Bevacizumab and Combination Chemotherapy in Patients With Lymph Node Positive Breast Cancer

Stage IIIA Breast Cancer Clinical Trial

Official title:

Phase II Feasibility Trial Incorporating Bevacizumab Into Dose Dense Doxorubicin and Cyclophosphamide Followed by Paclitaxel in Patients With Lymph Node Positive Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00119262
• Other study ID #: NCI-2012-02977
• Secondary ID: NCI-2012-02977U1
• Status: Completed
• Phase: Phase 2
• First received: July 12, 2005
• Last updated: April 29, 2014
• Start date: October 2005
• Est. completion date: September 2009

Study information

• Verified date: December 2012
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This phase II trial is studying how well giving bevacizumab together with combination chemotherapy works in treating patients who have undergone surgery for breast cancer that has spread to the lymph nodes. 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. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. 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 together with more than one chemotherapy drug (combination chemotherapy), may be a better way to block tumor growth.

Description:

PRIMARY OBJECTIVES:

I. To determine the incidence of clinically apparent cardiac dysfunction in patients with lymph node positive breast cancer treated with bevacizumab and dose dense doxorubicin/cyclophosphamide followed by paclitaxel (ddAC > T).

SECONDARY OBJECTIVES:

I. To evaluate changes in LVEF during treatment. II. To evaluate non-cardiac toxicity.

OUTLINE: This is a non-randomized, multicenter study. Patients are sequentially assigned to 1 of 2 treatment arms.

Arm A: Patients receive doxorubicin IV, cyclophosphamide IV over 20-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Patients also receive filgrastim (G-CSF) subcutaneously (SQ) on days 2-11 or pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients then receive paclitaxel IV over 3 hours and bevacizumab IV over 30-90 minutes on day 1. Patients also receive G-CSF or pegfilgrastim as above. Treatment with paclitaxel, bevacizumab, and G-CSF or pegfilgrastim repeats every 14 days for 4 courses. Patients then receive bevacizumab alone every 14 days for up to 18 courses.

Arm B: Patients receive doxorubicin, cyclophosphamide, and G-CSF or pegfilgrastim as in group I. Patients then receive paclitaxel, bevacizumab, and G-CSF or pegfilgrastim as in group I. Patients then receive bevacizumab alone every 14 days for up to 22 courses.

Treatment in both groups continues in the absence of disease recurrence or unacceptable toxicity.

Patients who require radiotherapy (post-lumpectomy) or who plan radiotherapy at the discretion of the investigator (post-mastectomy) undergo radiotherapy beginning within 6 weeks after the completion of chemotherapy.

Premenopausal patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive disease receive oral tamoxifen once daily for 5 years beginning at the time of radiotherapy or within 6 weeks after the completion of chemotherapy. Postmenopausal patients with ER and/or PR positive disease receive an aromatase inhibitor (e.g., anastrozole, letrozole, or exemestane) or tamoxifen followed by an aromatase inhibitor once daily for up to 10 years.

After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for up to 3 years from study entry.

ACCRUAL: A total of 226 patients (104 on arm A and 122 on arm B) were accrued for this study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 226
• Est. completion date: September 2009
• Est. primary completion date: August 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the breast with involvement of at least one axillary or internal mammary lymph node on routine histologic examination with hematoxylin and eosin staining; NOTE: patients with axillary or internal mammary node involvement only demonstrated by immunohistochemistry are not eligible

• Patients must have completed definitive breast surgery including total mastectomy and axillary dissection (modified radical mastectomy), total mastectomy and sentinel node biopsy, lumpectomy and axillary dissection, or lumpectomy and sentinel node biopsy; NOTE: axillary dissection is strongly encouraged in patients with lymph node involvement identified on sentinel node biopsy

• Margins of lumpectomy or mastectomy must be histologically free of invasive breast cancer and ductal carcinoma in situ (DCIS); patients with resection margins positive for lobular carcinoma in situ (LCIS) are eligible

• (ARM A ONLY) Interval between last surgery for breast cancer (lumpectomy, mastectomy, sentinel node biopsy, axillary dissection or re-excision of lumpectomy margins) and D1 must be > 28 days and =< 84 days

• ECOG performance status of 0-2

• Absolute neutrophil count >= 1000/mm^3

• Platelet count >= 100,000/mm^3

• Total bilirubin =< 1.5 mg/dL

• AST =< 2 upper limit of normal

• Serum creatinine =< 1.5 mg/dL

• Urine protein: creatinine ratio < 1.0

• PT INR =< 1.5

• PTT =< 1.5 x normal

• LVEF >= institutional limits of normal by MUGA or ECHO

• Prior to registration the investigator must specify if radiation is planned; patients who have undergone a lumpectomy must receive radiation; post-mastectomy radiation is at the investigator's discretion

• Patients with HER2+ (3+ by IHC or FISH+) breast cancer are not eligible and should be treated with a trastuzumab-based adjuvant therapy

• Patients with synchronous bilateral breast cancer (diagnosed within one month) are eligible if the higher TMN stage tumor meets the eligibility criteria for this trial

• Patients must not have clinical evidence of inflammatory disease or fixed axillary nodes (N2) at diagnosis

• Patients must not have received prior cytotoxic chemotherapy, hormonal therapy or radiation for this breast cancer; prior treatment with an anthracycline, anthracenedione or taxane for any condition is not allowed; NOTE: prior use of tamoxifen for chemoprevention is allowed but must be discontinued at study entry; similarly prior raloxifene use is allowed but must be discontinued at study entry

• Patients must not have had a major surgical procedure within 4 weeks of entry; NOTE:

non-operative biopsy or placement of a vascular access device is not considered a major surgery

• Patients must not have clinically significant cardiovascular disease including:

• New York Heart Association (NYHA) grade II or greater congestive heart failure

• Grade II or greater peripheral vascular disease

• Uncontrolled hypertension defined as SBP > 160 or DBP > 90

• Any prior history of cerebrovascular disease including TIA or stroke

• Patients must not require therapeutic anticoagulation; patients with a history of deep venous thrombosis or pulmonary embolism are not eligible; NOTE: prophylactic use of anticoagulants to maintain patency of a vascular assess device is permitted

• Patients may not require regular use of aspirin (daily for >= 10 days at doses of > 325 mg/day) or regular therapeutic doses of other nonsteroidal anti-inflammatory agents known to inhibit platelet function; additionally, patients using any of the following drugs known to inhibit platelet function are not eligible: dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and cilostazol (Pletal); NOTE: regular use of Cox-2 inhibitors is permitted; NOTE: low-dose aspirin is permitted

• Patients must not have a non-healing wound or fracture; patients with an abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months are excluded

• Patients must not have hypersensitivity to paclitaxel or drugs using the vehicle Cremophor, Chinese hamster ovary cell products or other recombinant human antibodies

• Patients who have experienced myocardial infarction or unstable angina within 12 months are excluded

• Patients who have had experienced an arterial thrombotic event within 12 months are excluded

• Patients must not have uncontrolled or clinical significant arrhythmia

• Women must not be pregnant or breast-feeding due to the potential harmful effects of bevacizumab on the developing fetus; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy

• Women of childbearing potential and sexually active males are required to use an accepted and effective method of contraception while on study and for at least 3-4 months after the last dose of bevacizumab

Study Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Neoplasms
• Breast Neoplasms, Male
• Male Breast Cancer
• Stage II Breast Cancer
• Stage IIIA Breast Cancer
• Stage IIIB Breast Cancer

Intervention

Drug:
• doxorubicin hydrochloride
Given IV
• cyclophosphamide
Given IV

Biological:
• bevacizumab
Given IV

Drug:
• paclitaxel
Given IV

Biological:
• filgrastim
Given SC
• pegfilgrastim
Given SC

Radiation:
• radiation therapy
Undergo radiation therapy

Drug:
• tamoxifen citrate
Given orally
• aromatase inhibition therapy
Receive aromatase inhibition therapy

Locations

Country	Name	City	State
United States	Eastern Cooperative Oncology Group	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Congestive Heart Failure Rate	Clinical congestive heart failure includes patients with symptomatic decline in LVEF to at or below the lower limit of normal (LLN), or symptomatic diastolic dysfunction. 223 treated patients were included in the analysis.	assessed on day 1 of cycles 5, 9, 17 and 25, and at end of treatment, then every 3 months for <2 years and every 6 months for 2-3 years from study entry	Yes
Secondary	Proportion of Patients With Absolute Decrease in Left Ventricular Ejection Fraction (LVEF) Levels Post Doxorubicin and Cyclophosphamide(AC)	The endpoint was measured by absolute decrease from baseline in LVEF of >15% or >10% decline from baseline to below the LLN post doxorubicin and cyclophosphamide (AC) Day 1 Cycle 5 (DIC5). 207 patients who were treated and had baseline and DIC5 LVEF values were included in the analysis.	assessed on day 1 of cycles 5, 9, 17, 25, and at end of treatment	Yes
Secondary	Proportion of Patients With Absolute Decrease in LVEF Levels Post Bevacizumab	The endpoint was measured by absolute decrease from baseline in LVEF of >15% or >10% decline from baseline to below the LLN post bevacizumab (the end of treatment). 158 patients who were treated and had baseline and end of treatment LVEF values were included in the analysis.	assessed on day 1 of cycles 5, 9, 17, 25, and at end of treatment	Yes