Randomized Phase II Study of Preoperative Letrozole (Femara) in Combination With Avastin in Hormone Receptor Positive Breast Cancer

Phase 2

Terminated

Conditions: Hormone-Sensitive Breast Cancer
Breast Cancer

Interventions: Drug: Bevacizumab
Drug: Letrozole

Registration Number: NCT00461773

Lead Sponsor: Yale University

Brief Summary: The purpose of this study is to evaluate the objective response rate of a combination of letrozole (Femara) and bevacizumab (Avastin) given preoperatively to postmenopausal patients with hormone sensitive breast cancer.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: Female

Target Recruitment: 5

Inclusion Criteria

Histologically confirmed operable or potentially operable invasive breast adenocarcinoma that is clinically palpable and measurable
Age ≥ 18 years
Clinical Stage T2-4, N0-3, M0 (Stage II-III)
Postmenopausal defined as Age ≥ 60 years and/or Age >45 years with amenorrhea 12 months with an intact uterus and/or History of bilateral oophorectomy and/or FSH and estradiol levels in postmenopausal range
ECOG PS 0, 1
Unifocal disease
ER and/or PR positive
Adequate hematological, renal, and hepatic functions Absolute neutrophil count ≥ 1,500/µL Platelet count ≥ 100,000/µL creatinine ≤ 1.5 mg/dL Serum total bilirubin ≤ 1.5 mg/dL Alkaline phosphatase ≤ 3X the ULN for the reference lab SGOT/SGPT ≤ 3X the ULN for the reference lab
Patients or their legal representatives must be able to read, understand and provide informed consent to participate in the trial
Use of effective means of contraception (men and women) in subjects of child-bearing potential

Exclusion Criteria

Prior history of and/or therapy for invasive breast cancer (includes chemotherapy, radiation, hormonal therapy including AIs, tamoxifen, raloxifene, fulvestrant or any other antiestrogen/SERM)
Clinically significant cardiovascular disease, EF <50%
Known CNS disease
History of deep vein thrombosis or pulmonary embolism
Proteinuria at screening as demonstrated by either Urine protein:creatinine (UPC) ratio ≥ 1.0 at screening OR Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
Presence of non-healing wound or fracture
Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study
Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)
Any prior history of hypertensive crisis or hypertensive encephalopathy
New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E)
History of myocardial infarction or unstable angina within 12 months prior to study enrollment
Any history of stroke or transient ischemic attack at any time
Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
Symptomatic peripheral vascular disease
Evidence of bleeding diathesis or coagulopathy
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0
Core biopsy or other minor surgical procedures such as fine needle aspirations or core biopsies within 7 days prior to Day 0
Pregnant (positive pregnancy test) or lactating. Use of effective means of contraception (men and women) in subjects of child-bearing potential is mandatory
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0
Known hypersensitivity to any component of bevacizumab or letrozole
Inability to comply with study and/or follow-up procedures

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
bevacizumab	Bevacizumab	brief exposure bevacizumab
bevacizumab and letrozole	Letrozole	brief exposure bevacizumab and letrozole
bevacizumab and letrozole	Bevacizumab	brief exposure bevacizumab and letrozole

Primary Outcome Measures

Name	Time	Method
Number of Patients With Objective Tumor Response	Up to 18 weeks	Clinical objective tumor response with 14 weeks of Neoadjuvant Letrozole combined with Bevacizumab was assessed using the following categories: Complete Response (CR): tumor is no longer visible. Partial response (PR): ≥ 50% decrease from baseline in the product of two perpendicular diameters, no new lesions. Progressive disease (PD): ≥ 25% increase of the product of two perpendicular diameters or new lesions. Stable Disease (SD): Neither CR, PR, or PD criteria met. Clinical tumor assessment was performed at baseline and every 2 weeks until week 18 prior to definitive surgery.

Secondary Outcome Measures

Name	Time	Method
Breast Conservation	Up to 14 weeks	To assess breast conservation (actual surgery performed and baseline feasible surgery) of 14 weeks of neoadjuvant letrozole combined with bevacizumab. At baseline and immediately prior to surgery, the investigator will record the extent of the least invasive feasible surgery option at that time point, according to the following categories: 1. Breast conserving surgery is feasible; 2. A mastectomy is needed; 3. Tumor is inoperable, but potentially operable after neoadjuvant treatment. Following surgery, the investigator will record the extent of the actual surgery performed according to the following categories: 1. Breast conserving surgery performed; 2. Mastectomy performed 3. No surgery performed (reason should be specified).
Pathologic Complete Response	Up to 18 weeks	To assess pathologic complete response after 14 Weeks of Neoadjuvant Letrozole combined with Bevacizumab, the pathologic response was determined on the surgically excised specimen at the time of definitive surgery. The size of the residual tumor would be measured grossly if possible and confirmed microscopically. The excised residual tumor was be assessed using RECIST criteria. RECIST: CR: Tumor is no longer visible PR: ≥ 30% decrease from baseline in the longest diameter, no new lesions PD: ≥ 20% increase in longest diameter recorded or new lesions SD: Neither CR, PR, or PD criteria met
Drug Tolerability	Up to 18 weeks	To assess the tolerability of 14 weeks of Neoadjuvant Letrozole combined with Bevacizumab, individual toxicities were graded according to the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 3.0. Information about all adverse events, whether volunteered by the subject, discovered by investigator questioning, or detected through physical examination, laboratory test or other means, were collected and recorded on the Adverse Event Case Report Form and followed as appropriate. An adverse event (AE) is any undesirable sign, symptom or medical condition occurring after starting study drug (or therapy) even if the event is not considered to be related to study drug (or therapy). Study drug (or therapy) includes the drug (or therapy) under evaluation, and any reference or placebo drug (or therapy) given during any phase of the trial. AE's graded 3 or 4 would be considered serious and be reported as measures of tolerability.
Tumor Response With Biological Correlates	2 weeks	To correlate response with biological correlates detected at baseline and after 1 cycle of treatment with either Bevacizumab alone or Bevacizumab combined with Letrozole.
Radiographic Tumor Response	18 weeks	To assess radiographic tumor response after 14 weeks of Neoadjuvant Letrozole combined with Bevacizumab, mammogram were performed at baseline and at week 18 prior to definitive surgery. Tumors response was assessed using RECIST criteria RECIST: CR: Tumor is no longer visible PR: ≥ 30% decrease from baseline in the longest diameter, no new lesions PD: ≥ 20% increase in longest diameter recorded or new lesions SD: Neither CR, PR, or PD criteria met