Study To Evaluate the Efficacy and Safety Of Bevacizumab, and Associated Biomarkers, In Combination With Paclitaxel Compared With Paclitaxel Plus Placebo as First-line Treatment Of Patients With Her2-Negative Metastatic Breast Cancer

• ClinicalTrials.gov Identifier: NCT01663727
• Recruitment Status: Completed
• First Posted: August 13, 2012
• Results First Posted: February 10, 2016
• Last Update Posted: January 22, 2019
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: August 9, 2012
• First Posted Date: August 13, 2012
• Results First Submitted Date: January 12, 2016
• Results First Posted Date: February 10, 2016
• Last Update Posted Date: January 22, 2019
• Actual Study Start Date: August 27, 2012
• Actual Primary Completion Date: November 30, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 12, 2016)

• Percentage of Participants With Progression or Death in Intent-to-Treat (ITT) Population [ Time Frame: Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 117.7 weeks) ]
  Tumor assessment was performed as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by investigator. Disease progression was defined as at least 20 percent (%) increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 millimeter (mm), unequivocal progression of existing non-target lesions, or presence of new lesions.
• Progression Free Survival (PFS) in ITT Population [ Time Frame: Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 117.7 weeks) ]
  PFS was defined as the interval between the date of randomization and the first documentation of progressive disease or death from any cause. Tumor assessment was performed as per RECIST v1.1 by investigator. Disease progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or presence of new lesions. PFS was estimated using Kaplan Meier method.
• Percentage of Participants With Progression or Death in High Baseline Plasma Vascular Endothelial Growth Factor-A (VEGF-A) ITT Population [ Time Frame: Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 111.3 weeks) ]
  Tumor assessment was performed as per RECIST v1.1 by investigator. Disease progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or presence of new lesions.
• PFS in High Baseline Plasma VEGF-A ITT Population [ Time Frame: Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 111.3 weeks) ]
  PFS was defined as the interval between the date of randomization and the first documentation of progressive disease or death from any cause. Tumor assessment was performed as per RECIST v1.1 by investigator. Disease progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or presence of new lesions. PFS was estimated using Kaplan Meier method.

Original Primary Outcome Measures (submitted: August 9, 2012)

• Progression-free survival based on investigator tumor assessment in the intent-to-treat patient population [ Time Frame: approximately 47 months ]
• Progression-free survival based on investigator tumor assessment in intent-to-treat patients with high plasma vascular endothelial growth factor A levels [ Time Frame: approximately 47 months ]

Current Secondary Outcome Measures (submitted: November 16, 2018)

• Percentage of Participants Who Died - ITT Population [ Time Frame: From randomization till death or clinical cut-off (up to 244 weeks) ]
• Overall Survival (OS) - ITT Population [ Time Frame: From randomization till death or clinical cut-off (up to 244 weeks) ]
  OS was defined as the interval between the date of randomization and death from any cause. OS was estimated using Kaplan Meier method.
• Percentage of Participants Who Died - High Baseline Plasma VEGF-A ITT Population [ Time Frame: From randomization till death or clinical cut-off (up to 244 weeks) ]
• OS - High Baseline Plasma VEGF-A ITT Population [ Time Frame: From randomization till death or clinical cut-off (up to 244 weeks) ]
  OS was defined as the interval between the date of randomization and death from any cause. OS was estimated using Kaplan Meier method.
• Percentage of Participants With an Objective Response - ITT Population [ Time Frame: Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 117.7 weeks) ]
  Objective response was defined as having a Complete Response (CR) or Partial Response (PR) according to a RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Measurable disease was defined by the presence of at least one measurable lesion by clinical measurement, chest x-ray, computed tomography (CT), or magnetic resonance imaging (MRI).
• Percentage of Participants With an Objective Response - High Baseline Plasma VEGF-A ITT Population [ Time Frame: Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 111.3 weeks) ]
  Objective response was defined as having a CR or PR according to a RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Measurable disease was defined by the presence of at least one measurable lesion by clinical measurement, chest x-ray, CT, or MRI.
• Duration of Response - ITT Population [ Time Frame: Baseline, every 8 weeks until documented disease progression or clinical cut-off (up to 117.7 weeks) ]
  Duration of response was defined as the time from the initial date of the objective response to documented disease progression or death (whichever occurred first). Objective response was defined as having a CR or PR according to a RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Disease progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or presence of new lesions. Analysis was performed using Kaplan Meier method.
• Duration of Response - High Baseline Plasma VEGF-A ITT Population [ Time Frame: Baseline, every 8 weeks until documented disease progression or clinical cut-off (up to 111.3 weeks) ]
  Duration of response was defined as the time from the initial date of the objective response to documented disease progression or death (whichever occurred first). Objective response was defined as having a CR or PR according to a RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Disease progression was defined at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or presence of new lesions. Analysis was performed using Kaplan Meier method.
• Percentage of Participants Who Were Alive at 1 Year - ITT Population [ Time Frame: 1 year ]
• Secondary: Percentage of Participants Who Were Alive at 1 Year - High Baseline Plasma VEGF-A ITT Population [ Time Frame: 1 year ]

Original Secondary Outcome Measures (submitted: August 9, 2012)

• Overall survival [ Time Frame: approximately 72 months ]
• Objective response rate for patients with measurable disease at baseline, defined as complete or partial response as assessed by investigator according to RECIST v1.1 [ Time Frame: approximately 72 months ]
• Duration of objective response for patients with measurable disease at baseline, as determined by investigator review of tumor assessments using RECIST v1.1 [ Time Frame: approximately 72 months ]
• One-year survival rate [ Time Frame: 12 months ]

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

Descriptive Information

• Brief Title: Study To Evaluate the Efficacy and Safety Of Bevacizumab, and Associated Biomarkers, In Combination With Paclitaxel Compared With Paclitaxel Plus Placebo as First-line Treatment Of Patients With Her2-Negative Metastatic Breast Cancer
• Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study To Evaluate the Efficacy and Safety Of Bevacizumab, and Associated Biomarkers, In Combination With Paclitaxel Compared With Paclitaxel Plus Placebo as First-line Treatment Of Patients With Her2-Negative Metastatic Breast Cancer
• Brief Summary: This is a Phase III, randomized, double-blind, placebo-controlled multicenter study to evaluate the efficacy and safety of bevacizumab administered in combination with paclitaxel in patients with previously untreated, locally recurrent, or metastatic HER2-negative breast cancer. Patients will be randomized to one of two treatment arms: bevacizumab or placebo. All patients will be given an intravenous (IV) infusion of of paclitaxel (90 mg/m2) for 3 weeks during each 28-day cycle. bevacizumab or placebo (10 mg/kg) will be administered by IV infusion on Days 1 and 15 of each 28-day cycle. Patients will be treated until disease progression, unacceptable toxicity or death from any cause occurs.
• 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: Metastatic Breast Cancer

Intervention

• Drug: Bevacizumab [Avastin]
  Intravenous repeating dose
• Drug: Paclitaxel
  Intravenous repeating dose
• Drug: Placebo
  Intravenous repeating dose

Study Arms

• Experimental: A
  Paclitaxel + Bevacizumab [Avastin]
  Interventions:

  • Drug: Bevacizumab [Avastin]
  • Drug: Paclitaxel
• Experimental: B
  Paclitaxel + Placebo
  Interventions:

  • Drug: Paclitaxel
  • Drug: Placebo

Publications *

• Masuda N, Takahashi M, Nakagami K, Okumura Y, Nakayama T, Sato N, Kanatani K, Tajima K, Kashiwaba M. First-line bevacizumab plus paclitaxel in Japanese patients with HER2-negative metastatic breast cancer: subgroup results from the randomized Phase III MERiDiAN trial. Jpn J Clin Oncol. 2017 May 1;47(5):385-392. doi: 10.1093/jjco/hyx001.
• Miles D, Cameron D, Bondarenko I, Manzyuk L, Alcedo JC, Lopez RI, Im SA, Canon JL, Shparyk Y, Yardley DA, Masuda N, Ro J, Denduluri N, Hubeaux S, Quah C, Bais C, O'Shaughnessy J. Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur J Cancer. 2017 Jan;70:146-155. doi: 10.1016/j.ejca.2016.09.024. Epub 2016 Nov 4.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 12, 2016): 481
• Original Estimated Enrollment (submitted: August 9, 2012): 480
• Actual Study Completion Date: November 21, 2017
• Actual Primary Completion Date: November 30, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed, HER2-negative adenocarcinoma of the breast, with measurable or non-measurable locally recurrent or metastatic disease. Locally recurrent disease must not be amenable to resection with curative intent.
• ECOG performance status of 0 or 1
• For women of childbearing potential, use of an acceptable and effective method of non-hormonal contraception
• For patients who have received recent radiotherapy, recovery prior to randomization from any significant acute toxicity, and radiation treatments have to be completed more than 3 weeks from randomization

Exclusion Criteria:

Disease-Specific Exclusions:

• HER2-positive status
• Prior chemotherapy for locally recurrent or metastatic disease
• Prior hormonal therapy < 2 weeks prior to randomization
• Prior adjuvant or neo-adjuvant chemotherapy is allowed, provided its conclusion has been for at least 12 months prior to randomization
• Investigational therapy within 28 days of randomization

General Medical Exclusions:

• Life expectancy of < 12 weeks
• Inadequate organ function
• Uncontrolled serious medical or psychiatric illness
• Active infection requiring intravenous (IV) antibiotics at screening
• Pregnancy or lactation
• History of other malignancies within 5 years prior to screening, except for tumors with a negligible risk for metastasis or death

Sex/Gender

• Sexes Eligible for Study: All

• 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, Belgium, Brazil, Bulgaria, Chile, Germany, Italy, Japan, Korea, Republic of, Panama, Romania, Russian Federation, South Africa, Ukraine, United Kingdom, United States
• Removed Location Countries: Slovakia, Vietnam

Administrative Information

• NCT Number: NCT01663727
• Other Study ID Numbers: GO25632; 2011-005335-97 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: January 2019