A Study of Avastin (Bevacizumab) in Combination With Herceptin (Trastuzumab)/Docetaxel in Patients With HER2 Positive Metastatic Breast Cancer.

A Randomized, Open-label Study to Compare the Effect of First-line Treatment With Avastin in Combination With Herceptin/Docetaxel and Herceptin/Docetaxel Alone on Progression-free Survival in Patients With HER2 Positive Locally Recurrent or Metastatic Breast Cancer.

This 2 arm study will compare the efficacy and safety of Avastin plus Herceptin/docetaxel, versus Herceptin/docetaxel alone, in patients with HER2 positive locally recurrent or metastatic breast cancer who have not received prior chemotherapy for their metastatic disease. Patients will be randomized 1:1 to receive either Avastin (15mg/kg iv q3weeks) + Herceptin (8mg/kg iv loading dose and 6mg/kg iv q3weeks maintenance) + docetaxel (100mg/m2 iv q3weeks) or Herceptin + docetaxel alone. The anticipated time on study treatment is until disease progression, and the target sample size is 100-500 individuals.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: bevacizumab [Avastin]; Drug: Docetaxel; Drug: Herceptin

• Study Type: Interventional
• Enrollment (Actual): 424
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1417
  • Cordoba, Argentina, 5004
  • La Plata, Argentina, B1902CMK
  • Mar del Plata, Argentina, 7600
  • Mendoza, Argentina, 5500
  • Salta, Argentina, 4400
  • San Martin, Argentina, 1650
  • Santa Fe, Argentina, 2000
  • Santa Fe, Argentina, 03000
• Australia
  • New South Wales
    • Lismore, New South Wales, Australia, 2480
    • Newcastle, New South Wales, Australia, 2298
    • Port Macquarie, New South Wales, Australia, 2444
    • Wahroonga, New South Wales, Australia, 2076
    • Wollongong, New South Wales, Australia, 2500
  • Queensland
    • Auchenflower, Queensland, Australia, 4066
    • Nambour, Queensland, Australia, 4560
  • Victoria
    • Fitzroy, Victoria, Australia, 3065
    • Geelong, Victoria, Australia, 3220
  • Western Australia
    • Perth, Western Australia, Australia, 6000
• Austria
  • Graz, Austria, 8036
  • Salzburg, Austria, 5020
  • Vöcklabruck, Austria, 4840
  • Wien, Austria, 1090
• Bosnia and Herzegovina
  • Banja Luka, Bosnia and Herzegovina, 78000
  • Sarajevo, Bosnia and Herzegovina, 71000
  • Tuzla, Bosnia and Herzegovina, 75000
• Brazil
  • GO
    • Goiania, GO, Brazil, 74605-070
  • RS
    • Porto Alegre, RS, Brazil, 90610-000
  • SC
    • Florianopolis, SC, Brazil, 88034-000
  • SP
    • Barretos, SP, Brazil, 14784-400
    • Sao Paulo, SP, Brazil, 01509-010
• Canada
  • Quebec, Canada, G1S 4L8
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
    • Sudbury, Ontario, Canada, P3E 5J1
    • Toronto, Ontario, Canada, M4N 3M5
  • Quebec
    • Montreal, Quebec, Canada, H3A 1A1
    • Montreal, Quebec, Canada, H3T 1E2
    • Montreal, Quebec, Canada, H2W 1S6
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
• Czech Republic
  • Praha 2, Czech Republic, 128 08
  • Praha 5, Czech Republic, 150 06
• France
  • Avignon, France, 84918
  • Besancon, France, 25030
  • Bordeaux, France, 33076
  • Caen, France, 14076
  • Clermont Ferrand, France, 63011
  • Dijon, France, 21079
  • Lille, France, 59020
  • Montpellier, France, 34298
  • Villejuif, France, 94805
• Italy
  • Emilia-Romagna
    • Parma, Emilia-Romagna, Italy, 43100
  • Friuli-Venezia Giulia
    • Udine, Friuli-Venezia Giulia, Italy, 33100
  • Lombardia
    • Milano, Lombardia, Italy, 20133
    • Pavia, Lombardia, Italy, 27100
• Mexico
  • Acapulco, Mexico, 39850
  • Guadalajara, Mexico, 45100
  • Merida, Mexico, 97500
  • Monterrey, Mexico, 66260
  • Torreon, Mexico, 27000
• Romania
  • Bucharest, Romania, 050098
  • Bucuresti, Romania, 022328
  • Cluj Napoca, Romania, 400015
  • Cluj-Napoca, Romania, 400015
  • Iasi, Romania, 700106
• Russian Federation
  • Kazan, Russian Federation, 420029
  • Moscow, Russian Federation, 115478
  • Obninsk, Russian Federation, 249036
  • Ryazan, Russian Federation, 390011
  • Saint-Petersburg, Russian Federation, 197758
  • UFA, Russian Federation, 450054
• Spain
  • Barcelona, Spain, 08003
  • Cordoba, Spain, 14004
  • Madrid, Spain, 28046
  • Zaragoza, Spain, 50009
  • Barcelona
    • Sabadell, Barcelona, Barcelona, Spain, 08208
• Turkey
  • Izmir, Turkey, 35100
  • Sıhhiye, ANKARA, Turkey, 06100
• United Kingdom
  • Exeter, United Kingdom, EX2 5DW
  • London, United Kingdom, SE1 7EH
  • Manchester, United Kingdom, M20 4BX
  • Nottingham, United Kingdom, NG5 1PB
  • Preston, United Kingdom, PR2 9HT
  • Rhyl, United Kingdom, LL18 5UJ
  • Stoke-on-Trent, United Kingdom, ST4 6QG
  • Weston Super Mare, United Kingdom, BS23 4TQ
• Uruguay
  • Montevideo, Uruguay, 11600
  • Montevideo, Uruguay, 11200

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• adult patients, >=18 years of age;
• HER2 positive breast cancer with locally recurrent or metastatic lesions;
• eligible for chemotherapy;
• baseline LVEF >=50%.

Exclusion Criteria:

• previous chemotherapy for metastatic or locally recurrent breast cancer;
• previous radiotherapy for metastatic breast cancer (except for metastatic bone pain relief);
• other primary tumor within last 5 years, with the exception of basal or squamous skin cancer, or in situ cancer of the cervix;
• clinically significant cardiovascular disease;
• chronic daily treatment with aspirin (>325mg/day) or clopidogrel (>75mg/day).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: bevacizumab [Avastin]; 15mg/kg iv every 3 weeks; Drug: Docetaxel; 100mg/m2 iv every 3 weeks; Drug: Herceptin; 8mg/kg iv loading dose, followed by 6mg/kg iv every 3 weeks
Active Comparator: 2	Drug: Docetaxel; 100mg/m2 iv every 3 weeks; Drug: Herceptin; 8mg/kg iv loading dose, followed by 6mg/kg iv every 3 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	PFS was defined as the time from randomization to time of first documented disease progression (unequivocal progression of existing non-target lesions) or death, whichever occurred first as assessed by Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v1.0). Progressive disease is defined using RECIST v1.0 as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started. Primary PFS variable was defined based on the investigators' assessments and the statistical conclusions on the primary efficacy endpoint were based on investigator assessed PFS. PFS was estimated using Kaplan-Meier methods.	Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS was defined as the time from randomization to the date of death, regardless of the cause of death. OS was estimated using Kaplan-Meier methods.	Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)
Percentage of Participants With a Best Overall Response (OR) of Confirmed Complete Response (CR) or Partial Response (PR) in Participants With Measurable Disease at Baseline	Best OR was assessed using RECIST v1.0 criteria. Participants were classified as responders if their best OR was either confirmed CR (disappearance of all target lesions) or confirmed PR (at least a 30% decrease in the sum of the longest diameter [LD] of target lesions, taking as reference the baseline sum LD). Participants without any post-baseline assessments were regarded as non-responders. The 95% CI for the one sample binomial using Pearson-Clopper method.	Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)
Duration of Response (DR)	DR was defined as the time when response (CR or PR per RECIST v1.0) was first documented to the date of disease progression per RECIST v1.0 (unequivocal progression of existing non-target lesions) or death. Progressive disease is defined using RECIST v1.0 as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started.	Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)
Time to Treatment Failure (TTF)	TTF was defined as the time between randomization and date of disease progression (per RECIST v1.0; unequivocal progression of existing non-target lesions), death, or withdrawal of treatment due to adverse events, withdrawal of informed consent, insufficient therapeutic response, refusal of treatment/failure to co-operate, or failure to return, whichever occurred first. Progressive disease is defined using RECIST v1.0 as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started.	Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)
Functional Assessment of Cancer Therapy - Generic (FACT-G) and Functional Assessment of Cancer Therapy - Breast (FACT-B) Subscale Scores	FACT-G is core questionnaire of Functional Assessment of Chronic Illness Therapy (FACIT) measurement system to evaluate quality of life (QoL) in cancer population. FACT-G consisted of 27 questions grouped in 4 domains of general Health-Related QoL (HRQoL): Physical Well-being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB) and Functional Well-Being (FWB); each ranged from 0 (not at all) to 4 (very much). FACT-G ranged between 0-108. Since questions could be reversed coded, as appropriate, before calculating FACT-G, 0 and 108 could be considered worst and best health states. FACT -B is used for assessment of HRQoL in participants with breast cancer. It consists of 36 items, summarized to 5 subscales: 7 items for each physical, functional, social/family; all 3 ranged from 0-28, emotional (6 items) ranged from 0-24, and breast cancer subscale (9 items) ranged from 0-36. All single-item measures ranges from 0-144. High scale score represents a better QoL.	Baseline, Cycles 3, 5, 11, and post progressive disease (PD; 14 to 28 days after disease progression [up to the clinical cutoff of 30 June 2011, up to 4.75 years])
Change From Baseline for FACT-G and FACT-B	FACT-G is core questionnaire of Functional Assessment of Chronic Illness Therapy (FACIT) measurement system to evaluate quality of life (QoL) in cancer population. FACT-G consisted of 27 questions grouped in 4 domains of general Health-Related QoL (HRQoL): Physical Well-being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB) and Functional Well-Being (FWB); each ranged from 0 (not at all) to 4 (very much). FACT-G ranged between 0-108. Since questions could be reversed coded, as appropriate, before calculating FACT-G, 0 and 108 could be considered worst and best health states. FACT -B is used for assessment of HRQoL in participants with breast cancer. It consists of 36 items, summarized to 5 subscales: 7 items for each physical, functional, social/family; all 3 ranged from 0-28, emotional (6 items) ranged from 0-24, and breast cancer subscale (9 items) ranged from 0-36. All single-item measures ranges from 0-144. High scale score represents a better QoL.	Baseline, Cycles 3, 5, 11, and post PD (14 to 28 days after disease progression [up to the clinical cutoff of 30 June 2011, up to 4.75 years])

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Gianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X, Mariani P, Andre F, Chan A, Lipatov O, Chan S, Wardley A, Greil R, Moore N, Prot S, Pallaud C, Semiglazov V. AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol. 2013 May 10;31(14):1719-25. doi: 10.1200/JCO.2012.44.7912. Epub 2013 Apr 8.

Study record dates

Study Major Dates

• Study Start: September 1, 2006
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: October 20, 2006
• First Submitted That Met QC Criteria: October 20, 2006
• First Posted (Estimate): October 23, 2006

Study Record Updates

• Last Update Posted (Estimate): August 28, 2015
• Last Update Submitted That Met QC Criteria: August 21, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Docetaxel; Trastuzumab; Bevacizumab
• Other Study ID Numbers: BO20231