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A Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in Advance Breast Cancer. (BOLERO-6)

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ClinicalTrials.gov Identifier: NCT01783444
Recruitment Status : Completed
First Posted : February 5, 2013
Last Update Posted : February 15, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This was a three-arm, randomized, open label, multi-center phase II study investigating the combination of everolimus (10mg daily) with exemestane (25mg daily) versus everolimus (10mg daily) versus capecitabine (1250mg/m2 twice daily for 14 days, 3-week cycle) in patients with estrogen-receptor positive, HER2 negative, advanced breast cancer after recurrence or progression on letrozole or anastrozole.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Capecitabine Drug: Exemestane Drug: Everolimus Phase 2

Detailed Description:

The reference therapy (control arm) used in the course of this trial was the combination arm of everolimus plus exemestane. The investigational therapies in the context of this study were everolimus monotherapy and capecitabine monotherapy. All treatments were taken orally until disease progression, intolerable toxicity or withdrawal of patient's informed consent. Patients were randomly assigned with equal allocation to one of the treatment arms:

  1. Exemestane (25mg daily) in combination with everolimus (10mg daily)
  2. Everolimus (10mg daily)
  3. Capecitabine (1250mg/m2 twice daily) orally for two weeks, followed by a one week rest period in 3-weeks cycles.

Treatment assignment was stratified by the presence of visceral disease (yes vs. no). Visceral refered to lung, liver, heart, ovary, spleen, kidney, adrenal gland, malignant pleural or pericardial effusion or malignant ascites.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 317 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in the Treatment of Postmenopausal Women With ER+Locally Advanced, Recurrent, or Metastatic Breast Cancer After Recurrence or Progression on Prior Letrozole or Anastrozole.
Actual Study Start Date : February 26, 2013
Actual Primary Completion Date : July 2, 2018
Actual Study Completion Date : July 30, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Capecitabine Monotherapy
Capecitabine monotherapy arm (1250mg/m2 twice daily) orally for two weeks, followed by a one week rest period in 3-weeks cycles.
Drug: Capecitabine
Capecitabine, for oral use 1250 mg/m2 twice daily for 2 weeks followed by one week rest (3-week cycle). Capecitabine will be locally supplied by the Investigator.
Other Name: Capecitabine monotherapy

Experimental: Everolimus Monotherapy
Everolimus (10mg daily).
Drug: Everolimus
Everolimus will be centrally dispensed via IWRS. Everolimus will be taken as oral tablets for oral use 10 mg (2 × 5 mg) daily.
Other Name: RAD001

Active Comparator: Everolimus with Exemestane
Everolimus (10mg daily) with exemestane (25mg daily).
Drug: Exemestane
Exemestane tablets of 25 mg will be taken orally once per day. Dose modifications in the management of adverse events is allowed.
Other Name: Control Arm




Primary Outcome Measures :
  1. Progression Free Survival (PFS) - Everolimus plus exemestane versus everolimus alone [ Time Frame: 28 months after first patient randomized or once approximatly 150 PFS have occurred ]
    Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) - Everolimus plus exemestane versus Capecitabine alone [ Time Frame: 28 months after first patient randomized or once approximatly 150 PFS events have occured ]
    Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.

  2. Overall Survival (OS) [ Time Frame: Every 3 months following the end of study visit until 2015 (up to 3 years) ]
    Overall Survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut-off, OS was censored at the date of last known date patient alive.

  3. Overall Response Rate (ORR) [ Time Frame: From the date of first dose of study medication until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately for 28 months ]
    Overall Response Rate (ORR) is defined as the proportion of participants with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST 1.1. ORR was analyzed in the full population. Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target/non target lesions: Complete Response (CR), disappearance of all target/non target lesions (all lymph nodes assigned as non-target lesions must be non-pathological in size (< 10 mm short axis)); Partial response (PR), >=30% decrease in the sum of the longest diameter of target lesions ; Overall Response (OR)= CR+PR.

  4. Clinical Benefit Rate (CBR) [ Time Frame: From the date of first dose of study medication until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 28 months ]
    Clinical Benefit Rate (CBR) is defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) or Non-CR/non-PD lasting more than 24 weeks based on local investigator's assessment according to RECIST 1.1. CBR was analyzed in the full population.

  5. Time to definitive deterioration in Eastern Cooperative Oncology Group (ECOG) performance status [ Time Frame: Baseline, Day 1, every 6 weeks for approximately 8 months ]
    The Eastern Cooperative Oncology Group (ECOG) Performance Status is a scale used to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis. The ECOG Performance Scores has 5 grades: 0 = fully active, able to carry on all pre-disease performance without restriction, 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work, 2 = ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours, 3 = capable of only limited self-care, confined to bed or chair more than 50% of waking hours, 4 = completely disabled, cannot carry on any self-care, totally confined to bed or chair and 5 = dead. Definitive deterioration is defined as no improvement in the ECOG status following observation of the deterioration.

  6. Time to 10% definitive deterioration in the global health status/Quality of life per EORTC-QLQ-C30 [ Time Frame: Baseline, every 6 weeks for approximately 8 months ]
    The global health status/QoL scale score of the QLQ-C30 is identified as the primary PRO variable of interest. Physical Functioning (PF), Emotional Functioning (EF) and Social Functioning (SF) scale scores of the QLQ-C30. The time to definitive 10% deterioration is defined as the time from the randomization date to the date of an event, which is defined as a worsening (decrease) in score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study or death due to any cause. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high /healthy level of functioning, a high score for the global health status / QoL represents a high QoL.

  7. Mean change in the global health status/Quality of life per EORTC module (BR23) over time [ Time Frame: Baseline, every 6 weeks for approximately 8 months ]
    EORTC Quality of Life Questionnaire - Breast Cancer Module (EORTC QLQ-BR23) is to be used in conjunction with the EORTC QLQ-C30 for assessing the quality of life of breast cancer patients. Functional scales (Body image, Sexual functioning, Sexual enjoyment and Future perspective) and Symptoms scales/Items (Sytemic therapy side effects, Breast symptoms, Arm symptoms and Upset by hair loss) are scored as part of the BR-23. The scores are linearly converted to a 0-100 scale, where higher function scores reflect improved function and higher symptom scores present a higher level of symptoms.

  8. Mean change in Treatment Satisfaction Questionnaire for Medication (TSQM) between Week 3 and Week 12 [ Time Frame: Week 3, Week 12 ]
    The TSQM was developed and validated as a general measure for treatment satisfaction. It contains 14 items assessing the following 4 domains: effectiveness (sum of scores for questions 1 - 3), side effects (sum of scores for questions 4 - 8), convenience (sum of scores for questions 9 - 11) and Global Satisfaction (sum of scores for questions 12 - 14). The scores of the domain were added together and an algorithm was used to create a score of 0 to 100. Higher scores indicated greater satisfaction. A positive change from baseline indicates improvement.



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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

Key Inclusion Criteria:

-Women with locally advanced, recurrent, or metastatic breast cancer along with confirmation of estrogen-receptor positive (ER+). Measurable disease defined as at least one lesion ≥ 10 mm by CT or MRI that can be accurately measured in at least one dimension (CT scan slice thickness ≤ 5 mm) OR • Bone lesions: lytic or mixed (lytic + blastic) in the absence of measurable disease as defined above

Key Exclusion Criteria:

-Patients who received more than one chemotherapy line. Patients with only non-measurable lesions other than lytic or mixed (lytic and blastic) bone metastasis.Previous treatment with exemestane, mTOR inhibitors, PI3K inhibitors or AKT inhibitors


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): NCT01783444


  Show 86 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01783444     History of Changes
Other Study ID Numbers: CRAD001Y2201
2012-003757-28 ( EudraCT Number )
First Posted: February 5, 2013    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019
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


Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Estrogen receptor positive, locally advanced, metastatic breast cancer, Everolimus, Exemestane, Capecitabine

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Capecitabine
Exemestane
Everolimus
Sirolimus
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists