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Open-label, Phase II, Study of Everolimus Plus Letrozole in Postmenopausal Women With ER+, HER2- Metastatic or Locally Advanced Breast Cancer (Bolero-4)

This study is currently recruiting participants.
See Contacts and Locations
Verified June 2017 by Novartis ( Novartis Pharmaceuticals )
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01698918
First received: October 1, 2012
Last updated: June 3, 2017
Last verified: June 2017
  Purpose
The purpose of this study is to find out if combining everolimus with letrozole is safe and has beneficial effects in postmenopausal women who have estrogen positive HER2 negative locally advanced or metastatic breast cancer. Additionally, this study aims to find out if everolimus plus exemestane is safe and has beneficial effects in women with estrogen positive locally advanced or metastatic breast cancer after treatment with everolimus plus letrozole. This study will also aim to find out if a mouth rinse can help reduce the severity of oral stomatitis, a common side effect of everolimus. This part of the study will be conducted only in countries where an alcohol free 0.5mg/5ml dexamethasone oral solution is commercially available.

Condition Intervention Phase
Hormone Receptor Positive Breast Cancer Drug: Everolimus Drug: Letrozole Drug: Exemestane Drug: Alcohol-free dexamethasone mouth rinse Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: An Open-label, Phase II, Single-arm Study of Everolimus in Combination With Letrozole in the Treatment of Postmenopausal Women With Estrogen Receptor Positive HER2 Negative Metastatic or Locally Advanced Breast Cancer

Resource links provided by NLM:


Further study details as provided by Novartis ( Novartis Pharmaceuticals ):

Primary Outcome Measures:
  • Percentage of patients progression-free after completion of 1st line treatment (everolimus + letrozole) [ Time Frame: 12 months after last patient recruited ]
    In this study Progression free survival is defined as the time from the date of enrollment to the date of first documented progression or death due to any cause. If a patient has not had an event, PFS will be censored at the date of the last adequate tumor assessment.


Secondary Outcome Measures:
  • Overall response rate and clinical benefit rate in patients receiving the first line study treatment (everolimus + letrozole) [ Time Frame: Baseline, every 8 weeks ]
    Overall response rate (ORR) is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) according to RECIST. Clinical benefit rate (CBR) is defined as the proportion of patients with best overall response of CR, PR or stable disease with a duration of 24 weeks or longer according to RECIST. ORR and CBR will be calculated based on the full analysis set, using local radiologist's/investigator's tumor assessment. Patients with only non-measurable disease at baseline will be included in the numerator if they achieve a complete response

  • Percentage of patients progression-free after completion of 2nd line treatment (everolimus + exemestane) [ Time Frame: Baseline, every 8 weeks ]
    In this study progression free survival in the second line is defined as the time interval between the start of the second line treatment and documented disease progression or death due to any cause reported during or after second line treatment

  • Overall survival of patients receiving first line study treatment (everolimus + letrozole) [ Time Frame: Continuous during the study and every 12 weeks after last treatment ]
    The overall survival (OS) following first line treatment with Everolimus + Letrozole is defined as the time from the date of receiving first line study treatment to date of death due to any cause.

  • Reduction in severity and duration of oral stomatitis [ Time Frame: Upon onset of 1st stomatitis, patient will complete diary daily until resolution of stomatitis ]
    Analysis for this objective will be based on Patient reported outcomes data for the first incidence of stomatitis AE. The mean, standard deviation and 95% confidence interval of each severity item in the questionnaire will be calculated at each day for the two therapeutic interventions for stomatitis groups and presented graphically. The duration of the first stomatitis incidence will be calculated using the dates reported in the PRO.

  • Assessment of safety based on the frequency of adverse events that fall outside normal pre-specified ranges [ Time Frame: Continuous during the study, up to 28 days after last treatment ]
    The assessment of safety will be based mainly on the frequency of adverse events and on the number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g., electrocardiogram, vital signs) will be considered as appropriate. All safety data will be listed. For all safety analyses, the safety population will be used.

  • Overall response rate and clinical benefit rate in patients receiving the second line study treatment (everolimus + exemestane) [ Time Frame: Baseline, every 8 weeks ]
    Overall response rate (ORR) is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) according to RECIST. Clinical benefit rate (CBR) is defined as the proportion of patients with best overall response of CR, PR or stable disease with a duration of 24 weeks or longer according to RECIST. ORR and CBR will be calculated based on the full analysis set, using local radiologist's/investigator's tumor assessment. Patients with only non-measurable disease at baseline will be included in the numerator if they achieve a complete response

  • Reduction in severity and duration of oral stomatitis [ Time Frame: Upon onset of 1st stomatitis and in countries where the alcohol-free dexamethasone solution (0.5mg/5ml) is commercially available, patient will be randomised to dexamethasone oral solution rinse or standard of care ]
    Analysis for this objective will be based on Patient reported outcomes data for the first incidence of stomatitis AE. The mean, standard deviation and 95% confidence interval of each severity item in the questionnaire will be calculated at each day for the two therapeutic interventions for stomatitis groups and presented graphically. The duration of the first stomatitis incidence will be calculated using the dates reported in the PRO.

  • Percentage of patients with clinical benfit during extension phase [ Time Frame: Every 12 weeks up to 36 months ]
    Clinical benefit as assessed by investigator at scheduled visits to determine continuation of treatment


Estimated Enrollment: 200
Actual Study Start Date: March 8, 2013
Estimated Study Completion Date: April 21, 2020
Estimated Primary Completion Date: April 21, 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Everolimus + letrozole/exemestane
Enrolled patients will receive everolimus in combination with letrozole in the first line setting until disease progression, unacceptable toxicity or withdrawal of consent. Following disease progression in the first line setting, patients will be offered everolimus in combination with exemestane. Patients who discontinue treatment in the first line setting due to unacceptable toxicity or due to withdrawal of consent will not be offered everolimus plus exemestane. Those patients treated in the second line setting will continue treatment until disease progression, unacceptable toxicity or withdrawal of consent.
Drug: Everolimus
Everolimus will be self-administered as a daily dose of 10mg (two 5mg tablets) taken orally continuously from study day 1 until progression of disease, unacceptable toxicity or withdrawal of consent. Everolimus should be taken at the same time every day. Everolimus tablets should be swallowed whole with a glass of water once daily, either consistently with food or consistently without food. Tablets should not be chewed or crushed.
Other Name: RAD001
Drug: Letrozole
1st line study treatment: Letrozole will be self administered as a daily dose of 2.5mg continuously from study day 1 until disease progression, unacceptable toxicity or withdrawal of consent and should be taken at the same time every day, consistently with or without food. Everolimus and letrozole tablets should be taken together.
Other Name: Femara
Drug: Exemestane
2nd Line Study Treatment: If patients progress on everolimus + letrozole, patients will be offered everolimus + exemestane. Exemestane will be self administered as a daily dose of 25mg taken orally continuously until disease progression, unacceptable toxicity or withdrawal of consent and should be taken at the same time every day after a meal. Everolimus and exemestane tablets should be taken together.
Other Name: Aromasin
Drug: Alcohol-free dexamethasone mouth rinse
At the onset of symptoms suggestive of stomatitis patients must contact the study site. Upon confirmation of stomatitis at the site, patients in countries where the alcohol-free 0.5mg/5ml dexamethasone oral solution is commercially available will be randomly assigned to take either dexamethasone 0.5 mg/5ml mouth rinse or the standard of care used to treat stomatitis at the patient's center. The mouth rinse will be self administered at a daily dose of 10ml 3 times per day. Patients will be instructed to swish and expectorate the mouth rinse. Patients will also be instructed to fill out the Oral Stomatitis Daily Questionnaire (OSDQ) at home every day until the patient recovers. The mouth rinse will be self administered at a daily dose of 10ml 3 times per day.Patients will be instructed to swish and expectorate the mouth rinse.
Other Name: alcohol-free dexamethasone 0.5 mg/5ml

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients 18 years old or greater
  • Patients with metastatic or locally advanced, unresectable breast cancer not amenable to curative treatment by surgery or radiotherapy
  • Histological or cytological confirmation of estrogen-receptor positive (ER+) human epidermal growth factor receptor 2 negative (HER2-) breast cancer
  • Postmenopausal women
  • No prior treatment for metastatic breast cancer

Exclusion Criteria:

  • Patients with only non-measurable lesions other than bone metastases (e.g., pleural effusion, ascites, etc)
  • Patients who have received prior hormonal or any other systemic therapy for metastatic breast cancer.
  • Patients may have received prior neoadjuvant or adjuvant endocrine therapy. In the case of neoadjuvant or adjuvant NSAI (letrozole/anastrozole) therapy patients must have completed therapy at least 1 year prior to study enrollment.
  • Previous treatment with mTOR inhibitors.
  • Known hypersensitivity to mTOR inhibitors, e.g., sirolimus (rapamycin).
  • Other protocol-defined inclusion/exclusion criteria may apply
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01698918

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682 Novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

  Hide Study Locations
Locations
United States, Alabama
University of Alabama Comprehensive Cancer Center SC-2 Active, not recruiting
Birmingham, Alabama, United States, 35294
United States, Arizona
Banner MD Anderson Cancer Center Active, not recruiting
Gilbert, Arizona, United States, 85234
United States, California
Loma Linda University Loma Linda Active, not recruiting
Loma Linda, California, United States, 92354
Breastlink Medical Group Dept. of BreastlinkResearchGrp Completed
Long Beach, California, United States, 90806
United States, Illinois
Lurie Children's Hospital of Chicago SC Withdrawn
Chicago, Illinois, United States, 60611
Oncology Specialists, SC Dept.of Oncology Specialists Active, not recruiting
Park Ridge, Illinois, United States, 60068-0736
United States, Kansas
St. Francis Health Comprehensive Cancer Center Completed
Topeka, Kansas, United States, 66606-169
United States, Kentucky
Norton Healthcare, Inc. SC Active, not recruiting
Louisville, Kentucky, United States, 40202
United States, Maryland
Holy Cross Hospital Holy Cross Terminated
Silver Spring, Maryland, United States, 20910
United States, Massachusetts
Baystate Medical Center SC Not yet recruiting
Springfield, Massachusetts, United States, 00119
Contact: Katherine Colbeck    413-794-9875    Katherine.colbeck@baystatehealth.org   
Principal Investigator: James Stewart         
United States, Missouri
Mercy Medical Research Institute SC Terminated
Manchester, Missouri, United States, 63021
United States, Nebraska
Nebraska Methodist Hospital SC-1 Withdrawn
Omaha, Nebraska, United States, 68114
United States, New Jersey
Saint Barnabas Medical Center CancerCenter of Saint Barnabas Active, not recruiting
Livingston, New Jersey, United States, 07039
United States, New Mexico
University of New Mexico Hospital SC Active, not recruiting
Albuquerque, New Mexico, United States, 87106
United States, New York
Broome Oncology SC Completed
Johnson City, New York, United States, 13790
Columbia University Medical Center- New York Presbyterian Columbia Completed
New York, New York, United States, 10032
United States, North Carolina
Cone Health Cancer Center Active, not recruiting
Greensboro, North Carolina, United States
Marion L. Shepard Cancer Center SC Terminated
Washington, North Carolina, United States, 27889
United States, Texas
Texas Oncology Dallas Presbyterian Withdrawn
Dallas, Texas, United States, 75251
Texas Oncology Harlington Withdrawn
Dallas, Texas, United States, 75251
Texas Oncology Paris Withdrawn
Dallas, Texas, United States, 75251
Texas Oncology Sherman Withdrawn
Dallas, Texas, United States, 75251
Texas Oncology Waco Withdrawn
Dallas, Texas, United States, 75251
East Texas Hematology Clinic SC Active, not recruiting
Lufkin, Texas, United States, 75904
United States, Utah
Utah Cancer Specialists Dept.of Utah Cancer Spec. (3) Active, not recruiting
Salt Lake City, Utah, United States, 84106
Argentina
Novartis Investigative Site Withdrawn
Caba, Buenos Aires, Argentina, C1181ACH
Novartis Investigative Site Completed
Santa Rosa, La Pampa, Argentina, 6300
Novartis Investigative Site Withdrawn
Posadas, Misiones, Argentina, 3300
Novartis Investigative Site Active, not recruiting
Rosario, Santa Fe, Argentina, S2000KZE
Brazil
Novartis Investigative Site Active, not recruiting
Porto Alegre, RS, Brazil, 90035-003
Novartis Investigative Site Withdrawn
Porto Alegre, RS, Brazil, 90560-030
Novartis Investigative Site Active, not recruiting
São Paulo, SP, Brazil, 01317-002
Novartis Investigative Site Active, not recruiting
São Paulo, SP, Brazil, 03102-002
France
Novartis Investigative Site Active, not recruiting
Besançon cedex, France, 25030
Novartis Investigative Site Active, not recruiting
Bordeaux, France, 33076
Novartis Investigative Site Withdrawn
Brest, France, 29200
Novartis Investigative Site Active, not recruiting
Hyères, France, 83400
Novartis Investigative Site Active, not recruiting
Le Chesnay, France, 78157
Novartis Investigative Site Active, not recruiting
Lyon Cedex, France, 69373
Novartis Investigative Site Active, not recruiting
Nancy, France, 54000
Novartis Investigative Site Active, not recruiting
Nantes Cedex, France, 44277
Hungary
Novartis Investigative Site Active, not recruiting
Gyula, Hungary, 5700
Novartis Investigative Site Withdrawn
Kaposvar, Hungary, 7400
Novartis Investigative Site Active, not recruiting
Kecskemet, Hungary, 6000
Novartis Investigative Site Withdrawn
Kistarcsa, Hungary, 2143
Novartis Investigative Site Active, not recruiting
Szekszard, Hungary, 7100
Japan
Novartis Investigative Site Active, not recruiting
Nagoya city, Aichi, Japan, 467-8602
Novartis Investigative Site Active, not recruiting
Sapporo, Hokkaido, Japan
Novartis Investigative Site Active, not recruiting
Morioka-city, Iwate, Japan, 020-8505
Novartis Investigative Site Active, not recruiting
Kawasaki-city, Kanagawa, Japan, 216-8511
Novartis Investigative Site Completed
Kumamoto City, Kumamoto, Japan, 860-8556
Korea, Republic of
Novartis Investigative Site Active, not recruiting
Seoul, Korea, Korea, Republic of, 06351
Novartis Investigative Site Active, not recruiting
Seoul, Korea, Republic of, 01812
Novartis Investigative Site Active, not recruiting
Seoul, Korea, Republic of, 06273
Netherlands
Novartis Investigative Site Active, not recruiting
Maastricht, Netherlands, 5800
Portugal
Novartis Investigative Site Recruiting
Lisboa, Portugal, 1400-038
Novartis Investigative Site Active, not recruiting
Lisboa, Portugal, 1649-035
Novartis Investigative Site Active, not recruiting
Porto, Portugal, 4200-072
Spain
Novartis Investigative Site Withdrawn
Sabadell, Barcelona, Spain, 08208
Novartis Investigative Site Active, not recruiting
Salamanca, Castilla y Leon, Spain, 37007
Novartis Investigative Site Active, not recruiting
Valencia, Comunidad Valenciana, Spain, 46010
Novartis Investigative Site Active, not recruiting
La Coruna, Galicia, Spain, 15006
Thailand
Novartis Investigative Site Active, not recruiting
Bangkok, Thailand, 10330
Novartis Investigative Site Active, not recruiting
Bangkok, Thailand, 10400
Novartis Investigative Site Active, not recruiting
Bangkok, Thailand, 10700
Turkey
Novartis Investigative Site Terminated
Altunizade, Turkey, 34662
Novartis Investigative Site Active, not recruiting
Antalya, Turkey, 07059
Novartis Investigative Site Active, not recruiting
Istanbul, Turkey, 34303
Novartis Investigative Site Active, not recruiting
Izmir, Turkey, 35040
United Kingdom
Novartis Investigative Site Completed
Bath, United Kingdom, BA1 3NG
Novartis Investigative Site Completed
Norwich, United Kingdom, NR1 3SR
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01698918     History of Changes
Other Study ID Numbers: CRAD001Y24135
2012-003065-17 ( EudraCT Number )
Study First Received: October 1, 2012
Last Updated: June 3, 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
metastatic breast cancer, locally advanced breast cancer, HER2-, ER+, everolimus, Afinitor

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Letrozole
Exemestane
Everolimus
Sirolimus
BB 1101
Ethanol
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Infective Agents, Local
Anti-Infective Agents

ClinicalTrials.gov processed this record on June 28, 2017