Beverly1: Efficacy and Tolerance Study of Bevacizumab in Her2- Inflammatory Breast Cancer Patients

Sponsor

UNICANCER (Other)

Overall Status

Completed

CT.gov ID

NCT00820547

Collaborator

(none)

100

Enrollment

Locations

Arm

128

Actual Duration (Months)

3.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab and combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving bevacizumab and radiation therapy after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This phase II trial is studying giving bevacizumab together with chemotherapy before surgery and bevacizumab and radiation therapy after surgery to see how well it works in treating patients with inflammatory breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Biological: bevacizumab Drug: cyclophosphamide Drug: docetaxel Drug: epirubicin hydrochloride Drug: fluorouracil	Phase 2

Detailed Description

OBJECTIVES:

Primary

Evaluate the complete histological response rate in patients with inflammatory HER2-negative breast cancer treated with bevacizumab and concurrent chemotherapy followed by bevacizumab and concurrent hormonal therapy after surgery and radiotherapy.

Secondary

Evaluate the progression-fee and overall survival of these patients at 3 and 5 years.
Evaluate the tolerance of bevacizumab in these patients.
Assess circulating metastatic disease before, during, and after treatment.
Assess circulating endothelial cells before, during, and after treatment.
Assess predictive factors of response by genomic and proteomic studies on frozen tumor samples and fluid samples (i.e., serum and plasma).

OUTLINE: This is a multicenter study.

Neoadjuvant induction therapy:
Courses 1-4: Patients receive bevacizumab IV over 30-90 minutes, fluorouracil IV, epirubicin hydrochloride IV over 10 minutes, and cyclophosphamide IV over 5 minutes on day 1.
Courses 5-8: Patients receive bevacizumab IV over 30-90 minutes and docetaxel IV over 1 hour on day 1.

Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.

Surgery: Patients undergo surgery 4-6 weeks after completion of bevacizumab.
Adjuvant therapy: Beginning 2-4 weeks after surgery, patients undergo radiotherapy for 6 weeks. Patients also receive bevacizumab IV over 30-90 minutes beginning 2-4 weeks after surgery, during the radiotherapy period. Treatment with bevacizumab repeats every 3 weeks for 30 weeks in the absence of disease progression or unacceptable toxicity. Patients who are estrogen receptor- or progesterone receptor-positive (≥ 10% by IHC) receive the following concurrent hormonal therapy beginning in week 7:
Premenopausal patients: Patients receive tamoxifen citrate for 5 years.
Postmenopausal patients: Patients receive aromatase-inhibitor therapy (or tamoxifen citrate if unable to tolerate anti-aromatase therapy) for 5 years.
Perimenopausal patients: Patients receive tamoxifen citrate for 2-3 years and aromatase-inhibitor therapy for 2-3 years OR tamoxifen citrate for 5 years followed by aromatase-inhibitor therapy for 2-3 years (if follicle-stimulating hormone > 30 IU/L and/or estradiol < 30 ng/L).

After completion of study treatment, patients are followed for at least 3 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

100 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase II Study Evaluating the Efficacy and Tolerance of Bevacizumab (Avastin) in HER2- Inflammatory Breast Cancer

Actual Study Start Date :

Jan 1, 2009

Actual Primary Completion Date :

Apr 1, 2015

Actual Study Completion Date :

Sep 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: (FEC / Docetaxel) + Bevacizumab Neoadjuvant treatment: 4 cycles FEC + Bevacizumab followed by 4 cycles Docetaxel + Bevacizumab Adjuvant: Bevacizumab for 1 year	Biological: bevacizumab During neoadjuvant phase: 15 mg/kg, d1 q3w, 8 cycles During adjuvant phase:15 mg/kg, d1 q3w, 10 cycles Drug: cyclophosphamide Neoadjuvant: 500 mg/m2 d1 q3w, 4 cycles Drug: docetaxel Neoadjuvant: 100 mg/m2 q3w, 4 cycles Drug: epirubicin hydrochloride Neoadjuvant: 100 mg/m2, d1 q3w, 4 cycles Drug: fluorouracil Neoadjuvant: 500 mg/m2, d1 q3w, 4 cycles

Arm

Intervention/Treatment

Experimental: (FEC / Docetaxel) + Bevacizumab

Neoadjuvant treatment: 4 cycles FEC + Bevacizumab followed by 4 cycles Docetaxel + Bevacizumab Adjuvant: Bevacizumab for 1 year

Biological: bevacizumab

During neoadjuvant phase: 15 mg/kg, d1 q3w, 8 cycles During adjuvant phase:15 mg/kg, d1 q3w, 10 cycles

Drug: cyclophosphamide

Neoadjuvant: 500 mg/m2 d1 q3w, 4 cycles

Drug: docetaxel

Neoadjuvant: 100 mg/m2 q3w, 4 cycles

Drug: epirubicin hydrochloride

Neoadjuvant: 100 mg/m2, d1 q3w, 4 cycles

Drug: fluorouracil

Neoadjuvant: 500 mg/m2, d1 q3w, 4 cycles

Outcome Measures

Primary Outcome Measures

Complete histologic response rate [Post surgery]

Secondary Outcome Measures

Progression-free survival [3 and 5 years]
Overall survival [3 and 5 years]
Toxicity as assessed by CTCAE v3.0 [3 and 5 years]
Predictive factors of response to bevacizumab [3 and 5 years]
Circulating peripheral cells (circulating endothelial and tumor cells): correlation of initial rate and association with histological response after surgery [Post-surgery]
Genomic and proteomic analyses and correlation with histologic response [Post surgery]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed inflammatory breast cancer, meeting 1 of the following staging criteria:
T4d, any N (AJCC stage IIIB or IIIC)
Gustave-Roussy Institute (IGR) classification Poussee evolutirie (PEV; measures tumor growth over time) 2
PEV 2: tumor with underlying breast tissue, especially skin, that is affected by subacute inflammation and edema involving < ½ of breast surface
IGR classification PEV 3
PEV 3: acute or subacute inflammation and edema involving > ½ of breast surface
Biopsy-confirmed presence of tumor embolism in surface lymph nodes
HER2-negative (HER2 0 or 1+, or HER2 2+ by IHC if FISH-negative allowed)
No metastatic disease
No non-inflammatory breast cancer with edema, ulceration, or satellite skin nodules
No bilateral breast cancer
Hormone receptor status known

PATIENT CHARACTERISTICS:

Any menopausal status allowed
WHO performance status 0-2
Life expectancy ≥3 months
LVEF normal by ECHO
ANC >1.5 x 10^9/L
Platelet count >100 x 10^9/L
INR ≤1.5 (except for patients on prophylactic anticoagulants)
aPTT ≤1.5 times upper limit of normal (ULN)
Total bilirubin normal
SGOT and SGPT ≤1.25 times ULN
Alkaline phosphatase ≤2.5 times ULN
Creatinine clearance ≥60 mL/min
Proteinuria <2+ or 24-hour urine protein ≤1 g
No unhealed wound, stomach ulcer, or bone fracture
No history of thrombotic or hemorrhagic disorders
No significant cardiovascular disease including the following:
Cerebrovascular accident within the past 6 months
Unstable angina
Cardiac failure
Myocardial infarction
Arrhythmia requiring treatment
No uncontrolled hypertension (i.e., systolic BP >150 mm Hg and/or diastolic BP >100 mm Hg)
No other active infection or serious illness that would preclude patient from receiving study treatment
No hypersensitivity to any active products or excipients of study drugs
Not pregnant or nursing
Fertile patients must use effective contraception during and for 6 months after completion of study treatment
No social or psychologic reasons that would prevent study compliance or follow-up
No patients who are incarcerated or on probation

PRIOR CONCURRENT THERAPY:

No prior chemotherapy, radiotherapy, or hormonal therapy for this disease
More than 4 weeks since prior surgery (diagnostic biopsy or installation of implant allowed)
More than 10 days since prior chronic non-inflammatory steroids (e.g., acetylsalicylic acid >325 mg/day) or platelet anticoagulation treatment (e.g., dipyridamole, ticlopidine, clodiprogel, cilostazol)
More than 10 days since prior oral or parenteral anticoagulant or thrombolytic drugs (preventative thrombolytic drugs allowed)
No concurrent participation in another experimental clinical trial

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Centre Paul Papin	Angers	France	49036
2	Institut Sainte Catherine	Avignon	France	84000
3	Centre Hospitalier Regional de Besancon - Hopital Jean Minjoz	Besancon	France	25030
4	Institut Bergonie	Bordeaux	France	33076
5	Polyclinique Bordeaux Nord Aquitaine	Bordeaux	France	33300
6	Centre Regional Francois Baclesse	Caen	France	14076
7	Centre Jean Perrin	Clermont-Ferrand	France	63011
8	Centre de Lutte Contre le Cancer Georges-Francois Leclerc	Dijon	France	21079
9	CMC Les Ormeaux	Le Havre	France	76600
10	Centre Oscar Lambret	Lille	France	59020
11	Centre Leon Berard	Lyon	France	69373
12	Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes	Marseille	France	13273
13	Centre Hospitalier General Andre Boulloche	Montbeliard	France	25209
14	Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle	Montpellier	France	34298
15	Centre Catherine de Sienne	Nantes	France	02
16	Centre Antoine Lacassagne	Nice	France	06189
17	Institut Curie Hopital	Paris	France	75248
18	Institut Jean Godinot	Reims	France	51056
19	Centre Eugene Marquis	Rennes	France	35042
20	Centre Henri Becquerel	Rouen	France	76038
21	Clinique Armoricaine De Radiologie	Saint Brieuc	France	F-22015
22	Centre Rene Huguenin	Saint Cloud	France	92211
23	CRLCC Nantes - Atlantique	Saint-Herblain	France	44805
24	Centre Paul Strauss	Strasbourg	France	67065
25	Hopitaux Universitaire de Strasbourg	Strasbourg	France	67091
26	Institut Claudius Regaud	Toulouse	France	31052
27	Centre Alexis Vautrin	Vandoeuvre-les-Nancy	France	54511
28	Institut Gustave Roussy	Villejuif	France	F-94805