Hormone Receptor Positive Breast CancerPhase 2BOLERO-4NCT01698918
Open-label, Phase II, Study of Everolimus Plus Letrozole in Postmenopausal Women With ER+, HER2- Metastatic or Locally Advanced Breast Cancer
A Phase 2 study testing Everolimus, Letrozole and Exemestane in people with Hormone Receptor Positive Breast Cancer, run by Novartis Pharmaceuticals at 52 sites in 13 countries.
Trial summary
The purpose of this study was to assess the efficacy and safety of first-line treatment with everolimus plus letrozole in postmenopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Hormone Receptor Positive Breast Cancer
- What is being tested?
- Everolimus, Letrozole and Exemestane
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 202 participants
- Where
- 52 sitesin 13 countries
- Study dates
- 7 Mar 2013to 13 Jan 2021
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with metastatic or locally advanced, unresectable breast cancer not amenable to curative treatment by surgery or radiotherapy
- Histological or cytological confirmation of ER+/ HER2- breast cancer
- Postmenopausal women
- No prior treatment for metastatic breast cancer
Who cannot join
- Patients with only non-measurable lesions other than bone metastases (e.g., pleural effusion, ascites, etc)
- Patients who had received prior hormonal or any other systemic therapy for metastatic breast cancer. Patients might 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 might apply
Trial locations and contacts
52 sites in 13 countries.
52 sites in 13 countries
United States15 sites
University of New Mexico Hospital SC
Albuquerque, New Mexico, 87106
University of Alabama Comprehensive Cancer Center SC-2
Birmingham, Alabama, 35294
Banner MD Anderson Cancer Center
Gilbert, Arizona, 85234
Cone Health Cancer Center
Greensboro, North Carolina, 27403
Broome Oncology SC
Johnson City, New York, 13790
Saint Barnabas Medical Center CancerCenter of Saint Barnabas
Livingston, New Jersey, 07039
Loma Linda University Loma Linda
Loma Linda, California, 92354
Breastlink Medical Group Dept. of BreastlinkResearchGrp
Long Beach, California, 90806
Norton Healthcare Inc SC
Louisville, Kentucky, 40202
East Texas Hematology Clinic SC
Lufkin, Texas, 75904
Columbia University Medical Center- New York Presbyterian Columbia
New York, New York, 10032
Oncology Specialists, SC Advocate Medical Group-Niles
Park Ridge, Illinois, 60068-0736
Utah Cancer Specialists Dept.of Utah Cancer Spec. (3)
Salt Lake City, Utah, 84106
Baystate Medical Center SC-2
Springfield, Massachusetts, 01199
St. Francis Health Comprehensive Cancer Center
Topeka, Kansas, 66606-169
France7 sites
Novartis Investigative Site
Besançon, 25030
Novartis Investigative Site
Bordeaux, 33076
Novartis Investigative Site
Hyères, 83400
Novartis Investigative Site
Le Chesnay, 78157
Novartis Investigative Site
Lyon, 69373
Novartis Investigative Site
Nancy, 54000
Novartis Investigative Site
Nantes, 44277
Japan5 sites
Novartis Investigative Site
Kawasaki, Kanagawa, 216-8511
Novartis Investigative Site
Kumamoto, Kumamoto, 860-8556
Novartis Investigative Site
Nagoya, Aichi-ken, 467-8602
Novartis Investigative Site
Sapporo, Hokkaido, 003-0804
Novartis Investigative Site
Shiwa-gun, Iwate, 028-3695
Brazil3 sites
Novartis Investigative Site
Porto Alegre, Rio Grande do Sul, 90035-003
Novartis Investigative Site
São Paulo, São Paulo, 01317-002
Novartis Investigative Site
São Paulo, São Paulo, 04014-002
Hungary3 sites
Novartis Investigative Site
Gyula, 5700
Novartis Investigative Site
Kecskemét, Bács-Kiskun county, 6000
Novartis Investigative Site
Szekszárd, 7100
Portugal3 sites
Novartis Investigative Site
Lisbon, 1400-038
Novartis Investigative Site
Lisbon, 1649-035
Novartis Investigative Site
Porto, 4200-072
South Korea3 sites
Novartis Investigative Site
Seoul, 01812
Novartis Investigative Site
Seoul, 06273
Novartis Investigative Site
Seoul, 06351
Spain3 sites
Novartis Investigative Site
A Coruña, Galicia, 15006
Novartis Investigative Site
Salamanca, Castille and León, 37007
Novartis Investigative Site
Valencia, Valencia, 46010
Thailand3 sites
Novartis Investigative Site
Bangkok, 10330
Novartis Investigative Site
Bangkok, 10400
Novartis Investigative Site
Bangkok, 10700
Turkey (Türkiye)3 sites
Novartis Investigative Site
Antalya, 07059
Novartis Investigative Site
Istanbul, 34303
Novartis Investigative Site
Izmir, 35040
Argentina2 sites
Novartis Investigative Site
Rosario, Santa Fe Province, S2000KZE
Novartis Investigative Site
Santa Rosa, La Pampa Province, 6300
About this study
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
The purpose of this study was to assess the efficacy and safety of first-line treatment with everolimus plus letrozole in postmenopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer.
Moreover, the study also aimed to investigate the efficacy and safety of second line treatment with everolumus plus examestane in participants whose disease progressed during everolimus plus letrozole therapy.
Read the detailed description
This was an open-label, phase II, multicenter, international, single-arm study for postmenopausal women with ER+/HER2- metastatic or locally advanced breast cancer.
This study was comprised of 2 phases:
- Core Phase: from first participant first visit to 24 months after enrollment of the last participant (and upon approval of amendment 5 dated 14-Feb-2017), up to approximately 4 years. The main purpose of the amendment 5 was to implement an Extension Phase up to 3 years.
During the core phase, all enrolled participants received everolimus in combination with letrozole in the first line setting until disease progression or any other reason for which the participant might be discontinued. Only those participants who had disease progression in the first line setting were offered second line treatment (everolimus in combination with exemestane). Participants who discontinued first line treatment due to reasons other than disease progression were not eligible for second line treatment. The participants who were treated in the second line setting continued treatment until disease progression, unacceptable toxicity or withdrawal of consent.
- Extension Phase: Participants that were still benefiting from everolimus at the end of the Core Phase (and upon approval of amendment 5 dated 14-Feb-2017) were transitioned to the Extension phase of the study. Participants were continued on their existing line of treatment (everolimus plus letrozole or everolimus plus exemestane) in the extension, up to 3 years or until progression or any other reason for which the participant might be discontinued. Participants entering the Extension Phase on first line treatment and deemed to no longer be clinically benefiting were not offered second line treatment in the context of the study
This study included a randomized, open-label sub-study for participants in countries where the alcohol-free 0.5mg/5ml dexamethasone oral solution was commercially available who experienced a stomatitis event: at the first onset of symptoms suggestive of stomatitis, participants were to contact the study site and based on preliminary confirmation of diagnosis, participants were asked to visit the study site within 24 hours. Upon confirmation of stomatitis, participants in countries where the alcohol-free 0.5 mg/5 mL dexamethasone oral solution was commercially available (US sites only) were randomly assigned in a 1:1 ratio to take either 0.5 mg/5 mL dexamethasone mouth rinse or the standard of care used to treat stomatitis at the participant's center.
All participants who experienced stomatitis (regardless of inclusion in the sub-study) were instructed to fill out the Oral Stomatitis Daily Questionnaire (OSDQ) at home every day until the participant recovered. For subsequent episodes of stomatitis, participants were instructed to contact the physician. If part of the randomized set upon telephone confirmation, they were instructed to utilize the same treatment they were assigned to after the first episode and complete the OSDQ booklet.
- Conditions
- Hormone Receptor Positive Breast Cancer
- Being tested
- Everolimus, Letrozole, Exemestane, Alcohol-free dexamethasone mouth rinse (Stomatitis sub-study), Standard of care to treat stomatitis (Stomatitis sub-study)
- Keywords
- Metastatic breast cancer, Locally advanced breast cancer, HER2-, ER+, Everolimus, Afinitor
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EverolimusDrug
Also called RAD001
Everolimus was self-administered as a daily dose of 10mg (two 5mg tablets) taken orally continuously until progression of disease, unacceptable toxicity or withdrawal of consent.
LetrozoleDrug
Also called Femara
1st line study treatment: Letrozole was self administered as a daily dose of 2.5mg continuously until disease progression or any other reason for which the patient might be discontinued
ExemestaneDrug
Also called Aromasin
2nd Line Study Treatment: Exemestane was self administered as a daily dose of 25mg taken orally continuously until disease progression or any other reason for which the patient might be discontinued
Alcohol-free dexamethasone mouth rinse (Stomatitis sub-study)Drug
Alcohol-free 0.5mg/5ml dexamethasone oral solution was self-administered at a daily dose of 10ml 3 times per day (participants with confirmed stomatitis who entered the stomatitis sub-study).
Standard of care to treat stomatitis (Stomatitis sub-study)Drug
Standard of care used to treat stomatitis at the patient's center (participants with confirmed stomatitis who entered the stomatitis sub-study).
| Study group | Role | What they receive |
|---|---|---|
| Everolimus+letrozole/exemestane (first line and second line treatment) | Experimental | Participants received everolimus in combination with letrozole as first-line treatment. Only participants who had disease progression in the first line setting (core phase) were offered second-line treatment (everolimus in combination with exemestane) Receives: Drug: Everolimus; Drug: Letrozole; Drug: Exemestane; Drug: Alcohol-free dexamethasone mouth rinse (Stomatitis sub-study); Drug: Standard of care to treat stomatitis (Stomatitis sub-study) |
What is being measured
The primary outcome is the main question the study is designed to answer.
First-line Treatment: Progression-free Survival (PFS)
PFS in the first line setting is defined as the time from the date of enrollment to the date of first documented progression based on local radiology review or death due to any cause. If a participant did not progress or was not known to have died at the date of the analysis cut-off or start of another antineoplastic therapy, the PFS date was censored to the date of last adequate tumor assessment prior to cut-off date or start of antineoplastic therapy. The median PFS was estimated and presented along with 95% confidence intervals. The primary analysis of PFS for first line was performed 12 months after the last patient's recruitment.
Measured: From the date of enrollment to the date of first documented progression or deaths, assessed up to approximately 2.8 years
Secondary outcomes (21)
First-line Treatment: Overall Response Rate (ORR)
ORR in first line setting is defined as the percentage of participants while on first-line treatment with best overall response of complete response (CR) or partial response (PR) according to RECIST version 1.0 based on local review. Confidence intervals were calculated based on the Exact Clopper-Pearson method.
ORR while on first-line treatment was assessed up to 24 months after the last patient's recruitment.
CR: disappearance of all target lesions PR: at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.
Measured: From the date of enrollment until discontinuation of first-line treatment, assessed up to approximately 3.8 years
First-line Treatment: Clinical Benefit Rate (CBR)
CBR in first line is defined as the percentage of participants while on first-line treatment with best overall response of CR, PR or stable disease (SD) with a duration of 24 weeks or longer, according to RECIST version 1.0 based on local review. Confidence intervals (CI) were calculated based on the Exact Clopper-Pearson method.
CBR while on first-line treatment was assessed up to 24 months after the last patient's recruitment.
CR: disappearance of all target lesions PR: at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.
SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease
Measured: From the date of enrollment until first-line treatment discontinuation, assessed up to approximately 3.8 years
Second-line Treatment: Progression-free Survival (PFS)
PFS in the second line setting is defined as the time interval between the start of the second-line treatment and documented disease progression based on local radiology review or death due to any cause reported during or after second-line treatment period. If a participant did not progress or was not known to have died at the date of the analysis cut-off or start of another antineoplastic therapy, the PFS date was censored to the date of last adequate tumor assessment prior to cut-off date or start of antineoplastic therapy. The median PFS was estimated and presented along with 95% confidence intervals.
PFS while on second-line treatment was assessed up to 24 months after the last patient's recruitment.
Measured: From the start of the second-line treatment until the date of first documented progression or death, assessed up to approximately 2.4 years
Second-line Treatment: Overall Response Rate (ORR)
ORR in second line is defined as the percentage of participants receiving second-line study treatment with best overall response of complete response (CR) or partial response (PR) according to RECIST version 1.0 based on local review. Confidence intervals (CI) were calculated based on the Exact Clopper-Pearson method.
ORR while on second-line treatment was assessed up to 24 months after the last patient's recruitment.
CR: disappearance of all target lesions PR: at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters
Measured: From the start of the second-line treatment up to approximately 2.4 years
Second-line Treatment: Clinical Benefit Rate (CBR)
CBR in second line is defined as the percentage of participants receiving second-line study treatment with best overall response of CR, PR or stable disease (SD) with a duration of 24 weeks or longer, according to RECIST version 1.0 based on local review. Confidence intervals (CI) were calculated based on the Exact Clopper-Pearson method.
CBR while on second-line treatment was assessed up to 24 months after the last patient's recruitment.
CR: disappearance of all target lesions PR: at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.
SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease
Measured: From the start of the second-line treatment up to approximately 2.4 years
Overall Survival (OS)
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 (including first-line and second-line treatment periods). If a participant was not known to have died, survival was censored at the date of last contact.
OS following first-line treatment was assessed up to 24 months after last patient's recruitment.
Measured: From the date of enrollment to date of death, assessed up to approximately 3.8 years
First-line Treatment: Time to First Stomatitis Episode as Assessed by the Oral Stomatitis Daily Questionnaire (OSDQ)
The time to first occurrence of stomatitis based on OSDQ is defined as time from first-line treatment administration to start date of the stomatitis episode recorded in the OSDQ in the first line. The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The first item asked the participants when they experienced the first symptoms of stomatitis. Start date of the first occurrence of stomatitis is defined as the first date ever recorded for this item in the questionnaire. Patient reported outcomes (PROs) were assessed up to 24 months after last patient's recruitment.
Measured: From first-line treatment administration until first stomatitis episode in the first line, assessed up to approximately 3.8 years
First-line Treatment: Duration of First Stomatitis Based on OSDQ
The duration of the first stomatitis episode was calculated using the start and end date recorded in the OSDQ. The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis. The first item of the questionnaire asked the participants the date when they experienced the first symptoms of stomatitis. Start date of the first occurrence of stomatitis is defined as the first date ever recorded for this item in the questionnaire. Stop date of the first stomatitis episode is defined as the last date the OSDQ was completed for this episode. Participants were censored if they died before resolution of stomatitis, received a new anticancer therapy, discontinued the study treatment with no resolution of the stomatitis or the stomatitis event was still on-going at the cut-off. PROs were assessed up to 24 months after last patient's recruitment.
Measured: From start date of first stomatitis episode in first line until its resolution, assessed up to 3.8 years
First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Overall Health at the End of the First Stomatitis Episode
The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily up to the resolution of the stomatitis episode. The second item asked the participant to rate their overall health from 0 (worst possible) to 10 (perfect health). The overall health OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.
Measured: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Mouth and Throat Soreness at the End of the First Stomatitis Episode
The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The third item asked the participant to rate their mouth and throat soreness from 0 (no soreness) to 4 (extreme soreness). The mouth and throat soreness OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.
Measured: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Mouth and Throat Soreness Limiting Swallowing, Drinking, Eating, Talking and Sleeping at the End of the First Stomatitis Episode
The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The fourth item asked the participant to rate how much their mouth and throat soreness limited them in 1) swallowing, 2) drinking, 3) eating, 4) talking and 5) sleeping. For each activity, mouth and throat soreness scores ranged from 0 (not limited) to 4 (unable to do). Scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.
Measured: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Mouth Pain Severity at the End of the First Stomatitis Episode
The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The fifth item asked the participant to rate their mouth pain severity from 0 (no pain) to 10 (unbearable pain). The mouth pain severity OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.
Measured: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Mouth Pain Severity Affecting Daily Activities at the End of the First Stomatitis Episode
The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The sixth item asked the participant to rate their mouth pain severity affecting daily activities score from 0 (no effect on daily activities) to 10 (completely prevented from doing daily activities). The mouth pain severity affecting daily activities OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.
Measured: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment (Stomatitis Sub-study): Time to First Stomatitis Episode as Assessed by the OSDQ
The time to first occurrence of stomatitis based on OSDQ is defined as time from first study treatment administration in the first line to start date of the first stomatitis episode recorded in the OSDQ. The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The first item asked the participants when they experienced the first symptoms of stomatitis. Start date of the first occurrence of stomatitis is defined as the first date ever recorded for this item in the questionnaire. PROs were assessed up to 24 months after last patient's recruitment.
Only participants who were randomized in the stomatitis sub-study were included in this analysis.
Measured: From first study treatment administration in the first line until first stomatitis episode, assessed up to approximately 3.8 years
First-line Treatment (Stomatitis Sub-study): Duration of First Stomatitis Based on OSDQ
The duration of the first stomatitis was calculated using the start and end date reported in the OSDQ. The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis. The first item asked the participants the date when they experienced the first symptoms of stomatitis. Start date of the first stomatitis is defined as the first date ever recorded for this item in the questionnaire. Stop date of the first stomatitis is defined as the last date the OSDQ was completed for this episode. Participants were censored if they died before resolution of stomatitis, received a new anticancer therapy, discontinued the study treatment with no resolution of the stomatitis or the stomatitis was still on-going at the cut-off. PROs were assessed up to 24 months after last patient's recruitment. Only participants who were randomized in the stomatitis sub-study were included in this analysis.
Measured: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment (Stomatitis Sub-study): Number of Participants With Shift of Response in OSDQ Score on Overall Health at the End of the First Stomatitis Episode
The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The second item asked the participant to rate their overall health from 0 (worst possible) to 10 (perfect health). The overall health OSDQ score are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.
Only participants who were randomized in the stomatitis sub-study were included in this analysis.
Measured: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment (Stomatitis Sub-study): Number of Participants With Shift of Response in OSDQ Score on Mouth and Throat Soreness at the End of the First Stomatitis Episode
The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The third item asked the participant to rate their mouth and throat soreness from 0 (no soreness) to 4 (extreme soreness). The mouth and throat soreness OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.
Only participants who were randomized in the stomatitis sub-study were included in this analysis.
Measured: From start date of stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment (Stomatitis Sub-study): Number of Participants With Shift of Response in OSDQ Score on Mouth and Throat Soreness Limiting Swallowing, Drinking, Eating, Talking and Sleeping at the End of the First Stomatitis Episode
The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The fourth item asked the participant to rate how much their mouth and throat soreness limited them in 1) swallowing, 2) drinking, 3) eating, 4) talking and 5) sleeping. For each activity, mouth and throat soreness scores ranged from 0 (not limited) to 4 (unable to do). Scores are presented as the shift from Day 1 of first stomatitis stomatitis value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first episode value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.
Only participants who were randomized in the stomatitis sub-study were included in this analysis.
Measured: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment (Stomatitis Sub-study): Number of Participants With Shift of Response in OSDQ Score on Mouth Pain Severity at the End of the First Stomatitis Episode
The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The fifth item asked the participant to rate their mouth pain severity from 0 (no pain) to 10 (unbearable pain). The mouth pain severity OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.
Only participants who were randomized in the stomatitis sub-study were included in this analysis.
Measured: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment (Stomatitis Sub-study): Number of Participants With Shift of Response in OSDQ Score on Mouth Pain Severity Affecting Daily Activities at the End of the First Stomatitis Episode
The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The sixth item asked the participant to rate their mouth pain severity affecting daily activities score from 0 (no effect on daily activities) to 10 (completely prevented from doing daily activities). The mouth pain severity affecting daily activities OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.
Only participants who were randomized in the stomatitis sub-study were included in this analysis.
Measured: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
Number of Participants With Clinical Benfit During Extension Phase
Number of participants with clinical benefit as judged by the investigator during the extension phase. The extension phase for up to 3 years for participants who were continuing to benefit from study treatment following the end of the core study phase (24 months after last patient's recruitment) was added in the amendment 5 (dated 14-Feb-2017). Results are presented by line of treatment
Measured: From the end of core phase (upon approval of amendment 5) up to approximately 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Oct 2012 (estimated)
- Study start7 Mar 2013
- Primary completion17 Dec 2015
- Study completion13 Jan 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hormone Receptor Positive Breast CancerStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- The main study was an open-label single-arm study. The stomatitis sub-study was a randomized open-label study with two arms: dexamethasone and standard of care.
- Masking
- None (open label)
- Enrolment
- 202 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01698918
- Sponsor's protocol ID
- CRAD001Y24135
- Other IDs
- 2012-003065-17
- Acronym
- BOLERO-4
- Status last verified
- Apr 2023
- First submitted
- 1 Oct 2012
- Last updated
- 3 May 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
Publications
Royce M, Bachelot T, Villanueva C, Ozguroglu M, Azevedo SJ, Cruz FM, Debled M, Hegg R, Toyama T, Falkson C, Jeong J, Srimuninnimit V, Gradishar WJ, Arce C, Ridolfi A, Lin C, Cardoso F. Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: A Clinical Trial. JAMA Oncol. 2018 Jul 1;4(7):977-984. doi: 10.1001/jamaoncol.2018.0060.
PubMed 29566104
Study at a glance
From the registry record, last updated by the sponsor on 3 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01698918
- Acronym / sponsor ID
- BOLERO-4 / CRAD001Y24135
- Conditions
- Hormone Receptor Positive Breast Cancer
- Keywords
- Metastatic breast cancer, Locally advanced breast cancer, HER2-, ER+, Everolimus, Afinitor
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 202 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 7 Mar 2013 (actual)
- Primary completion
- 17 Dec 2015 (actual)
- Study completion
- 13 Jan 2021 (actual)
- First posted
- 3 Oct 2012 (estimated)
- Results
- Posted 9 Feb 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study was to assess the efficacy and safety of first-line treatment with everolimus plus letrozole in postmenopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer.
Moreover, the study also aimed to investigate the efficacy and safety of second line treatment with everolumus plus examestane in participants whose disease progressed during everolimus plus letrozole therapy.
Detailed description
This was an open-label, phase II, multicenter, international, single-arm study for postmenopausal women with ER+/HER2- metastatic or locally advanced breast cancer.
This study was comprised of 2 phases:
- Core Phase: from first participant first visit to 24 months after enrollment of the last participant (and upon approval of amendment 5 dated 14-Feb-2017), up to approximately 4 years. The main purpose of the amendment 5 was to implement an Extension Phase up to 3 years.
During the core phase, all enrolled participants received everolimus in combination with letrozole in the first line setting until disease progression or any other reason for which the participant might be discontinued. Only those participants who had disease progression in the first line setting were offered second line treatment (everolimus in combination with exemestane). Participants who discontinued first line treatment due to reasons other than disease progression were not eligible for second line treatment. The participants who were treated in the second line setting continued treatment until disease progression, unacceptable toxicity or withdrawal of consent.
- Extension Phase: Participants that were still benefiting from everolimus at the end of the Core Phase (and upon approval of amendment 5 dated 14-Feb-2017) were transitioned to the Extension phase of the study. Participants were continued on their existing line of treatment (everolimus plus letrozole or everolimus plus exemestane) in the extension, up to 3 years or until progression or any other reason for which the participant might be discontinued. Participants entering the Extension Phase on first line treatment and deemed to no longer be clinically benefiting were not offered second line treatment in the context of the study
This study included a randomized, open-label sub-study for participants in countries where the alcohol-free 0.5mg/5ml dexamethasone oral solution was commercially available who experienced a stomatitis event: at the first onset of symptoms suggestive of stomatitis, participants were to contact the study site and based on preliminary confirmation of diagnosis, participants were asked to visit the study site within 24 hours. Upon confirmation of stomatitis, participants in countries where the alcohol-free 0.5 mg/5 mL dexamethasone oral solution was commercially available (US sites only) were randomly assigned in a 1:1 ratio to take either 0.5 mg/5 mL dexamethasone mouth rinse or the standard of care used to treat stomatitis at the participant's center.
All participants who experienced stomatitis (regardless of inclusion in the sub-study) were instructed to fill out the Oral Stomatitis Daily Questionnaire (OSDQ) at home every day until the participant recovered. For subsequent episodes of stomatitis, participants were instructed to contact the physician. If part of the randomized set upon telephone confirmation, they were instructed to utilize the same treatment they were assigned to after the first episode and complete the OSDQ booklet.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- The main study was an open-label single-arm study. The stomatitis sub-study was a randomized open-label study with two arms: dexamethasone and standard of care.
| Arm | Type | Receives |
|---|---|---|
| Everolimus+letrozole/exemestane (first line and second line treatment) | Experimental | Drug: Everolimus, Drug: Letrozole, Drug: Exemestane, Drug: Alcohol-free dexamethasone mouth rinse (Stomatitis sub-study), Drug: Standard of care to treat stomatitis (Stomatitis sub-study)Participants received everolimus in combination with letrozole as first-line treatment. Only participants who had disease progression in the first line setting (core phase) were offered second-line treatment (everolimus in combination with exemestane) |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Patients with metastatic or locally advanced, unresectable breast cancer not amenable to curative treatment by surgery or radiotherapy
- Histological or cytological confirmation of ER+/ HER2- breast cancer
- Postmenopausal women
- No prior treatment for metastatic breast cancer
Key exclusion criteria (5 listed)
- Patients with only non-measurable lesions other than bone metastases (e.g., pleural effusion, ascites, etc)
- Patients who had received prior hormonal or any other systemic therapy for metastatic breast cancer. Patients might 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 might apply
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EverolimusAlso: RAD001Everolimus was self-administered as a daily dose of 10mg (two 5mg tablets) taken orally continuously until progression of disease, unacceptable toxicity or withdrawal of consent. | Drug | Everolimus+letrozole/exemestane (first line and second line treatment) |
| LetrozoleAlso: Femara1st line study treatment: Letrozole was self administered as a daily dose of 2.5mg continuously until disease progression or any other reason for which the patient might be discontinued | Drug | Everolimus+letrozole/exemestane (first line and second line treatment) |
| ExemestaneAlso: Aromasin2nd Line Study Treatment: Exemestane was self administered as a daily dose of 25mg taken orally continuously until disease progression or any other reason for which the patient might be discontinued | Drug | Everolimus+letrozole/exemestane (first line and second line treatment) |
| Alcohol-free dexamethasone mouth rinse (Stomatitis sub-study)Alcohol-free 0.5mg/5ml dexamethasone oral solution was self-administered at a daily dose of 10ml 3 times per day (participants with confirmed stomatitis who entered the stomatitis sub-study). | Drug | Everolimus+letrozole/exemestane (first line and second line treatment) |
| Standard of care to treat stomatitis (Stomatitis sub-study)Standard of care used to treat stomatitis at the patient's center (participants with confirmed stomatitis who entered the stomatitis sub-study). | Drug | Everolimus+letrozole/exemestane (first line and second line treatment) |
Primary outcome
First-line Treatment: Progression-free Survival (PFS)
Time frame: From the date of enrollment to the date of first documented progression or deaths, assessed up to approximately 2.8 years
PFS in the first line setting is defined as the time from the date of enrollment to the date of first documented progression based on local radiology review or death due to any cause. If a participant did not progress or was not known to have died at the date of the analysis cut-off or start of another antineoplastic therapy, the PFS date was censored to the date of last adequate tumor assessment prior to cut-off date or start of antineoplastic therapy. The median PFS was estimated and presented along with 95% confidence intervals. The primary analysis of PFS for first line was performed 12 months after the last patient's recruitment.
21 secondary outcomes
First-line Treatment: Overall Response Rate (ORR)
Time frame: From the date of enrollment until discontinuation of first-line treatment, assessed up to approximately 3.8 years
First-line Treatment: Clinical Benefit Rate (CBR)
Time frame: From the date of enrollment until first-line treatment discontinuation, assessed up to approximately 3.8 years
Second-line Treatment: Progression-free Survival (PFS)
Time frame: From the start of the second-line treatment until the date of first documented progression or death, assessed up to approximately 2.4 years
Second-line Treatment: Overall Response Rate (ORR)
Time frame: From the start of the second-line treatment up to approximately 2.4 years
Second-line Treatment: Clinical Benefit Rate (CBR)
Time frame: From the start of the second-line treatment up to approximately 2.4 years
Overall Survival (OS)
Time frame: From the date of enrollment to date of death, assessed up to approximately 3.8 years
First-line Treatment: Time to First Stomatitis Episode as Assessed by the Oral Stomatitis Daily Questionnaire (OSDQ)
Time frame: From first-line treatment administration until first stomatitis episode in the first line, assessed up to approximately 3.8 years
First-line Treatment: Duration of First Stomatitis Based on OSDQ
Time frame: From start date of first stomatitis episode in first line until its resolution, assessed up to 3.8 years
First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Overall Health at the End of the First Stomatitis Episode
Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Mouth and Throat Soreness at the End of the First Stomatitis Episode
Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Mouth and Throat Soreness Limiting Swallowing, Drinking, Eating, Talking and Sleeping at the End of the First Stomatitis Episode
Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Mouth Pain Severity at the End of the First Stomatitis Episode
Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Mouth Pain Severity Affecting Daily Activities at the End of the First Stomatitis Episode
Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment (Stomatitis Sub-study): Time to First Stomatitis Episode as Assessed by the OSDQ
Time frame: From first study treatment administration in the first line until first stomatitis episode, assessed up to approximately 3.8 years
First-line Treatment (Stomatitis Sub-study): Duration of First Stomatitis Based on OSDQ
Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment (Stomatitis Sub-study): Number of Participants With Shift of Response in OSDQ Score on Overall Health at the End of the First Stomatitis Episode
Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment (Stomatitis Sub-study): Number of Participants With Shift of Response in OSDQ Score on Mouth and Throat Soreness at the End of the First Stomatitis Episode
Time frame: From start date of stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment (Stomatitis Sub-study): Number of Participants With Shift of Response in OSDQ Score on Mouth and Throat Soreness Limiting Swallowing, Drinking, Eating, Talking and Sleeping at the End of the First Stomatitis Episode
Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment (Stomatitis Sub-study): Number of Participants With Shift of Response in OSDQ Score on Mouth Pain Severity at the End of the First Stomatitis Episode
Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
First-line Treatment (Stomatitis Sub-study): Number of Participants With Shift of Response in OSDQ Score on Mouth Pain Severity Affecting Daily Activities at the End of the First Stomatitis Episode
Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
Number of Participants With Clinical Benfit During Extension Phase
Time frame: From the end of core phase (upon approval of amendment 5) up to approximately 3 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 May 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 29566104Royce M, Bachelot T, Villanueva C, Ozguroglu M, Azevedo SJ, Cruz FM, Debled M, Hegg R, Toyama T, Falkson C, Jeong J, Srimuninnimit V, Gradishar WJ, Arce C, Ridolfi A, Lin C, Cardoso F. Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: A Clinical Trial. JAMA Oncol. 2018 Jul 1;4(7):977-984. doi: 10.1001/jamaoncol.2018.0060.
- Individual participant dataSharing planned: Yes. Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
52 sites in 13 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Everolimus, Letrozole and Exemestane in people with Hormone Receptor Positive Breast Cancer, run by Novartis Pharmaceuticals at 52 sites in 13 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 May 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 52 sites in United States, France, Japan, Brazil, Hungary and 8 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Feb 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
First-line Treatment: Progression-free Survival (PFS) (time frame: From the date of enrollment to the date of first documented progression or deaths, assessed up to approximately 2.8 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01698918, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 May 2023.