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

Primary Purpose

Hormone-Sensitive Breast Cancer, Breast Cancer

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Letrozole
Bevacizumab
Sponsored by
Yale University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hormone-Sensitive Breast Cancer focused on measuring Neoadjuvant treatment

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • Yale University, Yale Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

bevacizumab

bevacizumab and letrozole

Arm Description

brief exposure bevacizumab

brief exposure bevacizumab and letrozole

Outcomes

Primary Outcome Measures

Number of Patients With Objective Tumor Response
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

Breast Conservation
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).
Radiographic Tumor Response
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
Pathologic Complete Response
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
Tumor Response With Biological Correlates
To correlate response with biological correlates detected at baseline and after 1 cycle of treatment with either Bevacizumab alone or Bevacizumab combined with Letrozole.
Drug Tolerability
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.

Full Information

First Posted
April 16, 2007
Last Updated
February 22, 2021
Sponsor
Yale University
Collaborators
Novartis, Genentech, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT00461773
Brief Title
Randomized Phase II Study of Preoperative Letrozole (Femara) in Combination With Avastin in Hormone Receptor Positive Breast Cancer
Official Title
Randomized Phase II Study of Preoperative Letrozole (Femara) in Combination With Avastin in Hormone Receptor Positive Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
February 2021
Overall Recruitment Status
Terminated
Why Stopped
Lack of recrual
Study Start Date
March 2007 (undefined)
Primary Completion Date
May 2010 (Actual)
Study Completion Date
May 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yale University
Collaborators
Novartis, Genentech, Inc.

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hormone-Sensitive Breast Cancer, Breast Cancer
Keywords
Neoadjuvant treatment

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
bevacizumab
Arm Type
Active Comparator
Arm Description
brief exposure bevacizumab
Arm Title
bevacizumab and letrozole
Arm Type
Active Comparator
Arm Description
brief exposure bevacizumab and letrozole
Intervention Type
Drug
Intervention Name(s)
Letrozole
Other Intervention Name(s)
Femara
Intervention Description
Letrozole 2.5 mg po qd
Intervention Type
Drug
Intervention Name(s)
Bevacizumab
Other Intervention Name(s)
Avastin
Intervention Description
bevacizumab 10 mg/kg IV
Primary Outcome Measure Information:
Title
Number of Patients With Objective Tumor Response
Description
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.
Time Frame
Up to 18 weeks
Secondary Outcome Measure Information:
Title
Breast Conservation
Description
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).
Time Frame
Up to 14 weeks
Title
Radiographic Tumor Response
Description
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
Time Frame
18 weeks
Title
Pathologic Complete Response
Description
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
Time Frame
Up to 18 weeks
Title
Tumor Response With Biological Correlates
Description
To correlate response with biological correlates detected at baseline and after 1 cycle of treatment with either Bevacizumab alone or Bevacizumab combined with Letrozole.
Time Frame
2 weeks
Title
Drug Tolerability
Description
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.
Time Frame
Up to 18 weeks

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gina Chung, M.D.
Organizational Affiliation
Yale University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yale University, Yale Cancer Center
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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