A Study Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy in Untreated Metastatic Breast Cancer (RIBBON 1)

NCT ID: NCT00262067

Last Updated: 2013-12-13

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 1237 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-12-31
• Study Completion Date: 2013-12-31

Brief Summary

This is a Phase III, multicenter, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of bevacizumab in combination with chemotherapy compared with chemotherapy alone in subjects with previously untreated metastatic breast cancer.

Detailed Description

This study includes a blinded treatment phase, an optional open-label post-progression phase, and a survival follow-up phase. During the blinded treatment phase, patients receive chemotherapy and study drug (bevacizumab or placebo) every 3 weeks until disease progression, treatment-limiting toxicity, or death due to any cause. The optional open-label post-progression phase consists of chemotherapy treatment (per investigator discretion) and optional treatment with open-label bevacizumab. Patients who complete the study or who discontinue from treatment (regardless of participation in the optional open-label post-progression phase) will be followed for survival and subsequent anti-cancer therapies every 4 months until death, withdrawal of consent, loss to follow-up, or study termination. Patients who discontinue from treatment during the blinded treatment phase for reasons other than disease progression will have tumor assessments every 9 weeks until documented disease progression or death.

Conditions

Metastatic Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Bevacizumab + chemotherapy

Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle plus one of several standard chemotherapies (taxanes, anthracycline-based regimens, or capecitabine) for metastatic breast cancer.

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: DRUG

Patients received bevacizumab until disease progression, treatment limiting toxicity, or death due to any cause up to a maximum treatment duration of 48 months. The dose of bevacizumab was based on the patient's weight at either screening or baseline and remained the same throughout the blinded treatment phase of the study. The initial dose was delivered over 90±10 minutes. If there were no infusion related adverse events (fever and/or chills), the second infusion was delivered over 60±10 minutes. If the 60 minute infusion was well tolerated, all subsequent infusions were delivered over 30±10 minutes.

Chemotherapy

Intervention Type: DRUG

The chemotherapy was selected by the investigator prior to randomization. Chemotherapy treatment continued until disease progression, unacceptable toxicity, investigator/patient decision, or death, whichever occurred first, except for the anthracycline-based regimens, which had a maximum treatment duration of 8 cycles.

Taxanes - 1 of the following 2 taxanes on Day 1 of every 21-day cycle

1. Docetaxel 75-100 mg/m^2 IV

2. Paclitaxel protein-bound particles (Abraxane®) 260 mg/m^2 IV

Anthracyclines - 1 of the following 4 anthracycline-based regimens on Day 1 of every 21-day cycle

1. 5-fluorouracil 500 mg/m^2 IV + epirubicin 90-100 mg/m^2 IV + cyclophosphamide 500 mg/m^2 IV

2. 5-fluorouracil 500 mg/m^2 IV + doxorubicin 50 mg/m^2 IV + cyclophosphamide 500 mg/m^2 IV

3. Doxorubicin 50-60 mg/m^2 IV + cyclophosphamide 500-600 mg/m^2 IV

4. Epirubicin 90-100 mg/m^2 IV + cyclophosphamide 500-600 mg/m^2 IV

Capecitabine: 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day cycle

Placebo + chemotherapy

Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + 1 of several standard chemotherapies (taxanes, anthracycline-based regimens, or capecitabine) for metastatic breast cancer.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo consisted of the vehicle for bevacizumab without the antibody.

Chemotherapy

Intervention Type: DRUG

The chemotherapy was selected by the investigator prior to randomization. Chemotherapy treatment continued until disease progression, unacceptable toxicity, investigator/patient decision, or death, whichever occurred first, except for the anthracycline-based regimens, which had a maximum treatment duration of 8 cycles.

Taxanes - 1 of the following 2 taxanes on Day 1 of every 21-day cycle

1. Docetaxel 75-100 mg/m^2 IV

2. Paclitaxel protein-bound particles (Abraxane®) 260 mg/m^2 IV

Anthracyclines - 1 of the following 4 anthracycline-based regimens on Day 1 of every 21-day cycle

1. 5-fluorouracil 500 mg/m^2 IV + epirubicin 90-100 mg/m^2 IV + cyclophosphamide 500 mg/m^2 IV

2. 5-fluorouracil 500 mg/m^2 IV + doxorubicin 50 mg/m^2 IV + cyclophosphamide 500 mg/m^2 IV

3. Doxorubicin 50-60 mg/m^2 IV + cyclophosphamide 500-600 mg/m^2 IV

4. Epirubicin 90-100 mg/m^2 IV + cyclophosphamide 500-600 mg/m^2 IV

Capecitabine: 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day cycle

Interventions

Bevacizumab

Patients received bevacizumab until disease progression, treatment limiting toxicity, or death due to any cause up to a maximum treatment duration of 48 months. The dose of bevacizumab was based on the patient's weight at either screening or baseline and remained the same throughout the blinded treatment phase of the study. The initial dose was delivered over 90±10 minutes. If there were no infusion related adverse events (fever and/or chills), the second infusion was delivered over 60±10 minutes. If the 60 minute infusion was well tolerated, all subsequent infusions were delivered over 30±10 minutes.

Intervention Type: DRUG

Placebo

Placebo consisted of the vehicle for bevacizumab without the antibody.

Intervention Type: DRUG

Chemotherapy

The chemotherapy was selected by the investigator prior to randomization. Chemotherapy treatment continued until disease progression, unacceptable toxicity, investigator/patient decision, or death, whichever occurred first, except for the anthracycline-based regimens, which had a maximum treatment duration of 8 cycles.

Taxanes - 1 of the following 2 taxanes on Day 1 of every 21-day cycle

1. Docetaxel 75-100 mg/m^2 IV

2. Paclitaxel protein-bound particles (Abraxane®) 260 mg/m^2 IV

Anthracyclines - 1 of the following 4 anthracycline-based regimens on Day 1 of every 21-day cycle

1. 5-fluorouracil 500 mg/m^2 IV + epirubicin 90-100 mg/m^2 IV + cyclophosphamide 500 mg/m^2 IV

2. 5-fluorouracil 500 mg/m^2 IV + doxorubicin 50 mg/m^2 IV + cyclophosphamide 500 mg/m^2 IV

3. Doxorubicin 50-60 mg/m^2 IV + cyclophosphamide 500-600 mg/m^2 IV

4. Epirubicin 90-100 mg/m^2 IV + cyclophosphamide 500-600 mg/m^2 IV

Capecitabine: 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day cycle

Intervention Type: DRUG

Other Intervention Names

Avastin

Eligibility Criteria

Inclusion Criteria

• Histologically or cytologically confirmed adenocarcinoma of the breast, with measurable or non-measurable locally recurrent or metastatic disease.
• Signed Informed Consent Form.
• Age ≥ 18 years.
• For women of childbearing potential, use of accepted and effective method of non-hormonal contraception.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Ability and capacity to comply with study and follow-up procedures.
• For anthracycline cohort only: Adequate left ventricular function at study entry, defined as a left ventricular ejection fraction (LVEF) ≥ 50% by either multigated acquisition (MUGA) scan scan or echocardiography (ECHO).
• For subjects who have received recent radiation therapy, recovery prior to baseline (Day 0) from any significant (Grade ≥ 3) acute toxicity.

Exclusion Criteria

• Unknown human epidermal growth factor receptor 2 (HER2) status or known HER2-positive status.
• Prior chemotherapy for locally recurrent or metastatic disease.
• Prior hormonal therapy less than 1 week prior to Day 0.
• Prior adjuvant or neoadjuvant chemotherapy within 12 months prior to Day 0.
• For anthracycline cohort only: Prior anthracycline as part of neoadjuvant or adjuvant therapy for localized breast cancer.
• Investigational therapy within 28 days of Day 0.
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, or anticipation of need for major surgical procedure during the course of the study.
• Minor surgical procedures, such as fine needle aspirations or core biopsies, within 7 days prior to Day 0.
• Prior therapy with bevacizumab, sorafenib, sunitinib, or other vascular endothelial growth factor (VEGF) pathway-targeted therapy.
• Known brain or other central nervous system (CNS) metastases.
• Blood pressure of > 150/100 mmHg.
• Unstable angina.
• New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF).
• History of myocardial infarction within 6 months prior to Day 0.
• History of stroke or transient ischemic attack within 6 months prior to Day 0.
• Clinically significant peripheral vascular disease.
• Evidence of bleeding diathesis or coagulopathy.
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0.
• Serious non-healing wound, ulcer, or bone fracture.
• Pregnancy (positive serum pregnancy test) or lactation.
• Inadequate organ function, as evidenced by any of the following laboratory values: Absolute neutrophil count < 1500/uL; platelet count < 100,000/uL; total bilirubin > 1.5 mg/dL; alkaline phosphatase, AST, and/or ALT > 2x upper limit of normal (ULN) (> 5x ULN in subjects with known liver or, for alkaline phosphatase elevations, bone involvement); alkaline phosphatase > 2x ULN (> 7x ULN in subjects with known bone involvement); serum creatinine > 2.0 mg/dL; partial thromboplastin time (PTT) and/or either international normalized ratio (INR) or prothrombin time (PT) > 1.5x upper limit of normal (except for subjects receiving anti-coagulation therapy); urine protein/creatinine ratio > 1.0 at screening for U.S. subjects, or urine dipstick for proteinuria >/= 1+ at screening followed by 24-hour urine collection demonstrating > 1 g protein/24 hr for ex-U.S. subjects.
• Uncontrolled serious medical or psychiatric illness.
• Active infection requiring intravenous (iv) antibiotics at Day 0.
• History of other malignancies within 5 years of Day 0 except for tumors with a negligible risk for metastasis or death, such as adequately controlled basal cell carcinoma or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix (subjects with a history of bilateral breast cancer will be eligible).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genentech, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Leonardo Faoro, MD

Role: STUDY_DIRECTOR

Genentech, Inc.

Locations

Fullerton, California, United States

Santa Barbara, California, United States

Iowa City, Iowa, United States

Sioux City, Iowa, United States

Wichita, Kansas, United States

Geelong, , Australia

Malvern, , Australia

Melbourne, , Australia

Perth, , Australia

Southport, , Australia

Wahroonga, , Australia

Waratah, , Australia

Wollongong, , Australia

Porto Alegre, , Brazil

Rio de Janeiro, , Brazil

Salvador, , Brazil

Santo André, , Brazil

São Paulo, , Brazil

Winnipeg, Manitoba, Canada

Montreal, Quebec, Canada

Montreal, Quebec, Canada

Marseille, , France

Paris, , France

Reims, , France

Saint-Herblain, , France

Strasbourg, , France

Athens, , Greece

Chania, , Greece

Heraklion, , Greece

Pátrai, , Greece

Thessaloniki, , Greece

Guatemala City, , Guatemala

Acapulco, , Mexico

Aguascalientes, , Mexico

Mérida, , Mexico

Monterrey, , Mexico

Monterrey, , Mexico

Amstelveen, , Netherlands

Apeldoorn, , Netherlands

Delft, , Netherlands

Oslo, , Norway

Oslo, , Norway

Panama City, , Panama

Callao, , Peru

Quezon City, , Philippines

Chelyabinsk, , Russia

Ivanovo, , Russia

Kazan', , Russia

Kazan', , Russia

Moscow, , Russia

Moscow, , Russia

Moscow, , Russia

Novosibirsk, , Russia

Obninsk, , Russia

Ryazan, , Russia

Saint Petersburg, , Russia

Samara, , Russia

Ufa, , Russia

Singapore, , Singapore

Singapore, , Singapore

Kyunggi-do, , South Korea

Seoul, , South Korea

Seoul, , South Korea

A Coruña, , Spain

Córdoba, , Spain

Elche, , Spain

Girona, , Spain

Madrid, , Spain

San Cristóbal de La Laguna, , Spain

Santander, , Spain

Seville, , Spain

Valencia, , Spain

Zaragoza, , Spain

Gävle, , Sweden

Örebro, , Sweden

Uppsala, , Sweden

Tainan City, , Taiwan

Taoyuan District, , Taiwan

Cherkassy, , Ukraine

Dnipropetrovsk, , Ukraine

Kiev, , Ukraine

Lviv, , Ukraine

Odesa, , Ukraine

Zaporizhzhya, , Ukraine

Chelsmford, , United Kingdom

Cottingham, , United Kingdom

Epping, , United Kingdom

Huddersfield, , United Kingdom

Nottingham, , United Kingdom

Sheffield, , United Kingdom

Swansea, , United Kingdom

Montevideo, , Uruguay

Countries

United States; Australia; Brazil; Canada; France; Greece; Guatemala; Mexico; Netherlands; Norway; Panama; Peru; Philippines; Russia; Singapore; South Korea; Spain; Sweden; Taiwan; Ukraine; United Kingdom; Uruguay

References

Wedam SB, Beaver JA, Amiri-Kordestani L, Bloomquist E, Tang S, Goldberg KB, Sridhara R, Ibrahim A, Kim G, Kluetz P, McKee A, Pazdur R. US Food and Drug Administration Pooled Analysis to Assess the Impact of Bone-Only Metastatic Breast Cancer on Clinical Trial Outcomes and Radiographic Assessments. J Clin Oncol. 2018 Apr 20;36(12):1225-1231. doi: 10.1200/JCO.2017.74.6917. Epub 2018 Mar 9.

Reference Type: DERIVED

PMID: 29522361 (View on PubMed)

Other Identifiers

BO20094

Identifier Type: OTHER

Identifier Source: secondary_id

AVF3694g

Identifier Type: -

Identifier Source: org_study_id