A Study of Bevacizumab (Avastin) in Combination With Neoadjuvant Treatment Regimens in Participants With Primary Human Epidermal Growth Factor Receptor 2 (HER2) Negative Breast Cancer

A Multicenter, Randomized, Phase II Clinical Trial to Evaluate the Effect of Avastin in Combination With Neoadjuvant Treatment Regimens on the Molecular and Metabolic Characteristics and Changes in the Primary Tumors With Reference to the Obtained Responses in Patients With Large Primary HER2 Negative Breast Cancers

This study will evaluate the effect of bevacizumab in combination with chemotherapy or endocrine therapy, as preoperative treatment, in participants with HER2 negative breast cancer. Participants will be randomized to receive either chemotherapy (FEC100: Epirubicine 100 milligrams per square meter [mg/m^2], 5-fluorouracil 600 mg/m^2, and cyclophosphamide 600 mg/m^2] for 12 weeks followed by taxane (paclitaxel/docetaxel) for 12 weeks or endocrine therapy (an aromatase inhibitor] daily for 24 weeks) with or without bevacizumab (15 milligrams per kilogram [mg/kg] as intravenous [IV] infusion every 3 weeks up 24 weeks).

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Epirubicine; Drug: 5-Fluorouracil (5FU); Drug: Cyclophosphamide; Drug: Paclitaxel; Drug: Docetaxel; Drug: Bevacizumab; Drug: Aromatase Inhibitor

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 2

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, 0379
    • The Norvegian Radium Hospital Montebello; Dept of Oncology
  • Oslo, Norway, 0407
    • Ullevael Sykehus; Dept of Oncology
  • Trondheim, Norway, 7000
    • St. Olavs Hospital; Kreftavdelingen

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:

• Histologically or cytologically confirmed, HER2-negative, men or pre- or post-menopausal women with primary operable adenocarcinoma of the breast, greater than or equal to (>=) 2.5 centimeters (cm) in size
• Eastern Cooperative Oncology Group (ECOG)/world health organization (WHO) performance status less than or equal to (</=) 2
• Normal baseline cardiac function (Left Ventricular Ejection Fraction [LVEF])

Exclusion Criteria:

• Stage IV (metastatic) disease
• Previous treatment for localized breast cancer less than (<) 24 months from diagnosis of present breast cancer
• Other previous or current cancer except for basal cell cancer or in situ cervical cancer
• Current or recent use of aspirin (greater than [>] 325 milligrams per day)
• Clinically significant cardiovascular disease

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

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Chemotherapy; Participants will receive epirubicine, 5-fluorouracil, and cyclophosphamide (FEC 100) for 12 weeks followed by taxane therapy (paclitaxel or docetaxel) for next 12 weeks.	Drug: Epirubicine; Participants will receive epirubicine at a dose of 100 mg/m^2 as IV infusion every 3 weeks for 12 weeks.; Drug: 5-Fluorouracil (5FU); Participants will receive 5FU at a dose of 600 mg/m^2 as IV infusion every 3 weeks for 12 weeks.; Drug: Cyclophosphamide; Participants will receive cyclophosphamide at a dose of 600 mg/m^2 as IV infusion every 3 weeks for 12 weeks.; Drug: Paclitaxel; Participants will receive paclitaxel at a dose of 80 mg/m^2 as IV infusion every week for 12 weeks.; Drug: Docetaxel; Participants will receive docetaxel at a dose of 100 mg/m^2 as IV infusion every 3 weeks for 12 weeks.
Experimental: Chemotherapy and Bevacizumab; Participants will receive epirubicine, 5-fluorouracil, and cyclophosphamide (FEC 100) for 12 weeks followed by taxane therapy (paclitaxel or docetaxel) for next 12 weeks. Participants will also receive concurrent treatment with bevacizumab every 3 weeks for 24 weeks.	Drug: Epirubicine; Participants will receive epirubicine at a dose of 100 mg/m^2 as IV infusion every 3 weeks for 12 weeks.; Drug: 5-Fluorouracil (5FU); Participants will receive 5FU at a dose of 600 mg/m^2 as IV infusion every 3 weeks for 12 weeks.; Drug: Cyclophosphamide; Participants will receive cyclophosphamide at a dose of 600 mg/m^2 as IV infusion every 3 weeks for 12 weeks.; Drug: Paclitaxel; Participants will receive paclitaxel at a dose of 80 mg/m^2 as IV infusion every week for 12 weeks.; Drug: Docetaxel; Participants will receive docetaxel at a dose of 100 mg/m^2 as IV infusion every 3 weeks for 12 weeks.; Drug: Bevacizumab; Bevacizumab will be administered at a dose of 15 mg/kg as IV infusion every 3 weeks (or 10 mg/kg every other week in participants receiving weekly paclitaxel), for 24 weeks.; Other Names: Avastin
Active Comparator: Endocrine Therapy; Participants will receive aromatase inhibitor therapy at discretion of the investigator for a period of 24 weeks.	Drug: Aromatase Inhibitor; Participants will receive aromatase inhibitor therapy, at a dose per investigator discretion, once daily for 24 weeks.
Experimental: Endocrine Therapy and Bevacizumab; Participants will receive aromatase inhibitor therapy at discretion of the investigator and concurrent treatment with bevacizumab for a period of 24 weeks.	Drug: Bevacizumab; Bevacizumab will be administered at a dose of 15 mg/kg as IV infusion every 3 weeks (or 10 mg/kg every other week in participants receiving weekly paclitaxel), for 24 weeks.; Other Names: Avastin; Drug: Aromatase Inhibitor; Participants will receive aromatase inhibitor therapy, at a dose per investigator discretion, once daily for 24 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of Participants With Messenger Ribonucleic Acid (mRNA) Markers of Pathological Complete Response, as Assessed by Magnetic Resonance Imaging (MRI)	Baseline up to end of study treatment (approximately 24 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Objective Pathological Complete Response, as Assessed by Clinical Assessment		Baseline up to end of study treatment (approximately 24 weeks)
Percentage of Participants With Type of Surgery	Percentage of participants with different surgery types (for example, Mastectomy, Tumorectomy/Breast conserving therapy (BCT), and Tumorectomy followed by mastectomy) will be reported.	At Surgery (Between Weeks 24 and 25)
Percentage of Participants With Axillary Lymph Node Dissection Performed		At Surgery (Between Weeks 24 and 25)
Pathological Tumor Size, as Assessed by Histopathological Examination		At Surgery (Between Weeks 24 and 25)
Percentage of Participants With Presence of Tumor Cells Close to Resection Margin		At Surgery (Between Weeks 24 and 25)
Percentage of Participants With Tumor Deposit in Other Body Parts		At Surgery (Between Weeks 24 and 25)
Tumor Free Resection Margin		At Surgery (Between Weeks 24 and 25)
Pathological Tumor Size as Measure Using Caliper		Cycles 1 to 10 (cycle length=21 days), and Week 25
Pathological Tumor Size as Measure Using MRI		Baseline, Weeks 12 and 25
Pathological Tumor Size as Measure Using Mamography		Baseline, Weeks 12 and 25
Pathological Breast Tumor Size as Measure Using Ultrasound		Baseline, Weeks 12 and 25
Pathological Axilla Tumor Size as Measure Using Ultrasound		Baseline, Weeks 12 and 25
Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status		Screening, Cycles 1 to 10 (cycle length=21 days), and Week 25
Percentage of Participants With Lymph Node Involvement		Cycles 1 to 10 (cycle length=21 days), and Week 25
Percentage of Participants With Objective Tumor Response, as Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST)		Weeks 12 and 25
Percentage of Participants With New Lesions		Weeks 12 and 25
Percentage of Participants With Molecular Changes in Protein Kinase Expression		Baseline up to end of study treatment (approximately 24 weeks)
Percentage of Participants With Molecular Changes in Messenger Ribonucleic Acid (mRNA)/microRNA(miRNA)		Baseline up to end of study treatment (approximately 24 weeks)
Percentage of Participants With Molecular Changes in Protein Expression		Baseline up to end of study treatment (approximately 24 weeks)
Percentage of Participants With Single Nucleotide Polymorphism (SNP) Profiles Predicting Treatment Response		Baseline up to end of study treatment (approximately 24 weeks)
Percentage of Participants With Treatment-Induced Changes in Tumor Cells as Determined by Number of Disseminated Tumor Cells in Bone Marrow		Baseline up to end of study treatment (approximately 24 weeks)
Percentage of Participants With Treatment-Induced Changes in Tumor Cells as Determined by Number of Circulating Tumor Cells in Peripheral Blood		Baseline up to end of study treatment (approximately 24 weeks)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Collaborators: Norwegian Radium Hospital

Publications and helpful links

General Publications

• Hoglander EK, Nord S, Wedge DC, Lingjaerde OC, Silwal-Pandit L, Gythfeldt HV, Vollan HKM, Fleischer T, Krohn M, Schlitchting E, Borgen E, Garred O, Holmen MM, Wist E, Naume B, Van Loo P, Borresen-Dale AL, Engebraaten O, Kristensen V. Time series analysis of neoadjuvant chemotherapy and bevacizumab-treated breast carcinomas reveals a systemic shift in genomic aberrations. Genome Med. 2018 Nov 29;10(1):92. doi: 10.1186/s13073-018-0601-y.
• Reinertsen KV, Engebraaten O, Loge JH, Cvancarova M, Naume B, Wist E, Edvardsen H, Wille E, Bjoro T, Kiserud CE. Fatigue During and After Breast Cancer Therapy-A Prospective Study. J Pain Symptom Manage. 2017 Mar;53(3):551-560. doi: 10.1016/j.jpainsymman.2016.09.011. Epub 2016 Dec 29.

Study record dates

Study Major Dates

• Study Start (Actual): November 7, 2008
• Primary Completion (Actual): November 9, 2022
• Study Completion (Actual): November 9, 2022

Study Registration Dates

• First Submitted: October 15, 2008
• First Submitted That Met QC Criteria: October 15, 2008
• First Posted (Estimate): October 16, 2008

Study Record Updates

• Last Update Posted (Estimate): January 9, 2023
• Last Update Submitted That Met QC Criteria: January 5, 2023
• Last Verified: January 1, 2023

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; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antibiotics, Antineoplastic; Hormone Antagonists; Steroid Synthesis Inhibitors; Estrogen Antagonists; Docetaxel; Cyclophosphamide; Paclitaxel; Fluorouracil; Epirubicin; Bevacizumab; Aromatase Inhibitors
• Other Study ID Numbers: ML21744