushing lever arm completely forward until the tip is fully covered (Figure 2). 
• 
Visually confirm that the lever arm has fully advanced and the needle tip is covered. 
If unable to activate, discard immediately into an approved sharps collector. 
Activation of the protective mechanism may cause minimal splatter of fluid that may 
remain on the needle after injection. For greatest safety, use a one-handed 
technique and activate away from self and others. 
• 
If the 250 mg/5 mL formulation is used, repeat the above steps for the second 
syringe. After single use, discard in an approved sharps collector in accordance with 
applicable regulations and institutional policy. 
• 
Review the official package insert for more information regarding the use of the 
SafetyGlide Needle. 
 
 


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8.2.3 
Side Effects 
The most commonly reported adverse experiences in the Faslodex® treatment groups, 
regardless of the investigator’s assessment of causality, were gastrointestinal symptoms 
(including nausea, vomiting, constipation, diarrhea and abdominal pain), headache, back 
pain, vasodilatation (hot flushes), and pharyngitis. 
Injection site reactions with mild transient pain and inflammation were seen with 
Faslodex® and occurred in 7% of patients (1% of treatments) given the single 5 mL 
injection (predominately European Trial) and in 27% of patients (4.6% of treatments) 
given the 2 x 2.5 mL injections (North American Trial). 
Other adverse events reported as drug-related and seen infrequently (<1%) include 
thromboembolic phenomena, myalgia, vertigo, leukopenia and hypersensitivity reactions 
including angioedema and urticaria. Vaginal bleeding has been reported infrequently 
(<1%), mainly in patients during the first 6 weeks after changing from existing hormonal 
therapy to treatment with Faslodex® If bleeding persists, further evaluation should be 
considered. 
 


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9 
Statistical Considerations 
The efficacy endpoints will be assessed among all eligible patients who receive protocol 
therapy. Safety endpoints will be assessed among all treated patients, regardless of 
eligibility. 
9.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is progression-free survival (PFS). PFS is defined as the 
time from randomization to documented disease progression or death. Based on results 
from the CONFIRM trial, median PFS among patients with AI-resistant disease on 
fulvestrant alone is 5.4 months. AI resistant disease is defined as: patients who have 
either relapsed while receiving adjuvant therapy with an aromatase inhibitor 
(anastrozole, letrozole, or exemestane) or have progressive disease while receiving an 
aromatase inhibitor for metastatic disease. (Patients previously treated with two or more 
prior cycles of fulvestrant are not eligible. Patients who have received one prior cycle 
(day 1 and day 15) of fulvestrant within 28 days of randomization are eligible so long as 
they meet other eligibility criteria). Randomization will be 1:1, stratified for balancing 
purposes using ECOG performance status (0 vs. 1), presence of measurable disease 
(yes vs. no), and prior chemotherapy (yes vs. no). 
We hypothesize that the addition of everolimus to fulvestrant will result in an 
improvement in median PFS to 9.2 months. A one-sided stratified logrank test with a 
type I error rate of 10% will be used to evaluate whether the addition of everolimus 
shows promising improvement in PFS relative to fulvestrant alone. To have 90% power 
to detect the hypothesized improvement, enrollment of approximately 120 eligible 
patients (60 per arm) and full information of 98 events (deaths or progressions) are 
required. Allowing up to 10 patients to be ineligible or to not start study treatment, 
approximately 130 patients will need to be enrolled. With accrual of approximately 130 
patients in 12 months, the required 98 events are expected to occur approximately 12 
months after accrual is completed. Other endpoints that will be evaluated include clinical 
benefit rate (proportion stable or responding for at least 6 months), objective response 
rate (CR+PR), time to progression (TTP; defined as the time from randomization until 
progression of the disease), and overall survival (OS; defined as the time from 
randomization until death or censored at the date of last follow-up). 
PFS will be evaluated using the stratified log-rank test described above, as will TTP and 
OS. Kaplan-Meier plots will be used to graphically portray these time-to-event endpoints. 
Clinical benefit rate and objective response rates will be compared between arms using 
Fisher’s exact tests. 90% exact binomial confidence intervals on the rates will be 
provided. 
9.2 Safety Analyses 
A descriptive comparison of overall toxicity and of grade 3-4 toxicity in the combination 
arm and the fulvestrant arm will be provided. Assuming 65 patients are treated on each 
arm, the exact binomial 90% confidence interval on the rate of severe toxicities will be no 
wider than 22% (+/- 11%). The probabilities of observing a rare toxicity (true rate of 5%) 
will be 96% on each arm. 


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9.3 Analyses of Other Secondary Endpoints 
Other endpoints that will be evaluated include overall survival, time to progression, and 
objective response rate. Overall survival will be characterized using Kaplan-Meier plots 
and other descriptive metrics. The objective response rate will be provided for each arm, 
with 90% exact binomial confidence intervals. Median time to progression will be 
estimated for each arm. 


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10 Adverse Event Reporting 
10.1 Collection of Safety Information 
Adverse Event (AE) is defined as any new untoward medical occurrence or worsening 
of a pre-existing medical condition in a patient administered a medicinal product in a 
clinical investigation and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a product (investigational or marketed), whether or not considered related 
to the product (investigational or marketed). Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs and symptoms, are 
considered clinically significant, or require therapy. 
Following written consent to participate in the study, all serious AEs should be collected 
on a patient. The collection of non-serious AE information should begin at initiation of 
therapy. 
All identified AEs must be recorded and described on the appropriate page of the Case 
Report Form (CRF). If known, the diagnosis of the underlying illness or disorder should 
be recorded, rather than individual symptoms. The following information should be 
documented for all AEs: date of onset and resolution, severity of the event; the 
investigator’s opinion of the relationship to investigational product (see definitions 
below); treatment required for the AE; cause of the event (if known); and information 
regarding resolution/outcome. 
Severity 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.0 will be utilized for AE reporting. A copy of the CTCAE Version 4.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov). 
All appropriate treatment areas should have access to a copy of the CTEP CTCAE 
Version 4.0 (see Appendix E). 
Attribution 
The following categories and definitions of causal relationship or attribution to study drug 
should be used to assess Adverse Events: 
• 
Definite: There is a reasonable causal relationship between the study drug and the 
event. The event responds to withdrawal of study drug (dechallenge) and recurs with 
rechallenge, if clinically feasible. 
• 
Probable: There is a reasonable causal relationship between the study drug and the 
event. The event responds to dechallenge. Rechallenge is not required. 
• 
Possible: There is a reasonable causal relationship between the study drug and the 
event. Dechallenge information is lacking or unclear. 
• 
Unlikely: There is doubtful causal relationship between the study drug and the event. 


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• 
Unrelated: There is clearly not a causal relationship between the study drug and the 
event or there is a causal relationship between another drug, concurrent disease, or 
circumstances and the event. 
Categories ‘Definite’, ‘probable’ and ‘possible’ are considered study drug related. 
Categories ‘not likely’ and ‘not related’ are considered not study drug-related. 
The development of a new cancer should be regarded as an AE. New cancers are those 
that are not the primary reason for administration of study treatment and have been 
identified after inclusion of the patient into the clinical study. 
AEs related to fulvestrant and/or everolimus/placebo will be followed for 30 days 
after the last dose of study therapy (fulvestrant and/or everolimus/placebo) until ≤ 
grade 1 or stabilization, and reported as SAEs if they become serious. Serious 
adverse events >30 days after last dose of fulvestrant and/or everolimus/placebo 
are not reported unless the event may be related to everolimus/placebo. 
10.2 Handling of Serious Adverse Events (SAEs) 
10.2.1 SAE Definitions 
A serious AE is any untoward medical occurrence occurring after informed consent is 
granted or that at any dose: 
• 
results in death, 
• 
is life-threatening (defined as an event in which the study patient was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe), 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization, 
• 
results in persistent or significant disability/incapacity, 
• 
is a congenital anomaly/birth defect, 
• 
is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the patient or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization. 
10.2.2 SAE Reporting Requirements 
All serious adverse events require expeditious handling and reporting to comply with 
regulatory requirements. The Principal Investigator has the obligation to report all 
serious adverse events to PrECOG, or their designee.  A study specific SAE form to be 
utilized for SAE reporting will be provided with supplemental study materials. 


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All serious adverse events that occur either during the  study period (Induction and/or 
Continuation) or within 30 days of discontinuation of dosing regardless of event 
relationship to the study medications (fulvestrant and/or everolimus/placebo) should be 
reported to PrECOG, or their designee within 24 hours of the investigator’s knowledge of 
the event or, when the event occurs on a weekend or national holiday, at the latest on 
the following working day. All deaths during treatment or within 30 days following 
completion of active protocol therapy must be reported. Serious adverse events that 
occur >30 days from last dose of fulvestrant and/or everolimus/placebo and are judged 
related to the everolimus/placebo (definitely, probably or possibly) must be reported to 
PrECOG, or their designee using the 24 hour timeline noted above. If only limited 
information is initially available, follow-up reports are required. Serious adverse events 
that occur >30 days from last dose of fulvestrant and are judged to be related to 
fulvestrant will follow normal reporting mechanisms for commercial drugs. 
SAE Hotline Phone Number: 
610-354-0404 during normal business hours (8:30 AM – 5 PM EST) 
484-574-2367 after normal business hours (after 5 PM EST) 
SAE Fax Number: 
888-801-8795 
PrECOG will notify Novartis Pharmaceuticals Drug Safety and Epidemiology Department 
(DS&E) of all SAE’s within 24 hours of the Awareness Date. Relevant follow-up 
information will be provided to Novartis DS&E as soon as it becomes available.  
In addition, Investigators should also report event(s) to their IRB as required. 
Collection of complete information concerning SAEs is extremely important. Full 
descriptions of each event will be followed. Thus, follow-up information which becomes 
available as the SAE evolves, as well as supporting documentation (e.g., hospital 
discharge summaries and autopsy reports), should be collected subsequently, if not 
available at the time of the initial report, and immediately sent using the same procedure 
as the initial SAE report. The original and all follow-up SAEs form must be kept on file at 
the study site. 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious 
adverse experiences will be forwarded to the product manufacturer by PrECOG (or their 
designee), if applicable. 
10.3 Reporting of Second Primary Cancers 
New cancers are those that are not the primary reason for administration of study 
treatment and have been identified after inclusion of the patient into the clinical study. 
All cases of new primary cancers that occur during or after protocol treatment must be 
reported to PrECOG within 30 days of diagnosis, regardless of relationship to protocol 
treatment. Secondary primary malignancies should also be reported as a SAE. This form 
is not for use for reporting recurrence or development of metastatic disease. A copy of 
the pathology report, if applicable, should be sent, if available. 
Note: Once data regarding survival and remission status are no longer required by the 
protocol, no follow-up data should be submitted, including the PrECOG Second Primary 
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11 Administrative 
11.1 Protocol Compliance 
The study shall be conducted as described in this protocol. All revisions to the protocol 
must be discussed with, and be prepared by PrECOG and/or representatives. The 
Investigator should not implement any deviation or change to the protocol or consent 
without prior review and documented approval from PrECOG and/or representatives and 
the IRB of an amendment, except where necessary to eliminate an immediate hazard(s) 
to study patients. 
If a deviation or change to the approved protocol is implemented to eliminate an 
immediate hazard(s) prior to obtaining IRB approval, notification will be submitted to the 
IRB for review and approval as soon as possible afterward. Documentation of approval 
signed by the chairperson or designee of the IRB(s) should be in the study records. If 
PrECOG and/or representatives provides an amendment that substantially alters the 
study design or increases the potential risk to the patient; the consent form must be 
revised and submitted to the IRB(s) for review and approval; the revised form must be 
used to obtain consent from patients currently enrolled in the study if they are affected 
by the amendment; and the new form must be used to obtain consent from new patients 
prior to study entry. Information as to who investigators should send correspondence will 
be provided in additional study documents. 
11.2 Institutional Review Board 
Before study initiation, the Investigator must have written and dated approval from their 
respective IRB for the protocol, consent form, patient recruitment materials/process and 
any other written information to be provided to patients. The Investigator should also 
provide the IRB with a copy of the Investigator Brochure or product labeling, and any 
updates. 
The Investigator should provide the IRB with reports, updates, and other information 
(e.g., Safety Updates, amendments, and administrative letters) according to regulatory 
requirements, IRB or study site procedures. 
11.3 Informed Consent Procedures 
Investigators must ensure that patients who volunteer for clinical trials or their legally 
acceptable representative are clearly and fully informed about the purpose, potential 
risks and other information. 
A protocol specific informed consent form (ICF) template will be provided to sites. 
Preparation of the site-specific consent form is the responsibility of the site Investigator 
and must include all applicable regulatory and IRB requirements, and must adhere to 
Good Clinical Practice (GCP) and to the ethical principles that have their origin in the 
Declaration of Helsinki. All changes to the ICF template will be approved by PrECOG 
and/or their representatives prior to implementation. 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
consent process will also include written authorization by patients to release medical 
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record at the study site for access to patient records and medical information relevant to 
the study, including the medical history. This will be documented in the informed consent 
form or other approved form obtained at the time of informed consent per institutional 
policies. This form should also be submitted to PrECOG and/or its agents for review 
prior to its implementation. 
The Investigator must provide the patient or legally acceptable representative with a 
copy of the consent form and written information about the study in the language in 
which the patient is most proficient. The language must be non-technical and easily 
understood. The Investigator should allow time necessary for patient or patient's legally 
acceptable representative to inquire about the details of the study, then informed 
consent must be signed and personally dated by the patient or the patient's legally 
acceptable representative and by the person who conducted the informed consent 
discussion. The patient or legally acceptable representative should receive a copy of the 
signed informed consent and any other written information provided to study patients 
prior to patient's participation in the trial. The investigator is responsible for assuring 
adequate documentation of this process and for storage and maintenance of the original 
signed consent form for each patient/subject. 
The informed consent and any other information provided to patients or the patient's 
legally acceptable representative, should be revised whenever important new 
information becomes available that is relevant to the patient's consent, and should 
receive IRB approval prior to use. The Investigator, or a person designated by the 
Investigator should inform the patient or the patient's legally acceptable representative of 
all pertinent aspects of the study and of any new information relevant to the patient's 
willingness to continue participation in the study. This communication should be 
documented in the patient record. During a patient's participation in the trial, any updates 
to the consent form and any updates to the written information will be provided to the 
patient. 
11.4 Safety Communication 
Investigators will be notified of all AEs that are serious, unexpected, and definitely, 
probably, or possibly related to the investigational product. Upon receiving such notices, 
the Investigator must review and retain the notice with the Investigator Brochure and 
submit a copy of this information to the Institutional Review Board (IRB) according to 
local regulations. The Investigator and IRB will determine if the informed consent 
requires revision. The Investigator should also comply with the IRB procedures for 
reporting any other safety information. All revisions should be submitted to PrECOG 
and/or agents for review. 
11.5 Monitoring 
Representatives and agents of PrECOG and, as applicable to the study, the 
manufacturer of Investigational Product must be allowed to visit all study site locations 
periodically to assess the data, quality and study integrity. The purpose of this visit is to 
review study records and directly compare them with source documents and discuss the 
conduct of the study with the Investigator, and verify that the facilities remain acceptable. 
The study may be evaluated by other auditors and government inspectors who must be 
allowed access to electronic Case Report Forms (eCRFs), source documents and other 


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study files. The investigator must notify PrECOG of any scheduled visits by regulatory 
authorities, and submit copies of all reports. Information as to who investigators should 
notify of an audit or where to address questions will be provided in additional study 
materials. Monitoring of drug accountability will also occur. 
11.6 Study Records 
An Investigator is required to maintain adequate regulatory files with corresponding 
communication and approvals, accurate histories, observations and other data on each 
individual treated. Full details of required regulatory documents will be provided in 
additional study materials. Data reported on the eCRF must be consistent with the 
source documents as part of the patient record. 
The confidentiality of records that could identify patients must be protected, respecting 
the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s). 
A study specific signature record will be maintained to document signatures and initials 
of all persons at a study site who are authorized to make entries and/or corrections on 
eCRFs as well as document other study-specific roles. 
11.7 Electronic Case Report Form (eCRF) Information 
Additional information regarding eCRF instructions, timelines for data entry/submission 
and query completion can be found in supplemental materials provided to the site. Sites 
will be expected to complete eCRFs as per the schedule provided and submit all 
relevant data as per the specified timelines. All items recorded on eCRFs must be found 
in source documents. 
The completed eCRF must be promptly reviewed, electronically signed, and dated by a 
qualified physician who is an Investigator or Sub-Investigator. 
Instructions for management of patients who do not receive any protocol therapy:  
If a patient is randomized and does not receive any assigned protocol treatment, 
baseline, Serious Adverse Event and follow-up data will still be entered and must be 
submitted according to the eCRF instructions. Document the reason for not starting 
protocol treatment on the appropriate electronic off-treatment form. 
11.8 Records Retention 
FDA Regulations (21CFR 312.62) require clinical investigators to retain all trial-related 
documentation, including source documents for the periods described below for studies 
performed under a US IND: 
• 
two years after the FDA approves the marketing application, or 
• 
two years after the FDA disapproves the application for the indication being studied, 
or 
• 
two years after the FDA is notified by the sponsor of the discontinuation of trials and 
that an application will not be submitted. 
The Investigator must retain investigational product disposition records, copies of eCRFs 
(or electronic files), and source documents for the maximum period required by 


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applicable regulations and guidelines, or Institution procedures, whichever is longer but 
not less than 5 years from the completion of the study. The Investigator must contact 
PrECOG and/or representatives prior to destroying any records associated with the 
study. 
Information as to who investigators should contact for questions will be provided in 
additional study documents. PrECOG and/or representatives will notify the Investigator 
when the trial records for this study are no longer needed. 


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12 Glossary of Terms and List of Abbreviations 
Term 
Definition 
4E-BP1 
4E-Binding Protein 
Ab 
Antibodies 
ADPKD 
Autosomal Dominant Polycystic Kidney Disease 
ADR 
Adverse Drug Reaction 
AE(s) 
Adverse Events(s) 
Akt/PKB 
Protein Kinase B 
AI 
Aromatase Inhibitor 
Alk Phos 
Alkaline Phosphatase 
ALT/SGPT 
Alanine Aminotransferase/Glutamic Pyruvic Transaminase/Serum Glutamic-
Pyruvic Transaminase 
AMD 
Age-Related Macular Degeneration 
ANC 
Absolute Neutrophil Count 
ASCO-CAP 
American Society of Clinical Oncology-College of American Pathologist 
AST/SGOT 
Aspartate 
Aminotransferase/Glutamic 
Oxaloacetic 
Transaminase/Serum 
Glutamic-Oxaloacetic Transaminase 
AUC 
Area Under the Concentration-Time Curve 
°C 
degrees Celsius 
Ca 
Calcium 
CBC 
Complete Blood Count 
CBR 
Clinical Benefit Rate 
CI 
Confidence Interval 
CISH 
Chromogenic In Situ Hybridization 
Cl 
Chloride 
cm 
centimeter 
Cmax 
Maximum plasma concentration 
CO2 
Carbon Dioxide 
CoA 
Coenzyme A 
COPD 
Chronic Obstructive Pulmonary Disease 
CPK 
Creatine Phosphokinase 
CR 
Complete Response 
CRC 
Colorectal Cancer 
Creat 
Creatinine 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computer Tomography 
CTC 
Common Toxicity Criteria 


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Term 
Definition 
CTCAE 
The CTEP Common Terminology Criteria for Adverse Events (CTCAE)  
CTEP 
Cancer Therapy Evaluation Program 
CYP3A4 
CytochromeP450 3A4 Isoenzyme 
DLBCL 
Diffuse Large B Cell Lymphoma 
DLCO 
Diffusing Capacity of the Lung for Carbon Monoxide 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DS&E 
Drug Safety and Epidemiology 
eCRF 
Electronic Case Report Form 
e.g. 
exempli gratia (for example) 
ER 
Estrogen Receptor 
FSH 
Follicle Stimulating Hormone 
EU 
European Union 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorine-18-2-fluoro-Deoxy-D-Glucose Positron Emission Tomography 
FISH 
Fluorescence In Situ Hybridization 
FKBP-12 
FK506-Binding Protein 12 
FSH 
Follicle Stimulating Hormone 
GBM 
Glioblastoma Multiforme 
GCP 
Good Clinical Practice 
GEP-NET 
Gastroenteropancreatic Neuroendocrine Tumor 
GERD 
Gastroesophageal Reflux Disease 
GF 
Growth Factor 
GI 
Gastrointestinal 
GnRH 
Gonadotropin-Releasing Hormone 
HBV 
Hepatitis B Virus 
HBcAb 
Hepatitis B core Antibodies 
HBsAb 
Hpatitis B surface Antibodies 
HbsAg 
Hepatitis B surface Antigen 
HCC 
Hepatocellular Cancer 
HCV 
Hepatitis C Virus 
HER-2 
Human Epidermal Growth Factor Receptor 2 
HIF-1 
Hypoxia-Inducible Factor-1 
HIPAA 
Health Information Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HMG 
3-hydroxy-3-methyl-glutaryl 
HR 
Hormone-Receptor 
HUVECS 
Human Umbilical Endothelial Cells 
IB 
Investigator Brochure (also called Investigator Drug Brochure, IDB) 


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Term 
Definition 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
INN 
International Non-Proprietary Name 
INR 
International Normal Ratio 
IRB  
Institutional Review Board 
IU 
International Unit 
IV 
Intravenous 
IWR 
Interactive Web Randomization 
K 
Potassium 
kg 
Kilogram 
L 
Liter 
LDH 
Lactate Dehydrogenase 
LDL 
Low-Density Lypoproteins 
LFTs 
Liver Function Tests 
LLN 
Lower Limit Normal 
LMW 
Low Molecular Weight 
Log10 
Decadic logarithm (common logarithm) 
M 
Meter 
mg 
Milligram 
Mg 
Magnesium 
min 
minute 
mL 
Milliliter 
mRCC 
Metastatic Renal Cell Carcinoma 
MRI 
Magnetic Resonance Imaging 
mTOR 
mammalian Target of Rapamycin 
N 
Number of patients or observations 
Na 
Sodium 
N/A 
Not Applicable 
NCI 
National Cancer Institute 
NSCLC 
Non-Small Cell Lung Cancer 
Ng 
Nanogram 
µM 
Micromolar 
Nm 
Nanometer 
nM 
Nanomolar 
OS 
Overall Survival 
PD 
Progressive Disease 
P13K 
Phosphoinositide 3-kinase  


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Term 
Definition 
PI 
Package Insert 
PBMC 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase Chain Reaction 
PET 
Proton Emission Tomography 
PFS 
Progression Free Survival 
PgP 
P-glycoprotein 
PK 
Pharmacokinetic 
Plt 
Platelet 
PNET 
Pancreatic Neuroendocrine Tumor 
PO 
Per Oral (by mouth route of administration) 
PR 
Partial Response 
PR-positive 
Progesterone Receptor 
PSA 
Prostate-Specific Antigen 
PTEN 
Phosphatase and Tensin Homolog Deleted on Chromosome 10 
PT/PTT 
Prothrombin Time/Partial Thromboplastin Time 
QC 
Quality Control 
QD 
Once Daily 
QT 
the interval between the beginning of the Q-wave and the end of the T-wave on 
an electrocardiogram 
QTc 
corrected Q to T wave interval on electrocardiogram 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criterion Solid Tumors 
RNA 
Ribonucleic Acid 
RR 
Response Rate 
RTK 
Receptor Tyrosine Kinase 
S6K1 
S6 Kinase 1 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SCLC 
Small Cell Lung Cancer 
SD 
Stable Disease 
SEGA 
Subependymal Giant Cell Astrocytoma 
SERD 
Selective Estrogen Receptor Down-Regulators 
SERM 
Selective Estrogen Receptor Modulator 
T Bili 
Total Bilirubin 
TKI 
Tyrosine Kinase Inhibitor 
TS 
Tuberous Sclerosis 
TSC 
Tuberous Sclerosis Complex 
TTP 
Time to Progression 


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Term 
Definition 
TUNNEL 
Terminal Deoxynucleotidyl Transferase (TdT)-Mediated dUTP-Biotin Nick End 
Labeling 
µg 
microgram 
ULN 
Upper Limit Normal 
US 
United States 
USP 
United States Pharmacopeia 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cell Count 
WHO 
World Health Organization 
 


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13 Appendix A: Eligibility Checklist 
 
 Pt Initials:   ___   ___   ___                Study Personnel: ____________________________ 
                   F       M       L                   Date of Evaluation: ___/___/____ 
 
INCLUSION CRITERIA 
 
Must be willing to sign a protocol-specific informed consent.  
Consent Date: _____/_____/_____     
 Consent in patient record 
 
Age > 18 and female. 
Birth Date: _____/_____/_____           
 Documentation in patient record 
 
ECOG Performance Status 0 or 1. 
PS        
  0    
  1    (must document in patient record) 
 
Patient must have histologically or cytologically confirmed adenocarcinoma of the breast. 
Pathology Date: _____/_____/______  
 Pathology must be in patient record 
 
Must have stage IV disease or inoperable locally advanced disease. 
 Documentation in patient record (via imaging scans as per RECIST Section 6.0) 
 
Patients must have ER and/or PR-positive disease as determined by their local pathology or 
reference laboratory by ASCO-CAP criteria.51 Tumors must be HER-2/neu negative or equivocal 
by standard ICH/FISH or ICH/CISH methodologies by ASCO-CAP criteria.52  
 ER+      
 PR+     
 ER+ and PR+   
 Tumor is HER-2/neu negative by standard ICH/FISH or ICH/CISH methodologies 
Pathology Date: _____/_____/______    
 Pathology must be in patient record 
 
Patients must have had relapse while receiving adjuvant therapy with an aromatase inhibitor 
(anastrozole, letrozole, or exemestane), OR progressive disease while receiving an aromatase 
inhibitor for metastatic disease. Note: Patients may have received an endocrine agent (e.g., 
Tamoxifen) between the time of progression on an AI and registration. 
 Documentation in patient record 
 
Patients previously treated with two or more prior cycles of fulvestrant are not eligible. Patients 
who have received one prior cycle (dose on day 1 and day 15) of fulvestrant within 28 days of 
randomization are eligible as long as they meet other eligibility criteria. 
 Documentation in patient record 
 
Patients must be post menopausal. (see Section 3.1) 
 Documentation in patient record 


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 
 Pt Initials:   ___   ___   ___                Study Personnel: ____________________________ 
                   F       M       L                   Date of Evaluation: ___/___/____ 
 
Patient may have received up to one prior systemic chemotherapy regimen for metastatic 
disease. 
 no prior systemic chemotherapy 
 one prior systemic chemotherapy regimen 
 documentation in patient record  
 
Adequate end organ function, as evidenced by the following obtained within 4 weeks of 
randomization: all must be present (see Section 7.0 for labs that may need to be repeated within 
≤ 7 days of Cycle 1, Day 1) 
 Total White Blood Cell Count (leucocytes, WBC) ≥ 3.0 x 109/L, absolute neutrophil count 
(ANC) ≥ 1.5 x 109/L  and platelet count ≥ 100 x 109/L 
(Total WBC value:_________unit__________) 
(ANC value:_________unit__________) 
(Platelet Count value:_________unit__________) 
 Hemoglobin ≥ 9 g/dL  
(value:_________unit___________) 
 Serum Bilirubin ≤ 1.5 x ULN   
(value:_________unit___________ULN_______) 
 AST or ALT ≤ 2.5 x ULN (≤ 5 x ULN in patients with liver metastases) 
(AST value:_________unit___________ULN_______) 
(ALT value:_________unit___________ULN_______) 
 Serum Creatinine ≤ 1.5 x ULN (value:_________unit___________ULN_______) 
 Serum Albumin ≥ 3 g/dL 
(value:_________unit__________) 
 Fasting Serum Cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND Fasting Triglycerides ≤ 2.5 x 
ULN Note: In case one or both of these thresholds are exceeded, the patient can only be 
included after initiation of appropriate lipid lowering medication. 
(Fasting Serum Cholesterol value:_________unit__________) 
(Fasting Triglycerides value:_________unit___________ULN_______) 
 PT with INR ≤ 1.5. (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin 
or on a stable dose of low molecular weight heparin for >2 weeks at time of randomization. 
(INR value:_________unit___________) 
(PT value:_________unit___________) 
 Documentation in patient record 


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 
 Pt Initials:   ___   ___   ___                Study Personnel: ____________________________ 
                   F       M       L                   Date of Evaluation: ___/___/____ 
 
Patients may have measurable disease, non-measurable disease (e.g., bone only metastases), 
or both. 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]. 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). 
 Measurable disease only 
 Non-measurable disease only 
 Both measurable and non-measurable disease 
 Documentation in patient record 
Note: Tumor lesions in a previously irradiated field are not considered measurable. 
 
Patients with basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix 
within the past five years must have been treated with curative intent. Patients with a history of 
prior malignancy are eligible provided they were treated with curative intent and have been free 
of disease for >3 years. 
 N/A   
 Date of treatment: _____/_____/_____    
 Documentation in patient record 
 
EXCLUSION CRITERIA 
 
Patients who have had any major surgery or significant traumatic injury within 4 weeks of 
randomization, or have not recovered from the side effects of any major surgery (defined as 
requiring general anesthesia) or patients that may require major surgery during the course of the 
study are not eligible. (Placement of vascular access device will not be considered major 
surgery.) 
Date of surgery: _____/_____/_____            
 N/A  
 Documentation in patient record 
 
Patients may not be receiving any other investigational agents or have received any 
investigational agent within 4 weeks of randomization. 
Date of last treatment: _____/_____/_____   
 N/A  
 Documentation in patient record 
 
Patients must not be receiving any concomitant anticancer treatment or have received anticancer 
treatment within 4 weeks of randomization (including chemotherapy, radiation therapy, antibody 
based therapy, e.g.), with the following exceptions: 
• Bisphosphonates, Zometa or Xgeva for bone metastases 
• Hormonal therapy (e.g., AI, Tamoxifen) 
• a GnRH analog is permitted if the patient had progressive disease on a GnRH analog 
plus a SERM or an AI; the GnRH analog may continue but the SERM or AI must be 
discontinued. 
Date of last treatment: _____/_____/_____   
 N/A  
 Documentation in patient record 


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 
 Pt Initials:   ___   ___   ___                Study Personnel: ____________________________ 
                   F       M       L                   Date of Evaluation: ___/___/____ 
 
Patients must not have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, 
everolimus). 
 N/A  
 Documentation in patient record 
 
Patients must not be receiving chronic, systemic treatment with corticosteroids or another 
immunosuppressive agent greater than or equal to 5 mg prednisone or its equivalent daily. 
Topical or inhaled corticosteroids are allowed. 
 N/A  
 Documentation in patient record  
 
Patients must not receive immunization with attenuated live vaccines within one week of 
randomization or during the study period. 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. 
 N/A  
 Documentation in patient record  
 
Patients must not have current or a prior history of brain metastases or leptomeningeal disease. 
Patients must not have rapidly progressive, life-threatening metastases. This includes patients 
with extensive hepatic involvement (>50% of the liver involved) and symptomatic lymphangitic 
metastases. 
 N/A  
 Documentation in patient record 
 
Patients must not have a known hypersensitivity/history of allergic reactions attributed to 
compounds of similar chemical or biologic composition to everolimus (or other rapamycins such 
as sirolimus, temsirolimus) or fulvestrant. 
 N/A  
 Documentation in patient record 
 
Since everolimus may cause bone marrow suppression, patients with congenital or acquired 
immune deficiency at increased risk of infection are not eligible. This includes patients being 
treated with chronic immunosuppressive agents (including greater than or equal to 5 mg 
prednisone or its equivalent daily), and patients with known HIV seropositivity. 
 N/A  
 Documentation in patient record  
 
Patients must not have any impairment of gastrointestinal function or gastrointestinal disease 
that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). 
 N/A  
 Documentation in patient record  
 
Patients must not have an active, bleeding diathesis. 
 N/A  
 Documentation in patient record  


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 
 Pt Initials:   ___   ___   ___                Study Personnel: ____________________________ 
                   F       M       L                   Date of Evaluation: ___/___/____ 
 
Patients must not have a history of any condition or uncontrolled intercurrent illness including, 
but not limited to, ongoing or active infection or psychiatric illness/social situations that in the 
opinion of the investigator might intefere with or limit the patient’s ability to comply with the 
protocol or pose additional or unacceptable risk to the patient. 
 N/A  
 Documentation in patient record 
 
Patients must not have any severe and/or uncontrolled medical conditions or other conditions 
that could affect their participation in the study such as: 
• 
Symptomatic congestive heart failure of New York Heart Association Class III or IV (see 
Appendix D) 
• 
Unstable angina pectoris, myocardial infarction within 6 months of randomization, serious 
uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease 
• 
History of symptomatic pulmonary disease or non-malignant pulmonary disease (e.g. 
COPD) requiring treatment. Such patients would be eligible if PFTs performed within 8 
weeks of treatment noted a DLCO greater than 50%.  
• 
Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN (Note: Optimal 
glycemic control should be achieved before starting trial therapy.) 
• 
Active (acute or chronic) or uncontrolled severe infections 
• 
Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh Class C). 
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. 
 N/A  
 Documentation in patient record 


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14 Appendix B: ECOG Performance Status Scale 
 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
61 Source: Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair 


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15 Appendix C: Medications that can Inhibit/Induce CYP3A4 
and PgP 
See Section 5.3.5.1 for guidelines on use of inhibitors and Section 5.3.5.2 for guidelines 
on use of inducers. Table 15-0 shows clinically relevant drug interactions for inhibitors 
and inducers of isoenzyme CYP3A. Table 15-1 shows clinically relevant drug 
interactions for substrates, inducers, and inhibitors of PgP and PgP/CYP3A. 
Table 15-0 
Clinically Relevant Drug Interactions: Inhibitors and Inducers of Isoenzyme 
CYP3A 
INHIBITORS 
Strong Inhibitors: 
clarithromycin, conivaptan, elvitegravir, indinavir, itraconazole, ketoconazole, lopinavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, 
tipranavir, troleandamycin, voriconazole 
(Krishna et al, 2009) 
Moderate Inhibitors: 
aprepitant, amprenavir, atazanavir, casopitant, cimetidine, ciprofloxacin, darunavir, diltiazem, 
dronedarone, erythromycin, fluconazole, fosamprenavir, grapefruit juice (citrus parasidi fruit 
juice), imatinib, tofisopam, verapamil 
INDUCERS 
amprenavir, aprepitant, armodafinil (R-modafinil), avasimibe, bosentan, carbamazepine, 
dexamethasone, efavirenz, etravirine, glucocorticoids, modafinil, nafcillin, nevirapine, 
oxcarbazepine, phenobarbital, phenytoin, pioglitazone, prednisone, rifabutin, rifampin, 
ritonavir, rufinamide, St. John’s wort, talviraline, tipranavir, topiramate, troglitazone 
 
 
 
 
 
 
 
 
 
 


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Table 15-1 
Clinically Relevant Drug Interactions: Substrates, Inducers, and Inhibitors of PgP 
and PgP/CYP3A 
SUBSTRATES 
Colchicines, digoxin, fexofenadine, indinavir, paclitaxel, topotecan, vincristine 
INDUCERS 
Rifampin, St. John’s wort 
PgP INHIBITORS and PgP/CYP3A DUAL INHIBITORS 
Amiodarone, captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, 
elacridar, erythromycin, felodipine, fexofenadine, ginkgo (ginkgo biloba), indinavir, 
itraconazole, lopinavir, mibefradil, milk thistle (silybum marianum), nifedipine, nitrendipine, 
quercetin, quinidine, ranolazine, ritonavir, saquinavir, Schisandra chinensis, St John’s wort 
(hypericum perforatum), talinolol, telmisartan, tipranavir, valspodar, verapamil 
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated 
Oct. 2, 2011, which summarizes DDI data from three sources including the FDA’s 
“Guidance for Industry, Drug Interaction Studies”, the University of Washington’s Drug 
Interaction Database, and Indiana University School of Medicine's Drug Interaction 
Table. 


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16 Appendix D: New York Heart Association (NYHA) Cardiac 
Classification 
of 
Functional 
Capacity 
and 
Objective 
Assessment 
In 1928 the New York Heart Association published a classification of patients with cardiac 
disease based on clinical severity and prognosis. This classification has been updated in seven 
subsequent editions of Nomenclature and Criteria for Diagnosis of Diseases of the Heart and 
Great Vessels (Little, Brown & Co.). The ninth edition, revised by the Criteria Committee of the 
American Heart Association, New York City Affiliate, was released March 4, 1994*. The new 
classifications are summarized below. 
The NYHA classification system relates symptoms to everyday activities and the patient’s quality 
of life. 
Class 
Symptoms 
Class I  
Patients with cardiac disease but without resulting limitation of physical 
activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath), or anginal pain. 
Class II  
Patients with cardiac disease resulting in slight limitation of physical 
activity. Comfortable at rest, but ordinary physical activity results in 
fatigue, palpitation, dyspnea or anginal pain. 
Class III  
Patients with cardiac disease resulting in marked limitation of physical 
activity. Comfortable at rest, but less than ordinary activity causes 
fatigue, palpitation, dyspnea or anginal pain. 
Class IV  
Patients with cardiac disease resulting in inability to carry out any 
physical activity without discomfort. Symptoms of heart failure or anginal 
syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort increases. 
Objective Assessment 
I:  
No objective evidence of cardiovascular disease  
II:  
Objective evidence of minimal cardiovascular disease  
III:  
Objective evidence of moderately severe cardiovascular disease  
IV: 
Objective evidence of severe cardiovascular disease  
Accessed October 2009* http://www.americanheart.org/presenter.jhtml?identifier=1712 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256. 
 


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17 Appendix E: CTEP Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0 
Common Terminology Criteria for Adverse Events (CTCAE) 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE Version 4.0. A copy of the CTCAE Version 4.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov). 
All appropriate treatment areas should have access to a copy of the CTEP CTCAE 
Version 4.0. 
 


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18 Appendix F: Patient Pill Diary 
Copies of this form will be made available to study staff in study materials. This form is 
appended as an example only, and may be modified during the study. 
Site Instructions: 
1. If this or a similar diary is used this may be considered source documentation, if the 
diary has been reviewed and signed by a member of the study staff. Patient 
compliance with protocol therapy can be assessed using a pill record or by other 
documentation in the patient record. 
2. Patients should be instructed to begin Day 1 with the beginning of each cycle, with 
each cycle being 28 days. 
3. If a dose modification occurs, patients should be given instructions for dosing, and 
the form can be modified as appropriate. Any dose changes should be recorded in 
the patient chart with appropriate rationale as per protocol. 
4. A new form can be used at any time during a cycle; as long as the patient is made 
aware of changes (e.g. study staff fills in dates and mark lines/dates not to be used). 
5. It is the responsibility of the investigator to appropriately dispense and monitor study 
medications and to comply with the protocol. 


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109 
Patient Name: _____________________________ 
Patient Study ID (filled in by Site Staff): 
______________________ 
Patient Instructions: 
1. Complete each form as instructed by your physician or study nurse. 
2. You will take 2 pill(s) each day. You should take the pill(s) the same time each day, and in the 
morning, if possible. If you forget to take a pill and remember by 10 PM, you may take the dose. 
Otherwise just skip that dose and begin as usual the next day. Please mark dates of any missed 
pills on your record. 
3. .Each dose should be swallowed whole with a glass of water and may be taken with or without food. 
The tablets must not be chewed or crushed. In cases where tablets cannot be swallowed, the tablets 
should be disintegrated in water just prior to being taken. Approximately 30 mL (2 tablespoons) of 
water should be put into a glass. The tablets should then be added and the contents stirred gently 
(for a maximum of 7 minutes) until the tablets are disintegrated. The contents should then be drunk. 
If you vomit after taking the study drug, you should NOT take another tablet that day. If you forget to 
take the medication and remembers by 10 PM, you may take the dose. Otherwise, skip that dose 
and begin as usual the next day. 
4. If you have any side effects or comments, please note in the comment section or on the back of the 
page. For questions or if you have any side effects that should be immediately reported to your 
study doctor, please call _______________________________at: (_____) _____ - _________. 
5. Please bring your pill(s) and this form to your study doctor when you go for each appointment. If 
your dose changes, the study nurse or doctor will let you know. You should note this on the form. 
Date 
Day 
# Pills 
Comments 
Date 
Day 
# Pills 
Comments 
 
1 
 
 
 
15 
 
 
 
2 
 
 
 
16 
 
 
 
3 
 
 
 
17 
 
 
 
4 
 
 
 
18 
 
 
 
5 
 
 
 
19 
 
 
 
6 
 
 
 
20 
 
 
 
7 
 
 
 
21 
 
 
 
8 
 
 
 
22 
 
 
 
9 
 
 
 
23 
 
 
 
10 
 
 
 
24 
 
 
 
11 
 
 
 
25 
 
 
 
12 
 
 
 
26 
 
 
 
13 
 
 
 
27 
 
 
 
14 
 
 
 
28 
 
 
Patient Signature: _________________________________             Date: ___________________ 
Physician Office to complete this section: 
Study Personnel Signature: __________________________          Date: ____________________ 


PrECOG Protocol Number: PrE0102 
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110 
19 References 
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4. 
Tokunaga E, Kataoka A, Kimura Y, et al. The association between Akt 
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Beeram M, Tan QT, Tekmal RR, Russell D, Middleton A, DeGraffenried LA. 
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Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell 
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Perey L, Paridaens R, Hawle H, et al. Clinical benefit of fulvestrant in 
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Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo 
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Di Leo A, Jerusalem G, Petruzelka L, et al. CONFIRM: A Phase III, 
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Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. 
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Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 
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28. 
Wang L, Harris TE, Roth RA, Lawrence JC, Jr. PRAS40 regulates mTORC1 
kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 
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29. 
Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of single-agent 
temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005; 
23(23):5347-56. 


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30. 
Lane HA, Wood JM, McSheehy PM, et al. mTOR inhibitor RAD001 (everolimus) 
has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. 
Clin Cancer Res 2009;15(5):1612-22. 
31. 
Mabuchi S, Altomare DA, Cheung M, et al. RAD001 inhibits human ovarian 
cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in 
an ovarian cancer model. Clin Cancer Res 2007;13(14):4261-70. 
32. 
Galanis E, Buckner JC, Maurer MJ, et al. Phase II trial of temsirolimus (CCI-
779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group 
Study. J Clin Oncol 2005;23:5294-304. 
33. 
O’Reilly T, McSheehy PM. Biomarker Development for the Clinical Activity of 
the mTOR Inhibitor everolimus (RAD001): Processes, Limitations, and Further 
Proposals. Tran Oncol; 2010 Apr; 3(2):65-79. 
34. 
Huang S, Houghton PJ. Inhibitors of mammalian target of rapamycin as novel 
antitumor agents: from bench to clinic. Curr Opin Investig Drugs. 2002 Feb; 3(2):295-
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35. 
Zitzmann K, De Toni EN, Brand S, et al. The novel mTOR inhibitor RAD001 
(everolimus) induces antiproliferative effects in human pancreatic neuroendocrine 
tumor cells. Neuroendocrinology 2007;85(1):54-60. 
36. 
Zeng Z, Sarbassov dos D, Samudio IJ, et al. Rapamycin derivatives reduce 
mTORC2 signaling and inhibit AKT activation in AML. Blood 2007;109(8):3509-12. 
37. 
Haritunians T, Mori A, O'Kelly J, Luong QT, Giles FJ, Koeffler HP. 
Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with 
other agents in mantle cell lymphoma. Leukemia 2007;21(2):333-9. 
38. 
Ikezoe T, Nishioka C, Bandobashi K, et al. Longitudinal inhibition of 
PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult 
T-cell leukemia cells. Leuk Res 2007;31(5):673-82. 
39. 
Wanner K, Hipp S, Oelsner M, et al. Mammalian target of rapamycin inhibition 
induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises 
DLBCL cells to rituximab. Br J Haematol 2006;134(5):475-84. 
40. 
Tuncyurek P, Mayer JM, Klug F, et al. Everolimus and mycophenolate mofetil 
sensitize human pancreatic cancer cells to gemcitabine in vitro: a novel adjunct to 
standard chemotherapy? Eur Surg Res 2007;39(6):380-7. 
41. 
Treeck O, Wackwitz B, Haus U, Ortmann O. Effects of a combined treatment 
with mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human 
cancer cells. Gynecol Oncol 2006;102(2):292-9. 
42. 
Sieghart W, Fuereder T, Schmid K, et al. Mammalian target of rapamycin 
pathway activity in hepatocellular carcinomas of patients undergoing liver 
transplantation. Transplantation 2007;83(4):425-32. 
43. 
Lu CH, Wyszomierski SL, Tseng LM, et al. Preclinical testing of clinically 
applicable strategies for overcoming trastuzumab resistance caused by PTEN 
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Torres-Arzayus MI, Yuan J, DellaGatta JL, Lane H, Kung AL, Brown M. 
Targeting the AIB1 oncogene through mammalian target of rapamycin inhibition in the 
mammary gland. Cancer Res 2006;66(23):11381-8. 


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45. 
Rossi F, Ehlers I, Agosti V, et al. Oncogenic Kit signaling and therapeutic 
intervention in a mouse model of gastrointestinal stromal tumor. Proc Natl Acad Sci U 
S A 2006;103(34):12843-8. 
46. 
Lane H, Tanaka C, Kovarik J, et al. Preclinical and clinical pharmacokinetic / 
pharmacodynamic (PK/PD) modeling to help define an optimal biological dose for the 
oral mTOR inhibitor, RAD001, in oncology [abstract]. J Clin Oncol; 2003; 22:237A. 
47. 
Tabernero J, Rojo F, Calvo E, et al. Dose- and schedule-dependent inhibition of 
the mammalian target of rapamycin pathway with everolimus: A phase I tumor 
pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 
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48. 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312965 
.htm (accessed 8/1/2012) 
49. 
Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal 
hormone-receptor-positive advanced breast cancer. N Engl J Med 2012 Feb 
9;366(6):520-9. Epub 2011 Dec 7. PubMed PMID: 22149876 
50. 
Sanchez CG, Ma CX, Crowder RJ, et al. Preclinical modeling of combined 
phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-
positive breast cancer. Breast Cancer Res 2011 Mar 1;13(2):R21. 
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Hammond ME, Hayes DF, Wolff AC, et al. American society of clinical 
oncology/college 
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immunohistochemical testing of estrogen and progesterone receptors in breast cancer. 
Oncol Pract. 2010 Jul;6(4):195-7. Epub 2010 Jun 23 PMCID: PMC2900870 PMID: 
21037871. 
52. 
Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical 
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1;25(1):118-45. Epub 2006 Dec 11. American Society of Clinical Oncology; College of 
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53. 
Yeo W, Lam KC, Zee B, et al. Hepatitis B reactivation in patients with 
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Loomba R, Rowley A, Wesley R, et al. Systematic review: the effect of 
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55. 
Divers J, RN BSN, Texas Oncology. Management of Stomatitis Associated with 
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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria 
in solid tumours: revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228-
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57. 
Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for 
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58. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for 
patients with progressive prostate cancer and castrate levels of testosterone: 
recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 
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59. 
Rustin GJ, Quinn M, Thigpen T, et al. Re: New guidelines to evaluate the 
response to treatment in solid tumors (ovarian cancer). J Natl Cancer Inst 
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60. 
Vergote I, Rustin GJ, Eisenhauer EA, et al. Re: new guidelines to evaluate the 
response to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer Intergroup. 
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61. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55. 
 


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115 
20 Investigator’s Statement 
1. 
I have carefully read this protocol entitled “Randomized, Double-Blind, 
Placebo-Controlled Phase II Trial of Fulvestrant (Faslodex) plus 
Everolimus in Post Menopausal Patients with Hormone-Receptor 
Positive Metastatic Breast Center Resistant to Aromatase Inhibitor 
Therapy, Version 2.0 dated 1/22/2014” (Protocol number PrE0102) 
and agree that it contains all the necessary information required to 
conduct the study. I agree to conduct the study as outlined in the protocol. 
2. 
I agree to conduct this study according to the moral, ethical and scientific 
principles governing clinical research as set out in the Declaration of 
Helsinki, the principles of GCP as described in 21 CFR and any applicable 
local requirements. 
3. 
I understand that this trial and any subsequent changes to this trial will not 
be initiated without approval of the appropriate Institutional Review Board, 
and that all administrative requirements of the governing body of the 
institution will be complied with fully. 
4. 
Informed written consent will be obtained from all participating patients in 
accordance with institutional and FDA requirements as specified in Title 
21, Code of Federal Regulations, Part 50. 
5. 
I understand that my signature on the Case Report Form indicates that I 
have carefully reviewed each page and accept full responsibility for the 
contents thereof. 
6. 
I understand that the information presented in this study protocol is 
confidential, and I hereby assure that no information based on the conduct 
of the study will be released without prior consent from PrECOG, LLC 
unless this requirement is superseded by the Food and Drug 
Administration. 
Principal Investigator: 
PI Name: 
 
 
 
 
 
 
 
 
 
 
Site Name: 
 
 
 
 
 
 
 
 
 
 
Signature of PI: 
 
 
 
 
 
 
 
 
 
Date of Signature: 
 
 
\ 
 
\ 
 
 
 
 
 
 
       MMM 
 
DD 
 
YYYY 

SAP_001.pdf: 
Statistical Analysis Plan  
PrECOG/PrE0102 
Version FINAL/ 24 March 2014 
 
 
1 
 
 
 
 
Statistical Analysis Plan 
Study code 
PrE0102 
Version 
FINAL 
Date 
24 March 2014 
Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Fulvestrant (Faslodex) plus 
Everolimus in Post-Menopausal Patients with Hormone-Receptor Positive Metastatic 
Breast Cancer Resistant to Aromatase Inhibitor Therapy  


Statistical Analysis Plan  
PrECOG/PrE0102 
Version FINAL/ 24 March 2014 
 
 
2 
 
 
 
 
 
DOCUMENT: 
 
Statistical Analysis Plan 
PROTOCOL 
 
 
Number: 
 
PrE0102 
Title: 
 
Randomized, Double-Blind, Placebo-Controlled Phase II 
Trial of Fulvestrant (Faslodex) plus Everolimus in Post-
Menopausal Patients with Hormone-Receptor Positive 
Metastatic Breast Cancer Resistant to Aromatase 
Inhibitor Therapy 
Version: 
 
1.0 
Date: 
 
19 December 2012 
 
 
 
SAP STATUS 
 
Final 
SAP VERSION DATE 
 
24 March 2014 
SPONSOR: 
 
PrECOG    
PREPARED BY: 
 
Quality Data Services, Inc. 
 
 
 
 
 
 


Statistical Analysis Plan  
PrECOG/PrE0102 
Version FINAL/ 24 March 2014 
 
 
3 
 
 
 
 
SIGNATURES/APPROVAL PAGE  
 
 AUTHORS 
  
 
 Biostatistician 
 Date 
 
 Biostatistician 
 Date 
 
 Sr. Director, Biometrics, 
 Date 
 
 
 
 
APPROVERS 
  
 
 
 
  
 
 
 
 Date 
 
 
 
  
 
 
 
 Date 
 
 
 


Statistical Analysis Plan  
PrECOG/PrE0102 
Version FINAL/ 24 March 2014 
 
 
4 
 
 
 
 
 
 
DOCUMENT HISTORY 
 
Version Date 
Modified By 
Summary of Changes 
Draft / 07 Oct 2013 
 
Draft 1 
Draft / 16 Oct 2013 
 
Draft 2: incorporated PrECOG 
comments for Draft 1 
Draft / 28 Feb 2014 
 
Draft 3: incorporated PrECOG 
comments for Draft 2 
Final / 24 Mar 2014 
 
Final: incorporated PrECOG 
comments for Draft 3 
 
 
 
 
 
 


Statistical Analysis Plan  
PrECOG/PrE0102 
Version FINAL/ 24 March 2014 
 
 
5 
 
 
 
 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................. 1 
1. LIST OF ABBREVIATIONS ............................................................................................ 8 
2. INTRODUCTION ........................................................................................................ 9 
2.1. Objective of the Abbreviated Statistical Analysis Plan .............................................. 9 
3. STUDY OBJECTIVES ................................................................................................... 9 
3.1. Primary Objective .................................................................................................. 9 
3.2. Secondary Objectives ............................................................................................. 9 
4. STUDY DESIGN ........................................................................................................ 10 
4.1. General Study Design and Plan .............................................................................. 10 
4.2. Study Population ................................................................................................. 10 
4.3. Treatment Administration and Duration of Therapy ............................................... 10 
4.4. Dose Modifications and Toxicity Management ....................................................... 12 
4.5. Withdrawal of Subjects from Study ....................................................................... 12 
4.6. Study Schedule of Assessments ............................................................................. 12 
5. MEASUREMENT OF EFFECT ...................................................................................... 13 
5.1. Evaluation of disease ............................................................................................ 13 
5.2. Response Criteria ................................................................................................. 13 
5.3. Efficacy Measurements Definitions ....................................................................... 13 
6. SAFETY MEASUREMENTS ........................................................................................ 14 
6.1. Adverse Events .................................................................................................... 14 
6.2. Concomitant Medications ..................................................................................... 16 


Statistical Analysis Plan  
PrECOG/PrE0102 
Version FINAL/ 24 March 2014 
 
 
6 
 
 
 
 
7. GENERAL STATISTICAL CONSIDERATIONS ................................................................. 17 
7.1. Methodology ....................................................................................................... 17 
7.2. Analysis Populations ............................................................................................ 17 
7.3. Subject Disposition............................................................................................... 18 
7.3.1. Accrual by Institution ......................................................................................... 18 
7.3.2. Case Status ........................................................................................................ 18 
7.3.3. Reasons Subjects were Ineligible ......................................................................... 19 
7.3.4. Reasons Subjects did not Start Treatment ............................................................ 19 
7.3.5. Stratification Factors .......................................................................................... 19 
7.4. Subject Characteristics ......................................................................................... 19 
7.5. Dosing and Number of Cycles in the Study ............................................................. 20 
7.6. Concomitant Medications ..................................................................................... 21 
7.7. Efficacy Analysis ................................................................................................... 21 
7.7.1. Response Analysis .............................................................................................. 21 
7.7.2. Progression-Free Survival (PFS), Time-to-Disease Progression (TTP), and Overall 
Survival (OS) ............................................................................................................... 22 
7.8. Safety Analysis ..................................................................................................... 22 
7.8.1. Adverse Events .................................................................................................. 22 


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8. REPORTING CONVENTIONS ..................................................................................... 23 
9. REFERENCES ........................................................................................................... 23 
10. TABLES, FIGURES, AND LISTINGS ............................................................................ 23 
11. APPENDIX 1:  LIST OF TABLES, LISTINGS AND FIGURES REQUESTED FOR 
PUBLICATION ............................................................................................................. 24 
12. APPENDIX 2:  SCHEDULED ASSESSMENTS ................................................................ 26 
13. APPENDIX 3:  DISEASE PARAMETERS AND METHODS FOR EVALUATION OF 
MEASURABLE DISEASE ................................................................................................ 29 
14. APPENDIX 4:  RESPONSE CRITERIA .......................................................................... 33 
15. APPENDIX 5:  BEST OVERALL RESPONSE .................................................................. 35 


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1.   LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE(s) 
Adverse Events(s) 
SAP 
Statistical Analysis Plan 
CSR 
Clinical Study Report 
AI 
Aromatase Inhibitor 
ITT 
Intention-to-Treat 
QDS 
Quality Data Services 
QD 
Once Daily 
CTCAE 
The CTEP Common Terminology Criteria for Adverse Events (CTCAE) 
PFS 
progression-free survival 
RECIST 
Response Evaluation Criteria in Solid Tumors 
CBC 
Complete Blood Count 
CBR 
Clinical Benefit Rate 
CR 
Complete Response 
SD 
Stable Disease 
PR 
Partial Response 
PD 
Progressive Disease 
CSR 
clinical study report 
WHO- DD 
World Health Organization Drug Dictionary 
TEAEs 
Treatment-emergent AEs 
MedDRA 
Medical Dictionary for Regulatory Activities 
ICH 
International Conference on Harmonization 
US 
United States 


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2.   INTRODUCTION 
2.1.   Objective of the Abbreviated Statistical Analysis Plan 
This abbreviated statistical analysis plan (SAP) describes the planned analysis of the safety and 
efficacy data from the study to be prepared for a publication based on an outline provided by 
sponsor (Appendix 1).  A detailed description of the planned tables, figures and listings (TFLs) to 
be prepared for the publication is provided in the accompanying TFL template document. 
The intent of this document is to provide guidance for the analysis of data related to safety and 
efficacy to describe any applicable statistical procedures.  In general, the analyses come directly 
from the protocol, unless they have been modified by agreement between the Sponsor and 
Quality Data Services, Inc. (QDS).  A limited amount of information concerning this study (e.g., 
objectives, study design, treatment schedule, variables and endpoints) is summarized to help 
the reader interpret the accompanying TFL templates.  This abbreviated SAP includes details 
about the variables and endpoints considered for the publication.  The SAP also includes 
clarifications for analysis population (changes from protocol specified definitions), additional 
endpoints and sensitivity analyses not specified in the protocol but required for the publication. 
Attached signatures indicate approval of the statistical analysis sections of the SAP, as well as 
accompanying TFL templates.  These sections must be agreed upon prior to database lock.  Any 
revisions to statistical analyses required for the publication will be document in SAP 
Amendment (s).  Any revisions to planned TLFs which do not require revisions to SAP will be 
documented in a Note to SAP. 
 
3.   STUDY OBJECTIVES 
3.1.   Primary Objective 
To assess progression-free survival in post-menopausal patients with hormone-receptor 
positive metastatic breast cancer that is resistant to aromatase inhibitor (Al) therapy treated 
with fulvestrant and everolimus compared to fulvestrant alone.  
 
3.2.   Secondary Objectives 
To describe the safety profile, objective response rate, time to progression and overall survival 
in post-menopausal patients with hormone-receptor positive metastatic breast cancer that is 
resistant to aromatase inhibitor (Al) therapy treated with fulvestrant and everolimus compared 
to fulvestrant alone 


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4.   STUDY DESIGN 
4.1.   General Study Design and Plan 
This is a randomized, double-blind, placebo controlled Phase II study. Approximately 130 
subjects will be enrolled at 25 centers within the US. Subjects will be randomized (1:1) to 
receive everolimus or placebo after consideration of stratification factors of performance status 
(0 vs.1), measurable disease (with or without non-measurable) vs. non-measurable disease, and 
prior chemotherapy for metastatic disease vs. no prior chemotherapy. The treatment plan is 
defined below. 
 
 
 
 
 
 
 
 
Note: 1 cycle = 28 days 
4.2.   Study Population 
Subjects enrolled in the study must be postmenopausal and have stage IV disease or inoperable 
locally advanced disease.  They must have ER and/or PR-positive disease as determined by their 
local pathology or reference laboratory by ASCO-CAP criteria. Tumors must be HER-2/neu 
negative or equivocal by standard ICH/FISH or ICH/CISH methodologies by ASCO-CAP criteria.  
Subjects must be Aromatase Inhibitor resistant, defined as: 
o relapsed while receiving adjuvant therapy with an aromatase inhibitor (anastrozole, 
letrozole, or exemestane) or, 
o progressive disease while receiving an aromatase inhibitor for metastatic disease 
 
4.3.   Treatment Administration and Duration of Therapy 
Stratify:  
 
PS (0 vs 1) 
 
Measurable 
Disease  
(yes or no) 
 
Prior Chemo 
vs No Prior 
Chemo 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
Arm A: Induction Phase 
fulvestrant 500 mg IM (two- 250 mg injections each 
dose) day 1 & 15 of cycle 1, then 500 mg IM (two- 250 
mg injections) day 1 of all subsequent cycles (every 28 
days for 12 cycles) plus 
everolimus 10 mg (two- 5 mg tablets) PO QD  
x 12 cycles 
Arm B: Induction Phase 
fulvestrant 500 mg IM (two- 250 mg injections each 
dose) day 1 & 15 of cycle 1, then 500 mg IM (two- 250 
mg injections) day 1 of all subsequent cycles (every 28 
days for 12 cycles) plus  
placebo 2 tablets PO QD  
x 12 cycles 
Continuation Phase: 
If no evidence of disease 
progression after 12 cycles, 
unblind and continue 
fulvestrant 500 mg IM day 1 of 
every cycle (every 28 days) 
alone (if originally randomized 
to placebo) or with everolimus 
(if originally randomized to 
everolimus) until disease 
progression or unacceptable 
toxicity. 


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Subjects must not start protocol treatment prior to randomization. Treatment is to begin within 
7 working days of randomization, and includes two phases: induction phase and continuation 
phase. 
During the Induction Phase, subjects will receive: 
• fulvestrant 500 mg IM (two-250 mg injections per dose) on day 1 & 15 of Cycle 1, then 
500 mg IM (two-250 mg injections) on day 1 of all subsequent cycles (every 28 days) 
plus everolimus 10 mg (two- 5 mg tablets) PO daily, OR 
• fulvestrant 500 mg IM (two-250 mg injections per dose) on day 1 & 15 of Cycle 1, then 
500 mg IM (two-250 mg injections) on day 1 of all subsequent cycles (every 28 days) 
plus placebo two tablets PO daily 
(as randomized). 
 
Subjects will be treated for a maximum of 12 cycles with fulvestrant plus everolimus/placebo 
during the Induction Phase. Induction treatment continues until there is evidence of 
progressive disease or unacceptable toxicity for a maximum of 12 cycles (as defined in Protocol 
Section 5.6). Subjects with no evidence of progressive disease who remain on study after 
completing 12 cycles of the Induction Phase are unblinded and proceed to the Continuation 
Phase. Subjects in the Continuation Phase will continue to receive fulvestrant alone (if originally 
randomized to placebo) or in combination with everolimus (if originally randomized to 
everolimus) until disease progression or unacceptable toxicity. Subjects in both the Induction 
and Continuation Phases will have tumor measurements performed every 12 weeks (+/- 1 
week). 
 
Protocol therapy will be discontinued for progressive disease at any time. Subjects are free to 
halt therapy at their request. Treatment may be discontinued if intercurrent co-morbidities 
occur, which, in the opinion of the treating physician, would preclude safe administration of 
study drugs. 
 
Subjects who discontinue everolimus/placebo because of suspected everolimus-associated 
toxicity should continue treatment with fulvestrant alone until disease progression. In unusual 
circumstances where fulvestrant must be discontinued prior to disease progression due to 
intolerable fulvestrant-associated toxicity, the medical monitor should be contacted. All 
subjects who have discontinued protocol therapy will be followed for survival and for 
progression, even if protocol therapy was discontinued because of toxicity or for other reasons. 
All surviving subjects who have discontinued induction protocol therapy (fulvestrant and 
everolimus/placebo) for any reason will be followed for 30 days for study drug related 
(fulvestrant and/or everolimus/placebo) toxicities to ≤ grade 1 (or if >grade 1, event must be 
permanent and stable). 
 


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4.4.   Dose Modifications and Toxicity Management 
Dose modifications for all drugs will be made using the general guidelines included in Protocol 
Section 5 (Tables 5-0, 5-1 and 5-2) and summarized below: 
• All dose reductions are permanent. Fulvestrant will not be dose reduced.  
• Regardless of the reason for holding any study drug treatment, the maximum allowable 
length of treatment interruption is ≤ 3 weeks. If the delivery of any study drug due to 
toxicity is delayed for more than 3 weeks, that drug should be permanently discontinued. 
• No more than 2 dose reductions for everolimus/placebo will be allowed. Further need for 
dose reduction will result in discontinuation of that drug. 
• If dose is delayed due to toxicity, labs/toxicity should be reevaluated at least weekly until 
recovery to treatment levels, or as indicated in the dose modification tables. 
• Subjects who discontinue everolimus/placebo because of suspected everolimus-associated 
toxicity should continue treatment with fulvestrant alone until disease progression. 
• In unusual circumstances where fulvestrant must be discontinued prior to disease 
progression due to intolerable fulvestrant-associated toxicity, the Medical Monitor should 
be contacted. 
 All toxicities will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE), Version 4.0. 
Toxicity management is defined in Section 5 of the protocol. 
4.5.   Withdrawal of Subjects from Study 
Subjects are to be discontinued from study therapy and be withdrawn from the study for the 
following reasons: 
• Withdrawal of the subject’s consent (subject’s decision to withdraw for any reason) 
• Termination of the study by PrECOG 
• Any clinical adverse event, laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject 
• Inability to comply with protocol 
• Discretion of the investigator 
• Disease progression (subject will be followed for survival) 
4.6.   Study Schedule of Assessments 
Study schedule of assessments is included in Appendix 2. 


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5.   MEASUREMENT OF EFFECT 
5.1.   Evaluation of disease 
For the purposes of this study, subjects should be re-evaluated for response every 12 weeks, +/- 
1 week. All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than four weeks before randomization. 
Response and progression are to be evaluated using the revised Response Evaluation Criteria in 
Solid Tumors (RECIST) guideline (Version 1.1).  For measurable disease, changes in the sums of 
the longest diameters (unidimensional measurement) of the tumor lesions and the shortest 
diameters in the case of malignant lymph nodes are used in the RECIST criteria.  For subjects 
without measurable disease, disappearance of disease, unequivocal progression, or the 
absence of either will be used to assess response.  Further details and methods of evaluation of 
disease are included in Protocol Sections 6.1.2-6.1.3 and in SAP Appendix 3. 
5.2.   Response Criteria 
Details about Response Criteria for target, non-target and new lesions are included in Protocol 
Sections 6.1.4.1, 6.4.1.2, 6.4.1.3, and in SAP Appendix 4. 
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). Since response is not the primary 
endpoint, no confirmation of response is required in this study. See Protocol Section 6.1.4.4 and 
SAP Appendix 5. 
5.3.   Efficacy Measurements Definitions 
Efficacy measurements include progression-free survival (PFS), overall survival, and time to 
progression, objective response rate, clinical benefit rate (CBR), duration of overall response 
(CR), duration of overall CR, and duration of stable response. 
Progression-free survival (PFS) is defined as the duration of time from time of randomization to 
time of progression or death, whichever occurs first. A subject who has neither progressed nor 
died will be censored on the date of last tumor assessment. 
Overall Survival (OS) is defined as the time from randomization until death or censored at the 
date of last follow-up. 
Time-to-progression (TTP) is defined as the time from randomization until progression of the 
disease.  Patients without progression will be censored at the date of last tumor assessment. 
Objective response rate is defined as the proportion of subjects with best overall response of 
CR (complete response) or PR (partial response). 


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Clinical benefit rate (CBR): is defined as the proportion of subjects with best overall response of 
CR (complete response) or PR (partial response) or with stable disease (SD) for at least 24 
weeks.   
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 PD the 
smallest measurements recorded since the treatment started). 
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. 
 
6.   SAFETY MEASUREMENTS 
Safety is to be evaluated by  
• Adverse events 
• Clinical laboratory tests,  
• Physical examination findings,   
• Vital signs measurements,  
 
The following sections include details and definitions for the safety measurements to be 
summarized per list of TLFs included in Appendix 1. 
6.1.   Adverse Events 
Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-
existing medical condition in a subject administered a medicinal product in a clinical 
investigation and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a product 
(investigational or marketed), whether or not considered related to the product (investigational 
or marketed).  
Treatment-emergent AEs:  any adverse event starting on or after the first treatment dose. 
 


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AE Severity: 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 will be 
utilized for AE reporting. A copy of the CTCAE Version 4.0 can be downloaded from the CTEP 
web site (http://ctep.cancer.gov). 
All appropriate treatment areas should have access to a copy of the CTEP CTCAE Version 4.0 
(see Protocol Appendix E) 
AE Attribution (Relationship) 
The following categories and definitions of causal relationship or attribution to study drug 
should be used to assess Adverse Events: 
• Definite: There is a reasonable causal relationship between the study drug and the 
event. The event responds to withdrawal of study drug (dechallenge) and recurs with 
rechallenge, if clinically feasible. 
• Probable: There is a reasonable causal relationship between the study drug and the 
event. The event responds to dechallenge. Rechallenge is not required. 
• Possible: There is a reasonable causal relationship between the study drug and the 
event. Dechallenge information is lacking or unclear. 
• Unlikely: There is doubtful causal relationship between the study drug and the event. 
• Unrelated: There is clearly not a causal relationship between the study drug and the 
event or there is a causal relationship between another drug, concurrent disease, or 
circumstances and the event. 
Categories ‘Definite’, ‘probable’ and ‘possible’ are considered study drug related. Categories 
‘not likely’ and ‘not related’ are considered not study drug-related. 
The development of a new cancer is to be regarded as an AE. New cancers are those that are 
not the primary reason for administration of study treatment and have been identified after 
inclusion of the subject into the clinical study. 
A serious AE is any untoward medical occurrence occurring after informed consent is granted or 
that at any dose: 
• results in death, 


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• is life-threatening (defined as an event in which the study subjects was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe), 
• requires inpatient hospitalization or causes prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, 
• is a congenital anomaly/birth defect, 
• is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may require 
intervention (e.g., medical, surgical) to prevent one of the other serious outcomes listed 
in the definition above.) Examples of such events include, but are not limited to, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization. 
Second Primary Cancers: 
New cancers are those that are not the primary reason for administration of study treatment 
and have been identified after inclusion of the subject into the clinical study. 
All cases of new primary cancers that occur during or after the start of protocol treatment are 
to be reported to PrECOG within 30 days of diagnosis, regardless of relationship to protocol 
treatment.  Secondary primary malignancies should also be reported as a SAE.  
6.2.   Concomitant Medications 
Bone modifying medications taken during the study are to be recorded on eCRF . 


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7.   GENERAL STATISTICAL CONSIDERATIONS 
Statistical analysis and programming of tables and listings will be conducted by QDS, using SAS® 
Release 9.2 (SAS Institute Inc., Cary, North Carolina, USA).  After the TFLs are approved as final, 
SAS programs used to perform statistical analyses and generate analysis datasets and TFLs will 
be archived in 2 formats (ASCII, and .PDF); the analysis SAS Datasets will archived in XPT format 
created using SAS PROC XPORT. 
The analyses described in this section are applicable for the planned TLFs listed in Appendix 1.  
7.1.   Methodology 
Continuous data will be summarized with the following descriptive statistics: number of 
observations, mean, (n) standard deviation (StdDev), median, minimum (min), and maximum 
(max). Categorical data will be summarized with frequencies and percentages. 
Listings will be presented by subject and all data will be presented.  Tables will be presented by 
treatment arms and only data pertaining to the specific population being analyzed will be used. 
7.2.   Analysis Populations 
The protocol defines the following analyses populations: 
Evaluable for toxicity: All treated subjects (defined as subjects who receive at least one dose of 
fulvestrant or everolimus/placebo) are evaluable for toxicity from the time of their first 
treatment with fulvestrant and everolimus/placebo. All subjects are to be followed for 30 days 
for toxicity after the last dose of study therapy (fulvestrant and/or everolimus/placebo) or until 
recovery from all toxicity (to ≤ grade 1) attributed to study therapy, whichever is longer (or if 
>grade 1, event must be permanent and stable). 
Evaluable for objective response: Subjects will be classified into two groups according to their 
measurable disease stratification level at randomization.  Subjects with measurable disease 
(with or without bone only metastases) will have their responses classified according to the 
definitions stated in Protocol Section 6.1.2 and SAP Appendices 3 through 5. Subjects in this 
stratum who are unevaluable for objective response will be included in the denominator when 
calculating the response rate. 
Evaluable for non-target disease response: Subjects who are stratified into the bone metastases 
only cohort at randomization will be considered evaluable for non-target disease. The response 
assessment is based on the presence, absence, or unequivocal progression of the lesions.  
Subjects who are free of new lesions and free of unequivocal progression will be considered to 
have clinical benefit.   


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Evaluable for efficacy:  The primary efficacy analysis will be done including eligible, treated 
subjects.   
Intent-to-treat (ITT) analysis population includes all subjects as randomized. Sensitivity analyses 
of efficacy will be done among all subjects as randomized (ITT population). 
The next sections will indicate the required analysis population for the planned analyses. This is 
also documented in each TLF template. 
7.3.   Subject Disposition 
The following summary tables will be prepared to describe subjects’ disposition and case status 
for all enrolled subjects: 
7.3.1.   Accrual by Institution 
Number and percentage of subjects enrolled and ineligible will be summarized by study site 
overall. Number of randomized subjects, withdrawn before treatment, eligible and treated will 
be summarized by site and by randomized treatment arm.  Percentages for ineligible will be 
based on all enrolled.  Percentages for randomized subjects are based on all enrolled. 
Percentages for withdrawn before treatment, eligible and treated will be based on the number 
randomized within each treatment arm. 
7.3.2.   Case Status 
Number and percentage of subjects enrolled and ineligible will be summarized overall. Number 
of randomized subjects, withdrawn before treatment, eligible and treated will be summarized 
by randomized treatment arm.  Percentages for ineligible will be based on all enrolled.  
Percentages for randomized subjects are based on all enrolled. Percentages for withdrawn 
before treatment, eligible and treated will be based on the number randomized within each 
treatment arm. 
Number and percentage of subjects who completed Induction phase, discontinued during 
induction phase, were unblinded during induction phase, continued in Continuation phase, 
completed study, and discontinued the study will be summarized by treatment arm and overall. 
Percentages are based on number of eligible and treated subjects. 
Subject’s reasons for discontinuation at the end of treatment will be summarized by the 
following categories: adverse events, death, progressive disease, symptomatic progression, 
physician decision, protocol non-compliance, withdrawal by subjects, study terminated by 
sponsor, or unknown.  If there are still subjects on treatment at the time the clinical study 
report is prepared, an additional category “Remain on treatment” will be included.  
Percentages will be calculated based on number of eligible and treated subjects. 


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7.3.3.   Reasons Subjects were Ineligible 
These will be summarized in a by subjects data listing including inclusion / exclusion criteria not 
met by subjects considered ineligible for the study 
7.3.4.   Reasons Subjects did not Start Treatment 
Per protocol, subjects are to start treatment within 7 days post randomization.  Subjects who 
were randomized and discontinued study prior to starting treatment will be listed.  This listing 
will include randomized subjects who discontinued prior to induction phase and do not have a 
corresponding record in EX domain or have only one record in EX domain indicating 
Fulvestrant or Everolimus/Placebo not administered.  Reason for discontinuation will be based 
on End of Treatment CRF (DS domain).  
7.3.5.   Stratification Factors 
A summary of responses for the 3 stratification factors considered for randomization will be 
prepared by treatment arm and overall. The 3 factors are: performance status (1 or 0), 
measurable disease (yes or no), and prior chemotherapy (yes or no).  This information will be 
based on IWR. 
Since performance status is assessed again on Day 1 of Cycle 1, a cross-tabulation between 
performance status as reported and recorded in IWR and performance status as recorded on 
Day 1 Cycle 1 will be prepared (overall and by treatment group). 
For both tables, percentages will be based on number of randomized subjects. 
7.4.   Subject Characteristics 
Demographic and baseline characteristics will be summarized overall and by treatment arm for 
randomized subjects.  The following variables will be summarized: 
• Age (years) as continuous variable 
• Sex (female, male) 
• Race categories 
• Ethnicity categories 
• Time since diagnosis (months) as continuous variable 
• Number and percentage of subjects who developed locally recurrent disease 
• Number and percentage of subjects who developed metastatic disease 
• Time since recurrence / progression (months) as continuous variable 


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• Sites of recurrence of metastasis 
• ER status 
• PR status 
• HER2 Neu and HER2Neu FISH results 
• Prior anti-cancer therapies (Number of regimens) 
• Prior bone-modifying medications (Number of regimens) 
Time since diagnosis = (date of informed consent – date of diagnosis + 1)/30.4375.  
Time since recurrence / progression = (date of informed consent – date of recurrence / 
progression + 1)/30.4375  
Partial dates for date of diagnosis or for date of recurrence / progression will be imputed as 
follows: 
• if the day is missing, it will be imputed it to be 15th of the month; for example, if date is 
recorded as JUL‐1990, the imputed the date will be 15‐JUL‐1990; 
• if the day and the month are missing, it will be imputed to 30-JUN; for example, if only 
1976 is recorded, the imputed date will be 30-JUN‐1976. 
Percentages will be based on number randomized.  Results will be summarized for all 
randomized subjects and for the Evaluable for Efficacy population (including eligible and 
treated subjects).  
7.5.   Dosing and Number of Cycles in the Study 
The number of cycles of treatment received will be summarized by reason off treatment for all 
subjects evaluable for toxicity by treatment arm.  The following rule will be applied: subjects 
who start treatment but discontinue during Cycle 1 will be reported for “reason off treatment” 
in Cycle 1; subjects who discontinue during Cycle 5 (for example) will be counted as “Completed 
Treatment” for cycles 1, 2 , 3, and 4 and under reason off treatment for Cycle 5. 
Dose during Induction and during Continuation phase will be summarized as a continuous 
variable.  Dose during a phase is computed as the average dose across all days when 
medication was taken (dosing interval).  Dosing interval is the interval between the date of the 
first dose in the phase till the last dose date recorded in the diary.  If during the dosing interval, 
dose modification indicates missed or dose withdrawn, the respective days are be counted with 
0 mg. 


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7.6.   Concomitant Medications 
A by-subject data listing of bone modifying medications will be prepared for all treated subjects. 
 
7.7.   Efficacy Analysis 
7.7.1.   Response Analysis 
Best overall response at the end of treatment will be summarized by treatment arm for all 
eligible, treated subjects.  The summary table will include counts and percentages for each 
response category (CR, PR, SD, PD, unevaluable). 
Objective response rate (defined as CR or PR among subjects with measurable disease) and 
clinical benefit rate (defined as CR, PR or SD for at least 24 weeks for subjects with measurable 
disease and as freedom from new lesions or unequivocal progression for at least 24 weeks 
among subjects with bone metastases only) will be estimated (n, %) for all eligible, treated 
subjects by treatment arm and disease stratum.  The 90% exact binomial confidence interval for 
each of the three rates:  
• Objective Response – Subjects with Measurable Disease 
• Clinical Benefit – Subjects with Measurable Disease 
• Clinical Benefit – Subjects with Bone Metastases Only 
will also be included in the summary table.  In the unlikely event that complete responses are 
observed among patients with bone metastases only, these will be described. 
A by-subject data listing will be prepared to indicate the reason subjects were not evaluable for 
response.  Include in this list subjects with: 
• No re-evaluation of disease with Reason Unevaluable = No Re-evaluation of Disease.  If 
subject discontinued study early, include reason for early termination in “Specify” 
column. If assessments were noted as “Not Done” at the time points/ visits prior to 
discontinuation, list visits when ‘not done’ and reason not done (one entry per time 
point). 
• Re-evaluation of disease not done within required time frame 
• Incomplete evaluation of disease (e.g., missing some target lesions that were evaluated 
at baseline). 


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7.7.2.   Progression-Free Survival (PFS), Time-to-Disease Progression (TTP), and Overall 
Survival (OS) 
Median time and 90% confidence interval for PFS, TTP, and OS will be summarized for all 
eligible, treated subjects by treatment arm using Kaplan-Meier estimates. If medians have not 
been reached, 2-year PFS, TTP and OS should be reported instead, with 90% confidence 
intervals, calculated using time-to-event methods. 
PFS = time from randomization to documented disease progression or death.  
TTP = time from randomization until progression of disease 
OS = time from randomization until death. 
Subjects who are lost to follow-up are censored at the time of last tumor assessment for TTP 
and PFS and at the time of the last known contact for OS.  All other subjects are censored at the 
time of analysis. 
In addition to the summary table, PFS and OS will be displayed by treatment arm using Kaplan-
Meier survival curves. 
As a sensitivity analysis, all of the above analyses described in Section 7.6.2 will be repeated for 
the as-randomized population (intent-to-treat analysis). 
7.8.   Safety Analysis 
7.8.1.   Adverse Events 
Adverse events (AEs) will be graded using CTC Version 4, coded using MedDRA dictionary 
version 16.0, and flagged as treatment emergent if start date of the adverse event is on or after 
Cycle 1 Day 1 dosing.  For adverse events with partial start date (i.e., with only month and year 
are recorded), the following imputation rule will be applied: 15th of the month or first dose 
date, whichever comes later. 
All AEs and treatment-related AEs will be summarized for all treated subjects by toxicity grade 
and by treatment arm.   
AEs with relationship reported as ‘Definite’, ‘probable’ and ‘possible’ are considered study drug 
related. AEs with relationship reported ‘not likely’ and ‘not related’ are considered not study 
drug-related.  AEs with missing relationship will be considered study drug related. 
The following by subject data listings will be prepared:  subjects with serious adverse events, 
subjects with Grade 5 adverse events, and subjects with second primary cancer. 


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8.   REPORTING CONVENTIONS 
The mean and median will be displayed to one decimal place greater than the original value and 
the standard deviation will be displayed to two decimal places greater than the original value. 
All statistical programming and analyses will be performed using SAS® Release 9.2 (SAS Institute 
Inc., Cary, North Carolina, USA). 
The following standards will be used in the data presentation: 
• Tables should be in landscape format.  Output should adhere to US / International 
Conference on Harmonization (ICH) margins and should not require changes for European 
page size.  A blank row will separate the header from the content of the table listing.  For 
tables that have “n (%)”, the placement should be centered below “N=xx” in the column 
header.  Frequency tables will be center justified.  Descriptive statistics will be decimal 
aligned.   
• Percentages presented in in-text tables should be rounded to one decimal using the SAS 
rounding function.  If “%” is part of the column heading, do not repeat the “%” sign in the 
body of the table.  Unless specified otherwise, “%” should reflect the total population of the 
treatment groups.  Any deviation from that should be part of the footnote.  For 0 counts, 
leave the corresponding percentage blank. 
• The heading should consist of four lines.  Line 1:  Sponsor identifier.  Line 2:  Protocol 
identifier.  Line 3: blank line.  Line 4:  Table/Appendix number Table Title – Population.  The 
title for in-text tables should begin with the Table/Appendix number. 
• All data listings will be sorted by Subject Number and time point (if applicable). 
• The date format for all dates is DDMMMYYYY.  
A solid line should appear both above and below the column headings of a table.  A solid line 
should appear at the end of the table or at the bottom of each page if the table extends to 
more than one page.  Footnotes should start after the bottom solid line. 
 
9.   REFERENCES 
References are provided in the protocol.  
 
10.   TABLES, FIGURES, AND LISTINGS 
See separate template document. 


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11.   APPENDIX 1:  LIST OF TABLES, LISTINGS AND FIGURES REQUESTED FOR PUBLICATION 
The following list of required TLFs was provided by PrECOG on 24May2013.   
 
PrE0102 Tables, Listings, Figures 
5/24/13 
 
Table (1): Accrual by Institution 
 
Table (2): Case Status (by arm and total): 
 
Number Enrolled 
 
Number Ineligible 
 
Number Withdrew before Treatment 
 
Eligible and Treated 
 
Listing (1):  Reasons ineligible 
Listing (2):  Reasons for not starting treatment 
 
Table (3) of Stratification Factors (by arm and total) 
 
Cross-tab (4) of Stratification Factors and Corresponding data from CRF (by arm and total) 
 
Table (5): Subject Characteristics at Study Entry (by arm and total) 
 
Table (6):  Number Cycles of Treatment Received by Reason off Treatment (by arm) 
 
Table (7):  Dosing:  Median and range dose during induction and continuation (by arm and agent) 
 
Toxicity Tables (include all subjects receiving at least 1 dose of study drug/placebo.  Count each subject 
once at the highest grade): 
 
 (8) All events, grade 1 to 5, regardless of attribution, by arm and grade 
 
 
Count 
 
 
Percent 
 
 (9) Treatment-related events, grade 1 to 5, by arm and grade 
 
 
Count 
 
 
Percent 
 
Above 2 tables should use CTCAE terminology if possible 
 
(10, 11) Same 2 tables, by System Organ Class rather than individual event 
 
Listing (3) of Serious Adverse Events 
 
Listing (4) of Subjects with Grade 5 Adverse Events 
 


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Table (12) of Best Overall Response, by response category and treatment arm, including unevaluable 
subjects as non-responders 
 
Table (13):  Objective Response rate and 90% exact binomial confidence interval, by arm, and Clinical 
Benefit Rate (CR+PR+SD) with 90% exact binomial confidence interval, by arm and both overall 
 
List (5) of Subjects Unevaluable for Response, with arm and reason 
 
Listing (6) of Second Primary Cancers 
 
Table (14) showing PFS, TTP and OS:  Median and 90% CI, or 2-year rates with 90% CI 
 
Listing (7) of Bone Modifying Medications 
 
Figure 1 – PFS by treatment arm 
Figure 2 – OS by treatment arm 
 
 
 
An additional listing for Bone Modifying Medication was requested via email on 11Jun2013.  
 
For completeness, an additional table summarizing adverse events was included in TLF 
templates.   


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12.   APPENDIX 2:  SCHEDULED ASSESSMENTS 
 


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13.   APPENDIX 3:  DISEASE PARAMETERS AND METHODS FOR EVALUATION OF MEASURABLE 
DISEASE 
The following text is from Protocol Section 6.1.2 and 6.1.3. 
Measurable lesions: are defined as those that can be accurately measured in at least one dimension 
(longest diameter in the plane of measurement) are to be recorded with a minimum size of: 
• 
≥ 20 mm by chest x-ray (if clearly defined and surrounded by aerated lung) 
• 
≥ 10 mm with CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10 mm) 
• 
≥ 10 mm with calipers by clinical exam when superficial 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph node must 
be ≥ 15 mm in short axis (perpendicular to longest diameter) 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 lesions: all other lesions (or sites of disease), including small lesions (longest diameter 
<10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses/organomegaly (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. 
Lytic bone lesions, with an identifiable soft tissue component, evaluated by CT or MRI, can be 
considered as measurable lesions if the soft tissue component otherwise meets the definition of 
measurability noted above. Blastic bone lesions are non-measurable. 
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 randomization. 


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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 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. 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not 
always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can 
document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT 
(with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. 
Note, however, that the PET portion of the CT introduces additional data which may bias an investigator 
if it is not routinely or serially performed. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review 
at a later date and, because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next. If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is 
concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response when 


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biopsies are obtained or to determine relapse in trials where recurrence following complete response 
(CR) or surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete clinical 
response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response 
(in recurrent prostate cancer) have been published.56-58 In addition, the Gynecologic Cancer Intergroup 
has developed CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer. 59 
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm: 
• 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
• 
No FDG-PET at baseline and a positive FDG-PET at follow-up:  
o If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. 
o If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). 
o If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
• 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 


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Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice 
that of the surrounding tissue on the attenuation corrected image. 


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14.   APPENDIX 4:  RESPONSE CRITERIA 
The following text is from Protocol Section 6.1.4.1 to 6.1.4.3 
Evaluation of Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and five 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 (those with the longest diameters), 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. 
The 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 of the diameters will be 
used as reference to further characterize any objective tumor regression in the measurable dimension 
of the disease. 
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 over the nadir. (Note: the appearance of one or more new lesions is also considered progression). 
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. (Note: a change of 20% or more that 
does not increase the sum of the diameters by 5 mm or more is coded as stable disease). 
Evaluation of Non-Target Lesions 
All other lesions or sites of disease including any measurable lesions over and above the 5 target lesions 
should be identified as non-target lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of unequivocal progression of each should 
be noted throughout follow-up. 
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). 


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Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to 
be considered in complete clinical response. 
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. 
When the patient also has measurable disease, there must be an overall level of substantial worsening 
in non-target disease such that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size of 
one or more non-target lesions is usually not sufficient to qualify for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the increase in overall disease burden should be 
comparable in magnitude to the increase that would be required to declare PD for measurable disease: 
i.e., an increase in tumor burden from “trace” to “large”, an increase in nodal disease from “localized” to 
“widespread”, or an increase sufficient to require a change in therapy. 
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). 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive Disease (PD). 
 


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15.   APPENDIX 5:  BEST OVERALL RESPONSE 
The following text is from Protocol Section 6.1.4.4 
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.  Note:  since response is not the primary 
endpoint, confirmation is not required. 
 
Patients with Measurable Disease (e.g., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
Confirmation not required 
CR 
Non-CR/Non-PD 
No 
PR 
Confirmation not required 
CR 
Not Evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/Not 
Evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/Not 
Evaluated 
No 
SD 
Confirmation not required 
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. 
**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. 
 
 
 
 


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Patients with Non-Measurable Disease (e.g., 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.