Everolimus Combined With Anti-estrogen Therapy in Hormone-Receptor-Positive HER-2 Negative Advanced Breast Cancer

• Sponsor: SCRI Development Innovations, LLC (Other)
• Overall Status: Completed
• CT.gov ID: NCT02291913
• Collaborator: Novartis (Industry)
• Enrollment: 48
• Locations: 8
• Arm: 1
• Actual Duration (Months): 49.4
• Patients Per Site: 6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Many patients with ER-positive or PR-positive breast cancer are treated with endocrine therapy. Although most ER/PR-positive tumors initially respond to hormonal therapy, patients often experience disease progression. Everolimus, in combination with exemestane, has shown activity in endocrine-resistant disease. This study will evaluate the efficacy of Everolimus+ anti-estrogen therapy in patients with ER-positive metastatic breast cancer who have progressed after receiving anti-estrogen therapy.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Everolimus; Drug: Exemestane; Drug: Tamoxifen; Drug: Fulvestrant; Drug: Anastrozole; Drug: Letrozole; Drug: Toremifine	Phase 2

Detailed Description

This is a multi-centered, open-labeled, Phase II study on metastastic breast cancer (MBC). The patient population includes locally recurrent or MBC patients with cytologically or histologically confirmed hormone receptor-positive breast cancer who have demonstrated disease progression on prior anti-estrogen therapy or therapies. Investigators propose to evaluate the efficacy of Everolimus in patients with ER-positive (estrogen receptor-positive) metastatic breast cancer who have progressed on anti-estrogen therapy. Forty-six (46) patients are planned for enrollment in the trial.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Open Label Study of Everolimus in Combination With Anti-estrogen Therapy in Hormone Receptor-Positive HER2-Negative Advanced Breast Cancer
• Actual Study Start Date: Dec 18, 2014
• Actual Primary Completion Date: Jan 31, 2019
• Actual Study Completion Date: Jan 31, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: everolimus Everolimus will be administered at a dose of 10 mg PO daily combined with any one of the following anti-estrogen therapies on which the patient most recently progressed (tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy). Anti-estrogen therapy will be administered at the US Food and Drug Administration (FDA) prescribed doses.

Drug: Everolimus; Other Names: Afinitor ; Drug: Exemestane; Anti-estrogen therapy; Drug: Tamoxifen; Anti-estrogen therapy; Drug: Fulvestrant; Anti-estrogen therapy; Drug: Anastrozole; Anti-estrogen therapy; Drug: Letrozole; Anti-estrogen therapy; Drug: Toremifine; Anti-estrogen therapy

Outcome Measures

Primary Outcome Measures

1. Median Progression Free Survival (PFS) [up to 3 years]

   PFS is defined as the time from Day 1 of study drug administration to disease progression as defined by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 criteria, or death on study. Participants who are alive and free from disease progression will be censored at the date of last radiologic tumor assessment. Participants who receive non-protocol therapy (subsequent therapy) prior to incurring an event will be censored at the date of last tumor assessment prior to the start of subsequent therapy. Participants who do not have a post-baseline tumor assessment will be censored at the date of first treatment (Day 1).

Secondary Outcome Measures

1. Number of Patients With Adverse Events (AEs) as a Measure of Safety and Tolerability [Up to 20 months]

   Assessments were made through analysis of the reported incidence of treatment-emergent AEs. All participants who received at least one dose of protocol treatment were followed for safety. Adverse events were collected from day of first dose to 30 days after last protocol treatment and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

2. Number of Patients With an Objective Response (CR or PR) Also Called the Overall Response Rate (ORR). [every 8 weeks until discontinuation, up to 20 months]

   Defined as the number of patients with objective evidence of complete or partial response (CR or PR) using RECIST version 1.1. A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters.

3. Number of Participants With CR, PR, or 6 Months of SD Also Called Clinical Benefit Rate (CBR) [Up to 20 months]

   The proportion of patients with Complete Response (CR) or Partial Response (PR) or 6 months or more of Stable Disease (SD). A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters. SD is not meeting the criteria for PR or a 20% increase in target lesions called Progressive Disease (PD).

4. Median Time From First Occurrence of CR or PR to Disease Progression or Death Also Called Duration of Response (DOR) [every 8 weeks until discontinuation, up to 20 months]

   Only those patients who achieved Complete Response or Partial Response will be included in the summaries of DOR. DOR is defined as time from first date of response of CR or PR to disease progression or death as defined by RECIST v1.1 criteria. Participants who are alive and free from disease progression will be censored at the date of last tumor assessment. Patients who receive non-protocol therapy (subsequent therapy) prior to incurring an event will be censored at the date of last tumor assessment prior to the start of subsequent therapy. A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters.

5. Median Overall Survival (OS) [up to 3 years from first treatment]

   Defined as the time from date of first study treatment to date of death due to any cause. Patients who are alive will be censored at the date of last known date alive.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Histologic diagnosis of unresectable, locally recurrent or MBC.

2. ER and/or PR-positive tumors with staining by immunohistochemistry (IHC) based on the most recent biopsy.

3. Only 1 previous chemotherapy regimen for MBC. Patients progressing while receiving adjuvant endocrine therapy or progressing <12 months from completion of adjuvant endocrine therapy are eligible.

4. Progressed on anti-estrogen therapy (tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy) defined as:

• Recurrence while on, or within 12 months of end of anti-estrogen therapy for early stage breast cancer, or

• Progression while on, or within one month of anti-estrogen therapy for locally advanced or metastatic breast cancer.

Note: No washout for anti-estrogen therapy required. Anti-estrogen therapy does not have to be the last treatment prior to study entry.

1. Post-menopausal or pre/peri-menopausal women on tamoxifen. LHRH agonists may be used to render ovarian suppression with postmenopausal ranges of estradiol or FSH per institutional guidelines.

2. HER2-negative breast cancer, defined as follows:

• Fluorescent In Situ Hybridization (FISH)-negative (FISH ratio <2.0), or

• IHC 0-1+, or

• IHC 2-3+ AND FISH-negative (FISH ratio <2.0).

1. Measureable disease as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 or evaluable bone lesions, lytic or mixed, in absence of measureable disease by RECIST criteria.

2. Adequate hematologic, hepatic and renal function.

3. International normalized ratio (INR) ≤1.5 or prothrombin time (PT)/partial thromboplastin time (PTT) within normal limits (WNL) of the institution (if patient is not on anti-coagulation therapy).

4. Age ≥ 18 years.

5. ECOG Performance Status score of 0-2.

6. Life expectancy of ≥ 12 weeks.

Exclusion Criteria:

1. Previous therapy or known intolerance/hypersensitivity with any approved or investigational mTOR inhibitor (e.g., temsirolimus, everolimus, sirolimus).

2. Patients who are ≤21 days after their most recent chemotherapy and have not recovered from side effects.

3. Use of an investigational drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of everolimus. For investigational drugs for which 5 half-lives is ≤21 days, a minimum of 10 days between termination of the investigational drug and administration of everolimus is required.

4. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤28 days or limited field radiation for palliation ≤7 days for metastatic disease prior to first dose of everolimus or has not recovered from side effects of such therapy.

5. Previously untreated brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if there is no evidence of central nervous system (CNS) disease progression, and at least 2 weeks have elapsed since treatment. Patients are not permitted to receive enzyme inducing anti-epileptic drugs (EIAEDs) during the study and should not be receiving chronic corticosteroid therapy for CNS metastases.

6. Patients with known active hepatitis B (HBV) or hepatitis C (HCV) infection. Patients with risk factors for hepatitis must have HBV DNA and HCV RNA testing by PCR, and are ineligible if these tests are positive.

7. Patients receiving immunization with attenuated live vaccines within 1 week of study entry or during study period.

NOTE: There are additional inclusion/exclusion criteria. The study center will determine patient eligibility and respond to any questions.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Florida Cancer Specialists-South	Fort Myers	Florida	United States	33916
2	Memorial Cancer Center	Hollywood	Florida	United States	33021
3	Woodlands Medical Specialists	Pensacola	Florida	United States	32503
4	Florida Cancer Specialists-East	West Palm Beach	Florida	United States	33401
5	Hope Cancer Center	Terre Haute	Indiana	United States	47802
6	Tennessee Oncology	Chattanooga	Tennessee	United States	37404
7	Tennessee Oncology PLLC	Nashville	Tennessee	United States	37203
8	Center for Cancer and Blood Disorders	Fort Worth	Texas	United States	76104

Sponsors and Collaborators

• SCRI Development Innovations, LLC
• Novartis

Investigators

• Study Chair: Denise A. Yardley, MD, SCRI Development Innovations, LLC

Study Documents (Full-Text)

• Study Protocol - Jun 19, 2014
• Statistical Analysis Plan - Dec 6, 2019

More Information

Publications

None provided.

• Responsible Party: SCRI Development Innovations, LLC
• ClinicalTrials.gov Identifier: NCT02291913
• Other Study ID Numbers: SCRI BRE 212
• First Posted: Nov 17, 2014
• Last Update Posted: Feb 17, 2020
• Last Verified: Feb 1, 2020

• 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 SCRI Development Innovations, LLC: ER-Positive Breast Cancer; HER2-Negative Breast Cancer; everolimus; anti-estrogen therapy; PR-Positive Breast Cancer; Afinitor
• Additional relevant MeSH terms: Breast Neoplasms; Tamoxifen; Everolimus; Letrozole; Fulvestrant; Anastrozole; Exemestane

Study Results

Participant Flow

Recruitment Details	Between December 2014 to December 2015, 48 patients who had locally recurrent or metastatic breast cancer with cytologically or histologically confirmed hormone receptor-positive breast cancer who have demonstrated disease progression on prior anti-estrogen therapy. Study was closed after enrollment goal was reached.

Arm/Group Title	Everolimus
Arm/Group Description	Everolimus will be administered at a dose of 10 mg PO daily combined with any one of the following anti-estrogen therapies on which the patient most recently progressed (tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy). Anti-estrogen therapy will be administered at the US Food and Drug Administration (FDA) prescribed doses. Everolimus Exemestane: Anti-estrogen therapy Tamoxifen: Anti-estrogen therapy Fulvestrant: Anti-estrogen therapy Anastrozole: Anti-estrogen therapy Letrozole: Anti-estrogen therapy Toremifine: Anti-estrogen therapy
Period Title: Overall Study
STARTED	48
COMPLETED	0
NOT COMPLETED	48

Baseline Characteristics

Arm/Group Title	Everolimus
Arm/Group Description	Everolimus will be administered at a dose of 10 mg by mouth daily combined with any one of the following anti-estrogen therapies on which the patient most recently progressed (tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy). Anti-estrogen therapy will be administered at the US Food and Drug Administration (FDA) prescribed doses. A treatment cycle was defined as 4 weeks, with radiological evaluations every 8 weeks. Everolimus Exemestane: Anti-estrogen therapy Tamoxifen: Anti-estrogen therapy Fulvestrant: Anti-estrogen therapy Anastrozole: Anti-estrogen therapy Letrozole: Anti-estrogen therapy Toremifine: Anti-estrogen therapy
Overall Participants	48
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	29 60.4%
>=65 years	19 39.6%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	48 100%
Male	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 4.2%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 8.3%
White	40 83.3%
More than one race	0 0%
Unknown or Not Reported	2 4.2%
Region of Enrollment (Count of Participants)
United States	48 100%

Outcome Measures

1. Primary Outcome

Title	Median Progression Free Survival (PFS)
Description	PFS is defined as the time from Day 1 of study drug administration to disease progression as defined by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 criteria, or death on study. Participants who are alive and free from disease progression will be censored at the date of last radiologic tumor assessment. Participants who receive non-protocol therapy (subsequent therapy) prior to incurring an event will be censored at the date of last tumor assessment prior to the start of subsequent therapy. Participants who do not have a post-baseline tumor assessment will be censored at the date of first treatment (Day 1).
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 cycle of study treatment and had at least one post-baseline radiologic assessment were evaluable for PFS analysis per protocol. 36 of the total 48 patients were analyzed for PFS. The remaining 12 treated patients did not meet this criteria to be analyzed.

Arm/Group Title	Everolimus
Arm/Group Description	Everolimus will be administered at a dose of 10 mg PO daily combined with any one of the following anti-estrogen therapies on which the patient most recently progressed (tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy). Anti-estrogen therapy will be administered at the US Food and Drug Administration (FDA) prescribed doses. Everolimus Exemestane: Anti-estrogen therapy Tamoxifen: Anti-estrogen therapy Fulvestrant: Anti-estrogen therapy Anastrozole: Anti-estrogen therapy Letrozole: Anti-estrogen therapy Toremifine: Anti-estrogen therapy
Measure Participants	36
Median (95% Confidence Interval) [months]	7.2

2. Secondary Outcome

Title	Number of Patients With Adverse Events (AEs) as a Measure of Safety and Tolerability
Description	Assessments were made through analysis of the reported incidence of treatment-emergent AEs. All participants who received at least one dose of protocol treatment were followed for safety. Adverse events were collected from day of first dose to 30 days after last protocol treatment and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Time Frame	Up to 20 months

Outcome Measure Data

Analysis Population Description

Number of participants who received at least one dose of study drug.

Arm/Group Title	Everolimus
Arm/Group Description	Everolimus will be administered at a dose of 10 mg PO daily combined with any one of the following anti-estrogen therapies on which the patient most recently progressed (tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy). Anti-estrogen therapy will be administered at the US Food and Drug Administration (FDA) prescribed doses. Everolimus Exemestane: Anti-estrogen therapy Tamoxifen: Anti-estrogen therapy Fulvestrant: Anti-estrogen therapy Anastrozole: Anti-estrogen therapy Letrozole: Anti-estrogen therapy Toremifine: Anti-estrogen therapy
Measure Participants	48
Count of Participants [Participants]	48 100%

3. Secondary Outcome

Title	Number of Patients With an Objective Response (CR or PR) Also Called the Overall Response Rate (ORR).
Description	Defined as the number of patients with objective evidence of complete or partial response (CR or PR) using RECIST version 1.1. A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters.
Time Frame	every 8 weeks until discontinuation, up to 20 months

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 cycle of study treatment and had at least one post-baseline radiologic assessment. 36 of the total 48 patients were analyzed for PFS. The remaining 12 treated patients did not meet this criteria to be analyzed.

Arm/Group Title	Everolimus
Arm/Group Description	Everolimus will be administered at a dose of 10 mg PO daily combined with any one of the following anti-estrogen therapies on which the patient most recently progressed (tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy). Anti-estrogen therapy will be administered at the US Food and Drug Administration (FDA) prescribed doses. Everolimus Exemestane: Anti-estrogen therapy Tamoxifen: Anti-estrogen therapy Fulvestrant: Anti-estrogen therapy Anastrozole: Anti-estrogen therapy Letrozole: Anti-estrogen therapy Toremifine: Anti-estrogen therapy
Measure Participants	36
Count of Participants [Participants]	2 4.2%

4. Secondary Outcome

Title	Number of Participants With CR, PR, or 6 Months of SD Also Called Clinical Benefit Rate (CBR)
Description	The proportion of patients with Complete Response (CR) or Partial Response (PR) or 6 months or more of Stable Disease (SD). A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters. SD is not meeting the criteria for PR or a 20% increase in target lesions called Progressive Disease (PD).
Time Frame	Up to 20 months

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 cycle of study treatment and had at least one post-baseline radiologic assessment. 36 of the total 48 patients were analyzed for PFS. The remaining 12 treated patients did not meet this criteria to be analyzed.

Arm/Group Title	Everolimus
Arm/Group Description	Everolimus will be administered at a dose of 10 mg PO daily combined with any one of the following anti-estrogen therapies on which the patient most recently progressed (tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy). Anti-estrogen therapy will be administered at the US Food and Drug Administration (FDA) prescribed doses. Everolimus Exemestane: Anti-estrogen therapy Tamoxifen: Anti-estrogen therapy Fulvestrant: Anti-estrogen therapy Anastrozole: Anti-estrogen therapy Letrozole: Anti-estrogen therapy Toremifine: Anti-estrogen therapy
Measure Participants	36
Count of Participants [Participants]	12 25%

5. Secondary Outcome

Title	Median Time From First Occurrence of CR or PR to Disease Progression or Death Also Called Duration of Response (DOR)
Description	Only those patients who achieved Complete Response or Partial Response will be included in the summaries of DOR. DOR is defined as time from first date of response of CR or PR to disease progression or death as defined by RECIST v1.1 criteria. Participants who are alive and free from disease progression will be censored at the date of last tumor assessment. Patients who receive non-protocol therapy (subsequent therapy) prior to incurring an event will be censored at the date of last tumor assessment prior to the start of subsequent therapy. A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters.
Time Frame	every 8 weeks until discontinuation, up to 20 months

Outcome Measure Data

Analysis Population Description

Only those patients who achieved Complete Response or Partial Response will be included in the summaries of DOR. A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters.

Arm/Group Title	Everolimus
Arm/Group Description	Everolimus will be administered at a dose of 10 mg PO daily combined with any one of the following anti-estrogen therapies on which the patient most recently progressed (tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy). Anti-estrogen therapy will be administered at the US Food and Drug Administration (FDA) prescribed doses. Everolimus Exemestane: Anti-estrogen therapy Tamoxifen: Anti-estrogen therapy Fulvestrant: Anti-estrogen therapy Anastrozole: Anti-estrogen therapy Letrozole: Anti-estrogen therapy Toremifine: Anti-estrogen therapy
Measure Participants	2
Median (95% Confidence Interval) [months]	8.8

6. Secondary Outcome

Title	Median Overall Survival (OS)
Description	Defined as the time from date of first study treatment to date of death due to any cause. Patients who are alive will be censored at the date of last known date alive.
Time Frame	up to 3 years from first treatment

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 cycle of study treatment and had at least one post-baseline radiologic assessment were evaluable for OS analysis per protocol. 36 of the total 48 patients were analyzed for OS. The remaining 12 treated patients did not meet this criteria to be analyzed.

Arm/Group Title	Everolimus
Arm/Group Description	Everolimus will be administered at a dose of 10 mg PO daily combined with any one of the following anti-estrogen therapies on which the patient most recently progressed (tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy). Anti-estrogen therapy will be administered at the US Food and Drug Administration (FDA) prescribed doses. Everolimus Exemestane: Anti-estrogen therapy Tamoxifen: Anti-estrogen therapy Fulvestrant: Anti-estrogen therapy Anastrozole: Anti-estrogen therapy Letrozole: Anti-estrogen therapy Toremifine: Anti-estrogen therapy
Measure Participants	36
Median (95% Confidence Interval) [months]	26.7

Adverse Events

Time Frame	Up to 20 months
Adverse Event Reporting Description	All patients who received at least one dose of protocol treatment were followed for safety. Adverse events and serious adverse events were collected from day of first dose to 30 days after last protocol treatment and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Arm/Group Title	Everolimus
Arm/Group Description	Everolimus will be administered at a dose of 10 mg PO daily combined with any one of the following anti-estrogen therapies on which the patient most recently progressed (tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy). Anti-estrogen therapy will be administered at the US Food and Drug Administration (FDA) prescribed doses. Everolimus Exemestane: Anti-estrogen therapy Tamoxifen: Anti-estrogen therapy Fulvestrant: Anti-estrogen therapy Anastrozole: Anti-estrogen therapy Letrozole: Anti-estrogen therapy Toremifine: Anti-estrogen therapy
All Cause Mortality
	Everolimus
	Affected / at Risk (%)	# Events
Total	32/48 (66.7%)
Serious Adverse Events
	Everolimus
	Affected / at Risk (%)	# Events
Total	15/48 (31.3%)
Blood and lymphatic system disorders
Anemia	1/48 (2.1%)	1
Cardiac disorders
Cardiac failure congestive	1/48 (2.1%)	1
Gastrointestinal disorders
Constipation	2/48 (4.2%)	2
Esophagitis	1/48 (2.1%)	1
Gastrointestinal hemorrhage	1/48 (2.1%)	1
General disorders
Non-Cardiac chest pain	1/48 (2.1%)	1
Pain	1/48 (2.1%)	2
Hepatobiliary disorders
Cholecystitis	1/48 (2.1%)	1
Infections and infestations
Diverticulitis	1/48 (2.1%)	1
Cellulitis	1/48 (2.1%)	1
Gastroenteritis	1/48 (2.1%)	1
Sepsis	1/48 (2.1%)	1
Metabolism and nutrition disorders
Dehydration	1/48 (2.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial cancer	1/48 (2.1%)	1
Gastric cancer	1/48 (2.1%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/48 (2.1%)	1
Respiratory failure	1/48 (2.1%)	1
Pulmonary embolism	1/48 (2.1%)	1
Vascular disorders
Embolism	1/48 (2.1%)	1
Other (Not Including Serious) Adverse Events
	Everolimus
	Affected / at Risk (%)	# Events
Total	48/48 (100%)
Blood and lymphatic system disorders
Anaemia	8/48 (16.7%)
Thrombocytopenia	5/48 (10.4%)
Neutropenia	4/48 (8.3%)
Gastrointestinal disorders
Nausea	18/48 (37.5%)
Stomatitis	15/48 (31.3%)
Diarrhoea	12/48 (25%)
Vomiting	10/48 (20.8%)
Constipation	5/48 (10.4%)
Abdominal Pain	3/48 (6.3%)
Dry Mouth	3/48 (6.3%)
Haemorrhoids	3/48 (6.3%)
General disorders
Fatigue	31/48 (64.6%)
Mucosal Inflammation	13/48 (27.1%)
Oedema Peripheral	7/48 (14.6%)
Pyrexia	3/48 (6.3%)
Infections and infestations
Urinary Tract Infection	9/48 (18.8%)
Cellulitis	3/48 (6.3%)
Sinusitis	3/48 (6.3%)
Investigations
Aspartate Aminotransferase Increased	5/48 (10.4%)
Alanine Aminotransferase Increased	3/48 (6.3%)
Weight Decreased	3/48 (6.3%)
Metabolism and nutrition disorders
Decreased Appetite	7/48 (14.6%)
Hyperglycaemia	5/48 (10.4%)
Dehydration	3/48 (6.3%)
Musculoskeletal and connective tissue disorders
Back Pain	7/48 (14.6%)
Musculoskeletal Pain	7/48 (14.6%)
Arthralgia	4/48 (8.3%)
Muscle Spasms	3/48 (6.3%)
Nervous system disorders
Headache	11/48 (22.9%)
Dizziness	4/48 (8.3%)
Psychiatric disorders
Insomnia	7/48 (14.6%)
Depression	3/48 (6.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	13/48 (27.1%)
Cough	9/48 (18.8%)
Epistaxis	5/48 (10.4%)
Pneumonitis	5/48 (10.4%)
Skin and subcutaneous tissue disorders
Rash	15/48 (31.3%)
Rash Pruritic	3/48 (6.3%)

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 more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.