Clinical trial NCT00820547: Efficacy and Tolerance Study of Bevacizumab in Her2- Inflammatory Breast Cancer Patients
Official title: Phase II Study Evaluating the Efficacy and Tolerance of Bevacizumab (Avastin) in HER2- Inflammatory Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: inflammatory breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
male breast cancer
HER2-negative breast cancer
Lead sponsor: UNICANCER
Sponsor class: OTHER
First posted: 2009-01-12
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Complete histologic response rate
timeFrame: Post surgery
Secondary outcomes:
measure: Progression-free survival
timeFrame: 3 and 5 years
measure: Overall survival
timeFrame: 3 and 5 years
measure: Toxicity as assessed by CTCAE v3.0
timeFrame: 3 and 5 years
measure: Predictive factors of response to bevacizumab
timeFrame: 3 and 5 years
measure: Circulating peripheral cells (circulating endothelial and tumor cells): correlation of initial rate and association with histological response after surgery
timeFrame: Post-surgery
measure: Genomic and proteomic analyses and correlation with histologic response
timeFrame: Post surgery
Other outcomes:
Locations:
city: Angers
country: France
facility: Centre Paul Papin
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Besancon
country: France
facility: Centre Hospitalier Regional de Besancon - Hopital Jean Minjoz
city: Bordeaux
country: France
facility: Institut Bergonie
city: Bordeaux
country: France
facility: Polyclinique Bordeaux Nord Aquitaine
city: Caen
country: France
facility: Centre Regional Francois Baclesse
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Dijon
country: France
facility: Centre de Lutte Contre le Cancer Georges-Francois Leclerc
city: Le Havre
country: France
facility: CMC Les Ormeaux
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes
city: Montbeliard
country: France
facility: Centre Hospitalier General Andre Boulloche
city: Montpellier
country: France
facility: Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
city: Nantes
country: France
facility: Centre Catherine de Sienne
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Institut Curie Hopital
city: Reims
country: France
facility: Institut Jean Godinot
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint Brieuc
country: France
facility: Clinique Armoricaine De Radiologie
city: Saint Cloud
country: France
facility: Centre Rene Huguenin
city: Saint-Herblain
country: France
facility: CRLCC Nantes - Atlantique
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Strasbourg
country: France
facility: Hopitaux Universitaire de Strasbourg
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Vandoeuvre-les-Nancy
country: France
facility: Centre Alexis Vautrin
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Institut Paoli-Calmettes
name: Patrice Viens, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bertucci F, Fekih M, Autret A, Petit T, Dalenc F, Levy C, Romieu G, Bonneterre J, Ferrero JM, Kerbrat P, Soulie P, Mouret-Reynier MA, Bachelot T, Lerebours F, Eymard JC, Deblock M, Lortholary A, Hardy-Bessard AC, Barthelemy P, Bonnefoi H, Charafe-Jauffret E, Bidard FC, Viens P, Lemonnier J, Pierga JY. Bevacizumab plus neoadjuvant chemotherapy in patients with HER2-negative inflammatory breast cancer (BEVERLY-1): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2016 May;17(5):600-11. doi: 10.1016/S1470-2045(16)00011-5. Epub 2016 Mar 28.