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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT00863655




Registration number
NCT00863655
Ethics application status
Date submitted
16/03/2009
Date registered
18/03/2009
Date last updated
2/05/2017

Titles & IDs
Public title
Everolimus in Combination With Exemestane in the Treatment of Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Who Are Refractory to Letrozole or Anastrozole
Scientific title
A Randomized Double-Blind, Placebo-Controlled Study of Everolimus in Combination With Exemestane in the Treatment of Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Who Are Refractory to Letrozole or Anastrozole
Secondary ID [1] 0 0
2008-008698-69
Secondary ID [2] 0 0
CRAD001Y2301
Universal Trial Number (UTN)
Trial acronym
BOLERO-2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Everolimus
Treatment: Drugs - Exemestane
Treatment: Drugs - Everolimus Placebo

Experimental: Everolimus + Exemestane - Everolimus 10 mg daily in combination with exemestane 25 mg daily

Active comparator: Placebo + Exemestane - Placebo of everolimus in combination with exemestane 25 mg daily


Treatment: Drugs: Everolimus
Everolimus was formulated as tablets of 5-mg strength and was packaged into blister packs . Everolimus (two 5 mg tablets daily) were administered in a blinded manner on their respective treatment arms by continuous oral daily dosing.

Treatment: Drugs: Exemestane
Exemestane 25 mg orally daily.

Treatment: Drugs: Everolimus Placebo
Placebo was formulated to be indistinguishable from the everolimus tablets. Matching placebo (two tablets daily) were administered in a blinded manner on their respective treatment arms by continuous oral daily dosing.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression-free Survival (PFS) Based on Local Radiology Review of Tumor Assessments.
Timepoint [1] 0 0
date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to about 19 months
Secondary outcome [1] 0 0
Overall Survival (OS) by Number of Deaths
Timepoint [1] 0 0
up to 53 months
Secondary outcome [2] 0 0
Overall Survival (OS) by Median
Timepoint [2] 0 0
up to 53 months
Secondary outcome [3] 0 0
Overall Response Rate (ORR)
Timepoint [3] 0 0
up to 21 months
Secondary outcome [4] 0 0
Clinical Benefit Rate (CBR)
Timepoint [4] 0 0
up to 21 months
Secondary outcome [5] 0 0
Proportion of Patients With no Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) Using Kaplan-Meier
Timepoint [5] 0 0
2, 4, 6, 9 months
Secondary outcome [6] 0 0
Patient-reported Outcomes (PROs): Time to Deterioration of PRO Scores Using Kaplan Meier - EORTC QLQ-C30
Timepoint [6] 0 0
Up to 21 months
Secondary outcome [7] 0 0
Proportion of Patients With Having no Overall Response Based on Investigator Assessment
Timepoint [7] 0 0
2, 4, 6, 9 months
Secondary outcome [8] 0 0
Duration of Response (Among Participants With Best Overall Response of CR or PR) Estimated Per Kaplan-Meier
Timepoint [8] 0 0
21 months
Secondary outcome [9] 0 0
Everolimus Concentrations at Week 4
Timepoint [9] 0 0
pre-dose, 2 hours post-dose
Secondary outcome [10] 0 0
Exemestane Concentrations at Week 4
Timepoint [10] 0 0
predose, 2 hours post-dose
Secondary outcome [11] 0 0
Estradiol Plasma Concentrations
Timepoint [11] 0 0
Baseline, Week 4

Eligibility
Key inclusion criteria
* Adult women (= 18 years of age) with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy.
* Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer
* Postmenopausal women.
* Disease refractory to non steroidal aromatase inhibitors (NSAI),
* Radiological or clinical evidence of recurrence or progression on or after the last systemic therapy prior to randomization.
* Patients must have at least one lesion that can be accurately measured or bone lesions in the absence of measurable disease as defined above.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
* HER2-overexpressing patients
* Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites etc.).
* Patients who received more than one chemotherapy line for Advanced Breast Cancer.
* Previous treatment with exemestane or mTOR inhibitors.
* Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin).
* Radiotherapy within four weeks prior to randomization
* Currently receiving hormone replacement therapy,

Other protocol-defined inclusion/exclusion criteria may apply

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
3/06/2009
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
4/12/2014
Sample size
Target
Accrual to date
Final
724
Recruitment in Australia
Recruitment state(s)
QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
Novartis Investigative Site - Nambour
Recruitment hospital [2] 0 0
Novartis Investigative Site - Redcliffe
Recruitment hospital [3] 0 0
Novartis Investigative Site - Bedford Park
Recruitment hospital [4] 0 0
Novartis Investigative Site - Parkville
Recruitment hospital [5] 0 0
Novartis Investigative Site - Subiaco
Recruitment postcode(s) [1] 0 0
4560 - Nambour
Recruitment postcode(s) [2] 0 0
4020 - Redcliffe
Recruitment postcode(s) [3] 0 0
5042 - Bedford Park
Recruitment postcode(s) [4] 0 0
3002 - Parkville
Recruitment postcode(s) [5] 0 0
3050 - Parkville
Recruitment postcode(s) [6] 0 0
6008 - Subiaco
Recruitment outside Australia
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
There are no treatments specifically approved after recurrence or progression on a non steroidal aromatase inhibitors (NSAI). In light of the need for new treatment options for postmenopausal women after failure of prior NSAI therapy, the purpose of this Phase III study is to compare efficacy and safety of a treatment with exemestane + everolimus to exemestane + placebo in postmenopausal women with estrogen receptor positive locally advanced or metastatic breast cancer refractory to NSAI.
Trial website
https://clinicaltrials.gov/study/NCT00863655
Trial related presentations / publications
Wedam SB, Beaver JA, Amiri-Kordestani L, Bloomquist E, Tang S, Goldberg KB, Sridhara R, Ibrahim A, Kim G, Kluetz P, McKee A, Pazdur R. US Food and Drug Administration Pooled Analysis to Assess the Impact of Bone-Only Metastatic Breast Cancer on Clinical Trial Outcomes and Radiographic Assessments. J Clin Oncol. 2018 Apr 20;36(12):1225-1231. doi: 10.1200/JCO.2017.74.6917. Epub 2018 Mar 9.
Chandarlapaty S, Chen D, He W, Sung P, Samoila A, You D, Bhatt T, Patel P, Voi M, Gnant M, Hortobagyi G, Baselga J, Moynahan ME. Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A Secondary Analysis of the BOLERO-2 Clinical Trial. JAMA Oncol. 2016 Oct 1;2(10):1310-1315. doi: 10.1001/jamaoncol.2016.1279. Erratum In: JAMA Oncol. 2019 Jan 1;5(1):122. doi: 10.1001/jamaoncol.2018.5678.
Hortobagyi GN, Chen D, Piccart M, Rugo HS, Burris HA 3rd, Pritchard KI, Campone M, Noguchi S, Perez AT, Deleu I, Shtivelband M, Masuda N, Dakhil S, Anderson I, Robinson DM, He W, Garg A, McDonald ER 3rd, Bitter H, Huang A, Taran T, Bachelot T, Lebrun F, Lebwohl D, Baselga J. Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From BOLERO-2. J Clin Oncol. 2016 Feb 10;34(5):419-26. doi: 10.1200/JCO.2014.60.1971. Epub 2015 Oct 26. Erratum In: J Clin Oncol. 2019 Feb 1;37(4):354. doi: 10.1200/JCO.18.02212. J Clin Oncol. 2019 Feb 1;37(4):355. doi: 10.1200/JCO.18.02265.
Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Lebrun F, Ito Y, Noguchi S, Perez A, Rugo HS, Deleu I, Burris HA 3rd, Provencher L, Neven P, Gnant M, Shtivelband M, Wu C, Fan J, Feng W, Taran T, Baselga J. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2dagger. Ann Oncol. 2014 Dec;25(12):2357-2362. doi: 10.1093/annonc/mdu456. Epub 2014 Sep 17.
Rugo HS, Pritchard KI, Gnant M, Noguchi S, Piccart M, Hortobagyi G, Baselga J, Perez A, Geberth M, Csoszi T, Chouinard E, Srimuninnimit V, Puttawibul P, Eakle J, Feng W, Bauly H, El-Hashimy M, Taran T, Burris HA 3rd. Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2. Ann Oncol. 2014 Apr;25(4):808-815. doi: 10.1093/annonc/mdu009. Epub 2014 Mar 10.
Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, Hortobagyi GN, Campone M, Pistilli B, Piccart M, Melichar B, Petrakova K, Arena FP, Erdkamp F, Harb WA, Feng W, Cahana A, Taran T, Lebwohl D, Rugo HS. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013 Oct;30(10):870-84. doi: 10.1007/s12325-013-0060-1. Epub 2013 Oct 25. Erratum In: Adv Ther. 2014 Sep;31(9):1008-9.
Campone M, Beck JT, Gnant M, Neven P, Pritchard KI, Bachelot T, Provencher L, Rugo HS, Piccart M, Hortobagyi GN, Nunzi M, Heng DY, Baselga J, Komorowski A, Noguchi S, Horiguchi J, Bennett L, Ziemiecki R, Zhang J, Cahana A, Taran T, Sahmoud T, Burris HA 3rd. Health-related quality of life and disease symptoms in postmenopausal women with HR(+), HER2(-) advanced breast cancer treated with everolimus plus exemestane versus exemestane monotherapy. Curr Med Res Opin. 2013 Nov;29(11):1463-73. doi: 10.1185/03007995.2013.836078. Epub 2013 Sep 4.
Noguchi S, Masuda N, Iwata H, Mukai H, Horiguchi J, Puttawibul P, Srimuninnimit V, Tokuda Y, Kuroi K, Iwase H, Inaji H, Ohsumi S, Noh WC, Nakayama T, Ohno S, Rai Y, Park BW, Panneerselvam A, El-Hashimy M, Taran T, Sahmoud T, Ito Y. Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2. Breast Cancer. 2014 Nov;21(6):703-14. doi: 10.1007/s12282-013-0444-8. Epub 2013 Feb 13.
Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9;366(6):520-9. doi: 10.1056/NEJMoa1109653. Epub 2011 Dec 7.
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT00863655