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

Study Description

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Brief Summary:

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 or disease	Intervention/treatment	Phase
Hormone Receptor Positive Breast Cancer	Drug: Everolimus; Drug: Letrozole; Drug: Exemestane; Drug: Alcohol-free dexamethasone mouth rinse	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	202 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
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
Actual Study Start Date :	March 7, 2013
Estimated Primary Completion Date :	June 22, 2020
Estimated Study Completion Date :	June 22, 2020

Arms and Interventions

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Arm

Intervention/treatment

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

Outcome Measures

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Primary Outcome Measures :

1. 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 :

1. 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
2. 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
3. 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.
4. 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.
5. 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.
6. 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
7. 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.
8. 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

Eligibility Criteria

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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

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  Show 56 Study Locations

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

Study Director:	Novartis Pharmaceuticals	Novartis Pharmaceuticals

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Royce M, Bachelot T, Villanueva C, Özgüroglu 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 Mar 22. doi: 10.1001/jamaoncol.2018.0060. [Epub ahead of print]

Responsible Party:	Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT01698918 History of Changes
Other Study ID Numbers:	CRAD001Y24135; 2012-003065-17 ( EudraCT Number )
First Posted:	October 3, 2012
Last Update Posted:	November 14, 2017
Last Verified:	November 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; 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; Central Nervous System Depressants