Clinical trial NCT00262067: A Study Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy in Untreated Metastatic Breast Cancer (RIBBON 1)
Official title: A Multicenter, Phase III, Randomized, Placebo-controlled Trial Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy Regimens in Subjects With Previously Untreated Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Metastatic Breast Cancer
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2005-12-06
Enrollment: 1237
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: Progression-free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)
Secondary outcomes:
measure: Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)
measure: Duration of Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)
measure: Overall Survival
timeFrame: Baseline to the data cut-off of 23 Feb 2009 (up to 3 years, 2 months)
measure: 1-year Survival
timeFrame: Baseline to the data cut-off of 23 Feb 2009 (up to 3 years, 2 months)
measure: Progression-free Survival (PFS) as Determined by the Independent Review Committee Using Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)
Other outcomes:
Locations:
city: Fullerton
country: United States
state: California
city: Santa Barbara
country: United States
state: California
city: Iowa City
country: United States
state: Iowa
city: Sioux City
country: United States
state: Iowa
city: Wichita
country: United States
state: Kansas
city: Geelong
country: Australia
city: Malvern
country: Australia
city: Melbourne
country: Australia
city: Perth
country: Australia
city: Southport
country: Australia
city: Wahroonga
country: Australia
city: Waratah
country: Australia
city: Wollongong
country: Australia
city: Porto Alegre
country: Brazil
city: Rio de Janeiro
country: Brazil
city: Salvador
country: Brazil
city: Santo Andre
country: Brazil
city: Sao Paulo
country: Brazil
city: Winnipeg
country: Canada
state: Manitoba
city: Montreal
country: Canada
state: Quebec
city: Montreal
country: Canada
state: Quebec
city: Marseille
country: France
city: Paris
country: France
city: Reims
country: France
city: Saint Herblain
country: France
city: Strasbourg
country: France
city: Athens
country: Greece
city: Hania
country: Greece
city: Heraklion
country: Greece
city: Patras
country: Greece
city: Thessaloniki
country: Greece
city: Guatemala City
country: Guatemala
city: Kyunggi-do
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Acapulco
country: Mexico
city: Aguascalientes
country: Mexico
city: Merida
country: Mexico
city: Monterrey
country: Mexico
city: Monterrey
country: Mexico
city: Amstelveen
country: Netherlands
city: Apeldoorn
country: Netherlands
city: Delft
country: Netherlands
city: Oslo
country: Norway
city: Oslo
country: Norway
city: Panama City
country: Panama
city: Callao
country: Peru
city: Quezon City
country: Philippines
city: Chelyabinsk
country: Russian Federation
city: Ivanovo
country: Russian Federation
city: Kazan
country: Russian Federation
city: Kazan
country: Russian Federation
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
city: Novosibirsk
country: Russian Federation
city: Obninsk
country: Russian Federation
city: Ryazan
country: Russian Federation
city: Samara
country: Russian Federation
city: St Petersburg
country: Russian Federation
city: UFA
country: Russian Federation
city: Singapore
country: Singapore
city: Singapore
country: Singapore
city: Córdoba
country: Spain
city: Elche
country: Spain
city: Girona
country: Spain
city: La Coruna
country: Spain
city: La Laguna
country: Spain
city: Madrid
country: Spain
city: Santander
country: Spain
city: Sevilla
country: Spain
city: Valencia
country: Spain
city: Zaragoza
country: Spain
city: Gaevle
country: Sweden
city: Uppsala
country: Sweden
city: Örebro
country: Sweden
city: Tainan
country: Taiwan
city: Taoyuan
country: Taiwan
city: Cherkassy
country: Ukraine
city: Dnipropetrovsk
country: Ukraine
city: Kiev
country: Ukraine
city: Lvov
country: Ukraine
city: Odessa
country: Ukraine
city: Zaporozhye
country: Ukraine
city: Chelsmford
country: United Kingdom
city: Cottingham
country: United Kingdom
city: Epping
country: United Kingdom
city: Huddersfield
country: United Kingdom
city: Nottingham
country: United Kingdom
city: Sheffield
country: United Kingdom
city: Swansea
country: United Kingdom
city: Montevideo
country: Uruguay
Study officials:
affiliation: Genentech, Inc.
name: Leonardo Faoro, MD
role: STUDY_DIRECTOR
References:
citation: 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.