NCT01698918

Completed

Phase 2

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

Novartis Pharmaceuticals16 sites in 2 countries202 target enrollmentMarch 7, 2013

ConditionsHormone Receptor Positive Breast Cancer

InterventionsEverolimus Letrozole Exemestane Alcohol-free dexamethasone mouth rinse (Stomatitis sub-study)Standard of care to treat stomatitis (Stomatitis sub-study)

DrugsEverolimus Letrozole Exemestane Alcohol-free dexamethasone mouth rinse (Stomatitis sub-study)Standard of care to treat stomatitis (Stomatitis sub-study)

Overview

Phase: Phase 2
Intervention: Everolimus
Conditions: Hormone Receptor Positive Breast Cancer
Sponsor: Novartis Pharmaceuticals
Enrollment: 202
Locations: 16
Primary Endpoint: First-line Treatment: Progression-free Survival (PFS)
Status: Completed
Last Updated: 3 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

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.

Registry

clinicaltrials.gov

Start Date

March 7, 2013

End Date

January 13, 2021

Last Updated

3 years ago

Study Type

Interventional

Study Design

Single Group

Sex

Female

Investigators

Sponsor

Novartis Pharmaceuticals

Responsible Party

Sponsor

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

Arms & Interventions

Everolimus+letrozole/exemestane (first line and second line treatment)

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)

Intervention: Everolimus

Everolimus+letrozole/exemestane (first line and second line treatment)

Intervention: Letrozole

Everolimus+letrozole/exemestane (first line and second line treatment)

Intervention: Exemestane

Everolimus+letrozole/exemestane (first line and second line treatment)

Intervention: Alcohol-free dexamethasone mouth rinse (Stomatitis sub-study)

Everolimus+letrozole/exemestane (first line and second line treatment)

Intervention: Standard of care to treat stomatitis (Stomatitis sub-study)

Outcomes

Primary Outcomes

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.

Secondary Outcomes

First-line Treatment: Clinical Benefit Rate (CBR)(From the date of enrollment until first-line treatment discontinuation, assessed up to approximately 3.8 years)
Overall Survival (OS)(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)(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(From start date of first stomatitis episode in first line until its resolution, assessed up to 3.8 years)
First-line Treatment: Overall Response Rate (ORR)(From the date of enrollment until discontinuation of first-line treatment, assessed up to approximately 3.8 years)
Second-line Treatment: Progression-free Survival (PFS)(From the start of the second-line treatment until the date of first documented progression or death, assessed up to approximately 2.4 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(From start date of stomatitis episode until its resolution, assessed up to 3.8 years)
Second-line Treatment: Overall Response Rate (ORR)(From the start of the second-line treatment up to approximately 2.4 years)
Second-line Treatment: Clinical Benefit Rate (CBR)(From the start of the second-line treatment up to approximately 2.4 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(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(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(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(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(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(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(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(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 Limiting Swallowing, Drinking, Eating, Talking and Sleeping at the End of the First Stomatitis Episode(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(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(From the end of core phase (upon approval of amendment 5) up to approximately 3 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(From start date of first stomatitis episode until its resolution, assessed up to 3.8 years)