Clinical trial NCT01698918: Open-label, Phase II, Study of Everolimus Plus Letrozole in Postmenopausal Women With ER+, HER2- Metastatic or Locally Advanced Breast Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hormone Receptor Positive Breast Cancer
Keywords: Metastatic breast cancer
Locally advanced breast cancer
HER2-
ER+
Everolimus
Afinitor
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-10-03
Enrollment: 202
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: First-line Treatment: Progression-free Survival (PFS)
timeFrame: From the date of enrollment to the date of first documented progression or deaths, assessed up to approximately 2.8 years
Secondary outcomes:
measure: First-line Treatment: Overall Response Rate (ORR)
timeFrame: From the date of enrollment until discontinuation of first-line treatment, assessed up to approximately 3.8 years
measure: First-line Treatment: Clinical Benefit Rate (CBR)
timeFrame: From the date of enrollment until first-line treatment discontinuation, assessed up to approximately 3.8 years
measure: Second-line Treatment: Progression-free Survival (PFS)
timeFrame: From the start of the second-line treatment until the date of first documented progression or death, assessed up to approximately 2.4 years
measure: Second-line Treatment: Overall Response Rate (ORR)
timeFrame: From the start of the second-line treatment up to approximately 2.4 years
measure: Second-line Treatment: Clinical Benefit Rate (CBR)
timeFrame: From the start of the second-line treatment up to approximately 2.4 years
measure: Overall Survival (OS)
timeFrame: From the date of enrollment to date of death, assessed up to approximately 3.8 years
measure: First-line Treatment: Time to First Stomatitis Episode as Assessed by the Oral Stomatitis Daily Questionnaire (OSDQ)
timeFrame: From first-line treatment administration until first stomatitis episode in the first line, assessed up to approximately 3.8 years
measure: First-line Treatment: Duration of First Stomatitis Based on OSDQ
timeFrame: From start date of first stomatitis episode in first line until its resolution, assessed up to 3.8 years
measure: First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Overall Health at the End of the First Stomatitis Episode
timeFrame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
measure: 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
timeFrame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
measure: 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
timeFrame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
measure: 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
timeFrame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
measure: 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
timeFrame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
measure: First-line Treatment (Stomatitis Sub-study): Time to First Stomatitis Episode as Assessed by the OSDQ
timeFrame: From first study treatment administration in the first line until first stomatitis episode, assessed up to approximately 3.8 years
measure: First-line Treatment (Stomatitis Sub-study): Duration of First Stomatitis Based on OSDQ
timeFrame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
measure: 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
timeFrame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
measure: 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
timeFrame: From start date of stomatitis episode until its resolution, assessed up to 3.8 years
measure: 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
timeFrame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
measure: 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
timeFrame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
measure: 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
timeFrame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
measure: Number of Participants With Clinical Benfit During Extension Phase
timeFrame: From the end of core phase (upon approval of amendment 5) up to approximately 3 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Comprehensive Cancer Center SC-2
state: Alabama
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Loma Linda
country: United States
facility: Loma Linda University Loma Linda
state: California
city: Long Beach
country: United States
facility: Breastlink Medical Group Dept. of BreastlinkResearchGrp
state: California
city: Park Ridge
country: United States
facility: Oncology Specialists, SC Advocate Medical Group-Niles
state: Illinois
city: Topeka
country: United States
facility: St. Francis Health Comprehensive Cancer Center
state: Kansas
city: Louisville
country: United States
facility: Norton Healthcare Inc SC
state: Kentucky
city: Springfield
country: United States
facility: Baystate Medical Center SC-2
state: Massachusetts
city: Livingston
country: United States
facility: Saint Barnabas Medical Center CancerCenter of Saint Barnabas
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Hospital SC
state: New Mexico
city: Johnson City
country: United States
facility: Broome Oncology SC
state: New York
city: New York
country: United States
facility: Columbia University Medical Center- New York Presbyterian Columbia
state: New York
city: Greensboro
country: United States
facility: Cone Health Cancer Center
state: North Carolina
city: Lufkin
country: United States
facility: East Texas Hematology Clinic SC
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists Dept.of Utah Cancer Spec. (3)
state: Utah
city: Santa Rosa
country: Argentina
facility: Novartis Investigative Site
state: La Pampa
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Besancon cedex
country: France
facility: Novartis Investigative Site
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Hyères
country: France
facility: Novartis Investigative Site
city: Le Chesnay
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Nancy
country: France
facility: Novartis Investigative Site
city: Nantes Cedex
country: France
facility: Novartis Investigative Site
city: Kecskemet
country: Hungary
facility: Novartis Investigative Site
state: Bacs Kiskun
city: Gyula
country: Hungary
facility: Novartis Investigative Site
city: Szekszard
country: Hungary
facility: Novartis Investigative Site
city: Nagoya-city
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Sapporo-city
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Shiwa-gun
country: Japan
facility: Novartis Investigative Site
state: Iwate
city: Kawasaki-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Kumamoto City
country: Japan
facility: Novartis Investigative Site
state: Kumamoto
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Maastricht
country: Netherlands
facility: Novartis Investigative Site
state: AZ
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Salamanca
country: Spain
facility: Novartis Investigative Site
state: Castilla Y Leon
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: La Coruna
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Antalya
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Bath
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.