Daily Everolimus in Combination With Trastuzumab and Vinorelbine in HER2/Neu Positive Women With Locally Advanced or Metastatic Breast Cancer (BOLERO-3)

• ClinicalTrials.gov Identifier: NCT01007942
• Recruitment Status: Completed
• First Posted: November 4, 2009
• Results First Posted: April 5, 2017
• Last Update Posted: April 5, 2017
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: November 2, 2009
• First Posted Date: November 4, 2009
• Results First Submitted Date: June 10, 2016
• Results First Posted Date: April 5, 2017
• Last Update Posted Date: April 5, 2017
• Study Start Date: October 2009
• Actual Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 20, 2017)

Progressive-free Survival (PFS) Per Investigator Assessment [ Time Frame: Every 6 weeks until disease progression or death which ever occurred first up to about 41 months ]

PFS was defined as the time from the date of randomization to the date of first radiologically documented tumor progression or death from any cause, whichever occurs first. PFS primary analysis performed when 415 events were reached. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

• Original Primary Outcome Measures (submitted: November 3, 2009): Compare progressive-free survival (PFS) between the two treatment arms: everolimus, trastuzumab, and vinorelbine combination versus trastuzumab and vinorelbine combination [ Time Frame: 21.5 (251 PFS) to 32.5 (417 PFS) months after first randomization ]

Current Secondary Outcome Measures (submitted: February 20, 2017)

• Overall Survival (OS) [ Time Frame: Every 3 months until death up to 41 months ]
  OS was defined as the time from date of randomization to the date of death from any cause. Final OS was conducted when 388 deaths occurred.
• Overall Response Rate (ORR) [ Time Frame: Every 6 weeks until disease progression or death which ever occurred first up to about 41 months ]
  ORR was defined as the percentage of participants whose best overall response was either complete response (CR) or partial response (PR) according to RECIST version 1.0. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
• Clinical Benefit Rate (CBR) [ Time Frame: Every 6 weeks until disease progression or death which ever occurred first up to about 41 months ]
  CBR was defined as the percentage of participants whose best overall response, according to RECIST, was either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.
• Median Time to Deterioration of the ECOG Performance Status Score [ Time Frame: baseline, until disease progression or death up to about 41 months ]
  Time to deterioration of ECOG performance status score was summarized at time of assessment. ECOG (Eastern Cooperative Oncology Group)performance scale is a standard criteria for measuring how treatment of cancer impacts their level of functioning in terms of their ability to care for themselves, daily activity, & physical ability (walking, working, etc.). Scale score ranges from 0 to 5, 5 being the worst. ECOG scale index: 0 - Fully active, able to carry on all pre-disease performance without restriction. 1 - Restricted in physically strenuous activity but ambulatory & able to carry out work of a light or sedentary nature, e.g., light housework, office work. 2 - Ambulatory & capable of all self-care but unable to carry out any work activities. Up & 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. 5 - Dead
• PRO: Time to Deterioration in Global Health Status/QoL Domain Score of the European Organization for the Research and Treatment of Cancer (EORTC)-Core Quality of Life Questionnaire (QLQ-C30) (by at Least 10%) [ Time Frame: Baseline, until disease progression or death up to about 41 months ]
  PRO = patient reported outcomes; Time to deterioration (≥ 10% worsening from baseline), in the global health status of EORTC QLQ-C30 scale was done in the 3 functional scales (emotional, physical, & social functioning [EF, PF, & SF]). It contains 30 items & is composed of multi-item scales & single-item measures. These include 5 functional scales (physical, role, emotional, social & cognitive functioning), 3 symptom scales (fatigue, pain, nausea, & vomiting), a global health status/QoL scale, and 6 single items (dyspnea, diarrhea, constipation, anorexia, insomnia & financial impact). Each of the multi-item scale includes a different set of items - no item occurs in more than 1 scale. Each item in the EORTC QLQ-C30 has 4 response categories (1=Not at all, 2= A little, 3= Quite a bit, 4= Very much) with the higher number representing a worse outcome. The global health domain score of the QLQ-C30 questionnaire was pre-specified as the primary QoL domain of interest & disclosed here.
• Everolimus Blood Concentrations by Leading Dose and Time Point [ Time Frame: Cycle 2, Day 1 ]
  Pre-dose (Cmin) and 2 hours post-dose (C2h) everolimus PK blood samples were collected at Cycle 2 Day 1. Only valid everolimus PK blood samples collected at steady state were used in the analyses.
• Vinorelbine Blood Concentrations by Leading Dose and Time Point [ Time Frame: Cycle 2, Day 1 ]
  Pre-infusion (Cmin) and end of infusion (C2h) vinorelbine PK blood samples were collected at Cycle 2 Day 1. Only valid vinorelbine PK blood samples collected at steady state were used in the analyses.
• Trastuzumab Blood Concentrations by Leading Dose and Time Point [ Time Frame: Cycle 3, Day 1 ]
  Pre-infusion (Cmin) and end of infusion (C2h) trastuzumab PK blood samples were collected at Cycle 3 Day 1. Only valid trastuzumab PK blood samples collected at steady state were used in the analyses.

Original Secondary Outcome Measures (submitted: November 3, 2009)

• Compare overall survival (OS) between the two treatment arms: everolimus, trastuzumab, and vinorelbine combination versus trastuzumab and vinorelbine combination. [ Time Frame: months after first randomization (384 OS events) ]
• Compare objective response rate (ORR) between the two treatment arms. [ Time Frame: 55 months after first randomization (384 OS events) ]
• Compare changes in Quality of Life (QoL) scores over time between the two treatment arms. [ Time Frame: at time of PFS analyses ]
• Compare clinical benefit rate (CBR) between the two treatment arms. [ Time Frame: at time of Overall Survival (OS) analysis ]
• Evaluate safety between the two treatment arms [ Time Frame: Monthly for certain pre-defined adverse event categories; at planned safety analysis after enrollment of first 60 patients (approximately 5 months after first randomization), and at PFS analyses ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Daily Everolimus in Combination With Trastuzumab and Vinorelbine in HER2/Neu Positive Women With Locally Advanced or Metastatic Breast Cancer
• Official Title: A Randomized Phase III, Double-blind, Placebo-controlled Multicenter Trial of Daily Everolimus in Combination With Trastuzumab and Vinorelbine, in Pretreated Women With HER2/Neu Over-expressing Locally Advanced or Metastatic Breast Cancer.
• Brief Summary: This phase III, double-blind, placebo-controlled multinational study will assess the combination everolimus, vinorelbine, and trastuzumab compared to the combination vinorelbine and trastuzumab with respect to progressive-free survival and over survival in HER2/neu positive women with locally advanced or metastatic breast cancer who are resistant to trastuzumab and have been pre-treated with a taxane.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• HER2/Neu Over-expressing Locally Advanced Breast Cancer
• Metastatic Breast Cancer

Intervention

• Drug: everolimus
  Oral everolimus was taken once 5 mg/day (2 × 2.5 mg tablets) and were packaged into blister packs.
  Other Name: RAD001
• Drug: Placebo
  Oral everolimus placebo was taken once 5 mg/day (2 × 2.5 mg tablets) and were packaged into blister packs.
• Drug: vinorelbine
  intravenous vinorelbine (25 mg/m2 weekly)
• Drug: trastuzumab
  intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only)

Study Arms

• Experimental: Everolimus + vinorelbine + trastuzumab
  Oral everolimus (5 mg/day) + intravenous vinorelbine (25 mg/m2 weekly) + intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only)
  Interventions:

  • Drug: everolimus
  • Drug: vinorelbine
  • Drug: trastuzumab
• Placebo Comparator: placebo + vinorelbine + trastuzumab
  Oral daily matching placebo + intravenous vinorelbine (25 mg/m2 weekly) + intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only
  Interventions:

  • Drug: Placebo
  • Drug: vinorelbine
  • Drug: trastuzumab

• Publications *: Andre F, O'Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, Masuda N, Wilks S, Arena F, Isaacs C, Yap YS, Papai Z, Lang I, Armstrong A, Lerzo G, White M, Shen K, Litton J, Chen D, Zhang Y, Ali S, Taran T, Gianni L. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014 May;15(6):580-91. doi: 10.1016/S1470-2045(14)70138-X. Epub 2014 Apr 14.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 20, 2017): 569
• Original Estimated Enrollment (submitted: November 3, 2009): 572
• Actual Study Completion Date: June 2015
• Actual Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed invasive breast carcinoma with locally recurrent or radiological evidence of metastatic disease. Locally recurrent disease must not be amenable to resection with curative intent.
• HER2+ status defined as IHC 3+ staining or in situ hybridization positive
• Patients with resistance to trastuzumab
• Prior taxane therapy
• Patients with an ECOG performance status of 0 - 2
• Patients with measurable disease as per RECIST criteria
• Documentation of negative pregnancy test for patients of child bearing potential prior to enrollment within 7 days prior to randomization. Sexually active pre-menopausal women must use adequate contraceptive measures, excluding estrogen containing contraceptives, while on study;
• Patients must meet laboratory criteria defined in the study within 21 days prior to randomization

Exclusion Criteria:

• Prior mTOR inhibitors or vinca alkaloid agents for the treatment of cancer
• More than three prior chemotherapy lines for advanced disease.
• Symptomatic CNS metastases or evidence of leptomeningeal disease. Previously treated asymptomatic CNS metastases are allowed provided that the last treatment for CNS metastases was completed >8 weeks prior to randomization
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus
• Peripheral neuropathy ≥ grade 2 at randomization
• Active cardiac disease
• History of cardiac dysfunction
• Any malignancy within 5 years prior to randomization, with the exception of adequately treated in-situ carcinoma of the cervix uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer
• Known hypersensitivity to any study medication
• Breastfeeding or pregnant

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, China, Czech Republic, France, Germany, Greece, Hungary, Israel, Italy, Japan, Mexico, Poland, Singapore, Slovakia, Spain, Thailand, Turkey, United Kingdom, United States
• Removed Location Countries: Puerto Rico

Administrative Information

• NCT Number: NCT01007942
• Other Study ID Numbers: CRAD001W2301; 2008-008697-31 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: External Affairs, Novartis Pharmaceuticals
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: February 2017