PrE0102: Study of Fulvestrant +/- Everolimus in Post-Menopausal, Hormone-Receptor + Metastatic Breast Ca Resistant to AI

• Sponsor: PrECOG, LLC. (Other)
• Overall Status: Completed
• CT.gov ID: NCT01797120
• Collaborator: Novartis (Industry)
• Enrollment: 131
• Locations: 25
• Arms: 2
• Actual Duration (Months): 51.4
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Fulvestrant; Drug: Everolimus; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 131 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: May 31, 2013
• Actual Primary Completion Date: Mar 22, 2017
• Actual Study Completion Date: Sep 12, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Fulvestrant & Everolimus 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.	Drug: Fulvestrant; 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.; Other Names: Faslodex ; Drug: Everolimus; 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.; Other Names: mTOR Inhibitor RAD001 Afinitor
Placebo Comparator: Fulvestrant & Placebo 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.	Drug: Fulvestrant; 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.; Other Names: Faslodex ; Drug: Placebo; Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.; Other Names: Sugar Pill

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [Every 3 months until progression or up to 3 years]

   Progression-free survival documented by Physical Exam, CT Scan or MRI 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 from randomization to documented disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Secondary Outcome Measures

1. Clinical Benefit Rate [Every 3 months until progression or up to 3 years]

   Clinical benefit rate is defined as number of patients with objective response (complete response or partial response) or stable disease for at least 24 weeks divided by number of patients randomized in each arm. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI and/or CT: Partial Response (PR) is defined as >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease; Complete Response (CR) is defined as disappearance of all target lesions.

2. Objective Response Rate [Every 3 months until progression or up to 3 years]

   Objective response rate is defined as number of patients with complete or partial response (by Physical Exam, CT or MRI) divided by number of patients randomized in each arm

3. Overall Survival [Every 3 months until progression or up to 3 years]

   Overall survival will be characterized using Kaplan-Meier plots and other descriptive metrics.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Signed informed consent.

2. ≥18 years.

3. ECOG Performance Status 0 or 1.

4. Histologically or cytologically confirmed adenocarcinoma of the breast.

5. Stage IV disease or inoperable locally advanced disease.

6. ER and/or PR-positive disease. Tumors must be HER-2/neu negative or equivocal.

7. Aromatase Inhibitor (AI) resistant, defined as:

• relapsed while receiving adjuvant therapy with an AI or,

• progressive disease while receiving an AI for metastatic disease

1. Received one prior cycle of fulvestrant within 28 days of randomization are eligible.

• ≥2 prior doses of fulvestrant are not eligible

1. Must be female and postmenopausal.

2. May have received ≤1 prior systemic chemotherapy regimen for metastatic disease.

3. Adequate organ function:

• Whole Blood Cells (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 (Upper Limit of Normal)

• Aspartate Aminotransferase (AST) or Alanine Aminotransferase (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.

• Prothrombin time (PT) with international normalized ratio (INR) ≤1.5

1. May have measurable disease, non-measurable disease, or both.

2. Basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix within the past five years treated with curative intent. History of prior malignancy are eligible if disease-free for >3 years.

Exclusion Criteria:

1. Major surgery or significant traumatic injury within 4 weeks of randomization or patients that may require major surgery during the course of the study.

2. Investigational agents within 4 weeks of randomization.

3. Anticancer treatment within 4 weeks of randomization, with the following exceptions:

• Bisphosphonates or Zometa for bone metastases

• a GnRH analog is permitted if the patient had progressive disease on a GnRH (Gonadotropin-Releasing Hormone) analog plus a SERM (Selective Estrogen Receptor Modulators) or an AI; the GnRH analog may continue but the SERM or AI must be discontinued.

1. Prior treatment with an mTOR inhibitor.

2. Receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent ≥ 5 mg prednisone or equivalent daily.

3. Receive immunization with attenuated live vaccines within one week of randomization or during the study period.

4. Current or a prior history of brain metastases or leptomeningeal disease. Must not have rapidly progressive, life-threatening metastases.

5. Known hypersensitivity/history of allergic reactions attributed to compounds of similar chemical or biologic composition to everolimus or fulvestrant.

6. Congenital or acquired immune deficiency at increased risk of infection.

7. Impairment of gastrointestinal function/disease that may significantly alter the absorption of everolimus.

8. Active, bleeding diathesis.

9. History of any condition or uncontrolled intercurrent illness 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.

10. 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

• 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 requiring treatment.

• Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN

• Active (acute or chronic) or uncontrolled severe infections

• Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh Class C).

Note: Detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Marin Cancer Care	Greenbrae	California	United States	94904
2	Stanford University	Stanford	California	United States	94305
3	SwedishAmerican Regional Cancer Center	Rockford	Illinois	United States	61104
4	McFarland Clinic, PC	Ames	Iowa	United States	50010-3014
5	Johns Hopkins University	Baltimore	Maryland	United States	21287
6	St. Joseph Mercy Hospital (MI Cancer Consortium)	Ann Arbor	Michigan	United States	48158
7	Metro MN	Saint Louis Park	Minnesota	United States	55416
8	Missouri Valley Cancer Consortium	Omaha	Nebraska	United States	68106
9	Montefiore Medical Center	Bronx	New York	United States	10466
10	Beth Israel	New York	New York	United States	10011
11	Ohio State University Medical Center	Columbus	Ohio	United States	43210
12	Toledo COP	Toledo	Ohio	United States	43617
13	Hematology & Oncology Associates of Northeastern PA, PC	Dunmore	Pennsylvania	United States	18512
14	Penn State University	Hershey	Pennsylvania	United States	17033
15	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
16	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
17	University of Pittsburgh- Magee Women's Hospital	Pittsburgh	Pennsylvania	United States	15213
18	Reading Hospital- McGlinn Family Regional Cancer Center	West Reading	Pennsylvania	United States	19611
19	Main Line Heath System	Wynnewood	Pennsylvania	United States	19096
20	University of Texas Southwestern	Dallas	Texas	United States	75390
21	Charleston Area Medical Center (CAMC)	Charleston	West Virginia	United States	25304
22	St. Vincent Hospital	Green Bay	Wisconsin	United States	54301
23	Gundersen Health System	La Crosse	Wisconsin	United States	54601
24	ProHealth Care Inc. (Waukesha)	Waukesha	Wisconsin	United States	53188
25	Aurora Cancer Care	Wauwatosa	Wisconsin	United States	53226

Sponsors and Collaborators

• PrECOG, LLC.
• Novartis

Investigators

• Study Chair: Noah S Kornblum, MD, Saint Barnabas Cancer Center, Montefiore Medical Center

Study Documents (Full-Text)

• Study Protocol - Jan 22, 2014
• Statistical Analysis Plan - Mar 24, 2014

More Information

Additional Information:

• Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With ER-Positive Metastatic Breast Cancer Resistant to Aromatase Inhibitor

Publications

None provided.

• Responsible Party: PrECOG, LLC.
• ClinicalTrials.gov Identifier: NCT01797120
• Other Study ID Numbers: PrE0102
• First Posted: Feb 22, 2013
• Last Update Posted: May 30, 2018
• Last Verified: Apr 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by PrECOG, LLC.: Post-Menopausal Patients; Hormone-Receptor Positive; Resistant to Aromatase Inhibitor Therapy; Fulvestrant; Faslodex; mTOR Inhibitor; Everolimus; RAD001; Afinitor
• Additional relevant MeSH terms: Breast Neoplasms; Everolimus; Fulvestrant

Study Results

Participant Flow

Recruitment Details	A total of 131 patients were enrolled from 23 institutions between May 2013 and November 2015.

Arm/Group Title	Fulvestrant & Everolimus	Fulvestrant & Placebo
Arm/Group Description	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. Fulvestrant: 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. Everolimus: 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.	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. Fulvestrant: 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. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.
Period Title: Overall Study
STARTED	66	65
COMPLETED	0	0
NOT COMPLETED	66	65

Baseline Characteristics

Arm/Group Title	Fulvestrant & Everolimus	Fulvestrant & Placebo	Total
Arm/Group Description	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. Fulvestrant: 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. Everolimus: 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.	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. Fulvestrant: 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. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.	Total of all reporting groups
Overall Participants	66	65	131
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64	59	63
Sex: Female, Male (Count of Participants)
Female	66 100%	65 100%	131 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	56 84.8%	49 75.4%	105 80.2%
Black	8 12.1%	11 16.9%	19 14.5%
Others	2 3%	5 7.7%	7 5.3%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	Progression-free survival documented by Physical Exam, CT Scan or MRI 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 from randomization to documented disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	Every 3 months until progression or up to 3 years

Outcome Measure Data

Analysis Population Description

all randomized patients

Arm/Group Title	Fulvestrant & Everolimus	Fulvestrant & Placebo
Arm/Group Description	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. Fulvestrant: 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. Everolimus: 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.	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. Fulvestrant: 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. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.
Measure Participants	66	65
Median (95% Confidence Interval) [months]	10.3	5.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fulvestrant & Everolimus, Fulvestrant & Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Log Rank
	Comments	Log rank test was stratified on ECOG performance status, measurable disease, and prior chemotherapy for metastatic disease
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.40 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Clinical Benefit Rate
Description	Clinical benefit rate is defined as number of patients with objective response (complete response or partial response) or stable disease for at least 24 weeks divided by number of patients randomized in each arm. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI and/or CT: Partial Response (PR) is defined as >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease; Complete Response (CR) is defined as disappearance of all target lesions.
Time Frame	Every 3 months until progression or up to 3 years

Outcome Measure Data

Analysis Population Description

all randomized patients

Arm/Group Title	Fulvestrant & Everolimus	Fulvestrant & Placebo
Arm/Group Description	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. Fulvestrant: 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. Everolimus: 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.	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. Fulvestrant: 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. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.
Measure Participants	66	65
Number (95% Confidence Interval) [proportion of patients]	0.636	0.415

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fulvestrant & Everolimus, Fulvestrant & Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	Objective Response Rate
Description	Objective response rate is defined as number of patients with complete or partial response (by Physical Exam, CT or MRI) divided by number of patients randomized in each arm
Time Frame	Every 3 months until progression or up to 3 years

Outcome Measure Data

Analysis Population Description

all randomized patients

Arm/Group Title	Fulvestrant & Everolimus	Fulvestrant & Placebo
Arm/Group Description	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. Fulvestrant: 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. Everolimus: 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.	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. Fulvestrant: 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. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.
Measure Participants	66	65
Number (95% Confidence Interval) [proportion of patients]	0.182	0.123

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fulvestrant & Everolimus, Fulvestrant & Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.47
	Comments
	Method	Fisher Exact
	Comments

4. Secondary Outcome

Title	Overall Survival
Description	Overall survival will be characterized using Kaplan-Meier plots and other descriptive metrics.
Time Frame	Every 3 months until progression or up to 3 years

Outcome Measure Data

Analysis Population Description

all randomized patients

Arm/Group Title	Fulvestrant & Everolimus	Fulvestrant & Placebo
Arm/Group Description	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. Fulvestrant: 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. Everolimus: 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.	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. Fulvestrant: 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. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.
Measure Participants	66	65
Median (95% Confidence Interval) [months]	28.3	31.4

Adverse Events

Time Frame	Assessed at the end of each cycle (1 cycle=4 weeks) while on treatment and 30 days after the last dose of protocol therapy. Treatment continued for a maximum of 48 weeks (12 cycles) in the absence of disease progression, unacceptable toxicity or withdrawal of consent.
Adverse Event Reporting Description	All-cause mortality is the death rate among all patients, rather than in patients who received at least one dose of protocol therapy and reported toxicity data.
Arm/Group Title	Fulvestrant & Everolimus		Fulvestrant & Placebo
Arm/Group Description	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. Fulvestrant: 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. Everolimus: 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.		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. Fulvestrant: 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. Placebo: Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.
All Cause Mortality
	Fulvestrant & Everolimus		Fulvestrant & Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/66 (45.5%)		21/65 (32.3%)
Serious Adverse Events
	Fulvestrant & Everolimus		Fulvestrant & Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/64 (48.4%)		5/65 (7.7%)
Blood and lymphatic system disorders
Anemia	2/64 (3.1%)		1/65 (1.5%)
Lymphocytopenia	2/64 (3.1%)		0/65 (0%)
Hypertension	2/64 (3.1%)		0/65 (0%)
Neutropenia	2/64 (3.1%)		0/65 (0%)
Thrombocytopenia	1/64 (1.6%)		0/65 (0%)
Cardiac disorders
Thromboembolic Event	1/64 (1.6%)		0/65 (0%)
Gastrointestinal disorders
Oral mucositis	7/64 (10.9%)		0/65 (0%)
Diarrhea	2/64 (3.1%)		1/65 (1.5%)
General disorders
Fatigue	4/64 (6.3%)		3/65 (4.6%)
Hepatobiliary disorders
Elevated AST	2/64 (3.1%)		1/65 (1.5%)
Elevated ALT	1/64 (1.6%)		0/65 (0%)
Infections and infestations
Esophageal Candidiasis	1/64 (1.6%)		0/65 (0%)
Esophagitis	1/64 (1.6%)		0/65 (0%)
Laryngeal Inflammation	1/64 (1.6%)		0/65 (0%)
Urinary Tract Infection	1/64 (1.6%)		0/65 (0%)
Metabolism and nutrition disorders
Hypertriglyceridemia	1/64 (1.6%)		0/65 (0%)
Hyperglycemia	2/64 (3.1%)		0/65 (0%)
Hyponatremia	2/64 (3.1%)		0/65 (0%)
Hypokalemia	1/64 (1.6%)		0/65 (0%)
Hypophosphatemia	1/64 (1.6%)		0/65 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/64 (3.1%)		0/65 (0%)
Pneumonitis	4/64 (6.3%)		0/65 (0%)
Hypoxia	1/64 (1.6%)		0/65 (0%)
Skin and subcutaneous tissue disorders
Rash	1/64 (1.6%)		0/65 (0%)
Pruritus	1/64 (1.6%)		0/65 (0%)
Surgical and medical procedures
Surgical and Medical Procedures	1/64 (1.6%)		0/65 (0%)
Other (Not Including Serious) Adverse Events
	Fulvestrant & Everolimus		Fulvestrant & Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	59/64 (92.2%)		38/65 (58.5%)
Blood and lymphatic system disorders
Anemia	18/64 (28.1%)		3/65 (4.6%)
Neutropenia	5/64 (7.8%)		2/65 (3.1%)
Thrombocytopenia	5/64 (7.8%)		0/65 (0%)
White blood cell decreased	4/64 (6.3%)		1/65 (1.5%)
Cardiac disorders
Hot flashes	5/64 (7.8%)		4/65 (6.2%)
Gastrointestinal disorders
Oral mucositis	26/64 (40.6%)		8/65 (12.3%)
Anorexia	22/64 (34.4%)		4/65 (6.2%)
Nausea	16/64 (25%)		12/65 (18.5%)
Diarrhea	13/64 (20.3%)		4/65 (6.2%)
Dysgeusia	8/64 (12.5%)		6/65 (9.2%)
Vomitting	7/64 (10.9%)		3/65 (4.6%)
Dry mouth	4/64 (6.3%)		0/65 (0%)
Insomnia	4/64 (6.3%)		0/65 (0%)
General disorders
Fatigue	23/64 (35.9%)		11/65 (16.9%)
Weight loss	9/64 (14.1%)		3/65 (4.6%)
Chills	7/64 (10.9%)		0/65 (0%)
Headache	6/64 (9.4%)		6/65 (9.2%)
Hepatobiliary disorders
AST increased	4/64 (6.3%)		1/65 (1.5%)
ALT increased	4/64 (6.3%)		1/65 (1.5%)
Metabolism and nutrition disorders
Hyperglycemia	10/64 (15.6%)		3/65 (4.6%)
Hypertriglyceridemia	10/64 (15.6%)		2/65 (3.1%)
Hypercholesterolemia	12/64 (18.8%)		2/65 (3.1%)
Hypokalemia	4/64 (6.3%)		1/65 (1.5%)
Respiratory, thoracic and mediastinal disorders
Cough	15/64 (23.4%)		1/65 (1.5%)
Dyspnea	8/64 (12.5%)		2/65 (3.1%)
Epistaxis	8/64 (12.5%)		0/65 (0%)
Pneumonitis	7/64 (10.9%)		0/65 (0%)
Skin and subcutaneous tissue disorders
Rash	23/64 (35.9%)		3/65 (4.6%)
Dry skin	8/64 (12.5%)		0/65 (0%)
Pruritus	12/64 (18.8%)		2/65 (3.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.