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Everolimus in Combination With Trastuzumab and Paclitaxel in the Treatment of HER2 Positive Locally Advanced or Metastatic Breast Cancer (BOLERO-1)

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ClinicalTrials.gov Identifier: NCT00876395
Recruitment Status : Completed
First Posted : April 6, 2009
Results First Posted : December 19, 2018
Last Update Posted : December 19, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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Brief Summary:
The purpose of this Phase III study was to confirm the value of adding everolimus to weekly paclitaxel and trastuzumab as treatment of HER2-overexpressing metastatic breast cancer.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Everolimus Drug: Placebo Drug: Trastuzumab Drug: Paclitaxel Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 719 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized Phase III, Double-Blind, Placebo-Controlled Multicenter Trial of Everolimus in Combination With Trastuzumab and Paclitaxel, as First Line Therapy in Women With HER2 Positive Locally Advanced or Metastatic Breast Cancer
Actual Study Start Date : September 10, 2009
Actual Primary Completion Date : May 30, 2014
Actual Study Completion Date : October 23, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: Everolimus + Paclitaxel + Trastuzumab
Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22
 Drug: Everolimus
Everolimus was administered in a continuous oral daily dosing of 10 mg (two 5-mg tablets).
Other Name: RAD001

Drug: Trastuzumab
Trastuzumab, 2 mg/kg weekly was used intravenously.

Drug: Paclitaxel
Paclitaxel, 80 mg/m2 weekly was used intravenously.
Placebo Comparator: Placebo + Paclitaxel + Trastuzumab
Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22
 Drug: Placebo
Everolimus placebo was administered in a continuous oral daily dosing of 10 mg (two 5-mg tablets).

Drug: Trastuzumab
Trastuzumab, 2 mg/kg weekly was used intravenously.

Drug: Paclitaxel
Paclitaxel, 80 mg/m2 weekly was used intravenously.


Outcome Measures
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Primary Outcome Measures :
  1. Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - Full Population [ Time Frame: 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 56 months ]
    PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the full patient population.

  2. Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - (Hormone Receptor (HR)-Negative Population [ Time Frame: 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 56 months ]
    PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the HR-negative patient population.


Secondary Outcome Measures :
  1. Overall Survival (OS) - Full Population [ Time Frame: up to about 76 months ]
    OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the full patient population.

  2. Overall Survival (OS) - HR-negative Population [ Time Frame: up to about 76 months ]
    OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the HR-negative patient population.

  3. Overall Response Rate (ORR) - Full Population [ Time Frame: up to about 23 months ]
    ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.

  4. Overall Response Rate (ORR) - HR-negative Population [ Time Frame: up to about 23 months ]
    ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.

  5. Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - Full Population [ Time Frame: up to about 23 months ]
    CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.

  6. Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - HR-negative Population [ Time Frame: up to about 23 months ]
    CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.

  7. Time to Overall Response Based on Investigator - Full Population [ Time Frame: up to about 23 months ]
    Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.

  8. Time to Overall Response Based on Investigator - HR-negative Population [ Time Frame: up to about 23 months ]
    Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.

  9. Overall Response (OR) - Full Population [ Time Frame: up to about 23 months ]
    OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.

  10. Overall Response (OR) - HR-negative Population [ Time Frame: up to about 23 months ]
    OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. This was assessed in the HR-negative patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.

  11. Everolimus Blood Level Concentrations at Steady States for Everolimus [ Time Frame: predose, 2 hours post-dose at Cycle 2/Day 1, Cycle 2/Day 15, Cycle 2/ Day 22 ]
    Blood levels at steady states for everolimus 10 mg/day and 5 mg/day. Only valid samples are included. Some patients had dose reduction to 5 mg daily dose therefore the everolimus blood concentration for them have been summarized separately. Cycle = 28 days

  12. Paclitaxel Plasma Concentrations [ Time Frame: Cycle 2/Day 15 (Pre-infusion and end of infusion) ]
    Blood levels at steady states for everolimus/placebo

  13. Trastuzumab Serum Concentrations [ Time Frame: Cycle 4/Day 1 (Pre-infusion and end of infusion) ]
    Blood levels at steady states for everolimus/placebo

  14. Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - Full Population [ Time Frame: up to about 56 months ]
    Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed.

  15. Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - HR-negative Population [ Time Frame: up to about 56 months ]
    Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult Women (≥ 18 years old).
  • Histologically or cytologically confirmed invasive breast carcinoma with local recurrence or radiological evidence of metastatic disease.
  • Must have at least one lesion that can be accurately measured or bone lesions in the absence of measurable disease.
  • HER2+ patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive).
  • Prior trastuzumab and/or chemotherapy (taxanes included) as neo-adjuvant or adjuvant treatment is allowed but should be discontinued > 12 months prior to randomization.
  • Prior treatment for breast cancer with endocrine therapy (adjuvant or metastatic settings) is allowed but should be discontinued at randomization. Patients treated with bisphosphonates at entry or who start bisphosphonates during study may continue this therapy during protocol treatment.
  • Documentation of negative pregnancy test.
  • Organ functions at time of inclusion.

Exclusion Criteria:

  • Prior mTOR inhibitors for the treatment of cancer.
  • Other anticancer therapy for locally advanced or metastatic breast cancer except for prior hormonal therapy.
  • Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites, etc).
  • Radiotherapy to ≥ 25% of the bone marrow within 4 weeks prior to randomization
  • History of central nervous system metastasis.
  • Impairment of gastrointestinal (GI) function or GI disease or active ulceration of the upper gastrointestinal tract.
  • Serious peripheral neuropathy.
  • Cardiac disease or dysfunction.
  • Uncontrolled hypertension.
  • HIV.
  • Pregnant,
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00876395


Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00876395    
Other Study ID Numbers: CRAD001J2301
2008-006556-21 ( EudraCT Number )
First Posted: April 6, 2009    Key Record Dates
Results First Posted: December 19, 2018
Last Update Posted: December 19, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description:

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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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Breast Cancer
HER2+
mTOR
everolimus
RAD001
first line
metastatic
 locally advanced
Trastuzumab
Paclitaxel
First Line Therapy
HER2 Positive
Metastatic Breast Cancer
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Trastuzumab
Everolimus
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
 Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
MTOR Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs