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

• Sponsor: Yale University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00461773
• Collaborator: Novartis (Industry), Genentech, Inc. (Industry)
• Enrollment: 5
• Location: 1
• Arms: 2
• Duration (Months): 38
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Hormone-Sensitive Breast Cancer; Breast Cancer	Drug: Letrozole; Drug: Bevacizumab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Study of Preoperative Letrozole (Femara) in Combination With Avastin in Hormone Receptor Positive Breast Cancer
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: May 1, 2010
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: bevacizumab brief exposure bevacizumab	Drug: Bevacizumab; bevacizumab 10 mg/kg IV; Other Names: Avastin
Active Comparator: bevacizumab and letrozole brief exposure bevacizumab and letrozole	Drug: Letrozole; Letrozole 2.5 mg po qd; Other Names: Femara ; Drug: Bevacizumab; bevacizumab 10 mg/kg IV; Other Names: Avastin

Outcome Measures

Primary Outcome Measures

1. 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

1. 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).

2. 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

3. 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

4. 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.

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale University, Yale Cancer Center	New Haven	Connecticut	United States	06520

Sponsors and Collaborators

• Yale University
• Novartis
• Genentech, Inc.

Investigators

• Principal Investigator: Gina Chung, M.D., Yale University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT00461773
• Other Study ID Numbers: 0609001793
• First Posted: Apr 18, 2007
• Last Update Posted: Mar 16, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by Yale University: Neoadjuvant treatment
• Additional relevant MeSH terms: Breast Neoplasms; Bevacizumab; Letrozole

Study Results

Participant Flow

Arm/Group Title	Bevacizumab	Bevacizumab and Letrozole
Arm/Group Description	brief exposure bevacizumab Bevacizumab: bevacizumab 10 mg/kg IV	brief exposure bevacizumab and letrozole Letrozole: Letrozole 2.5 mg once orally daily Bevacizumab: bevacizumab 10 mg/kg IV
Period Title: Overall Study
STARTED	3	2
COMPLETED	3	2
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Bevacizumab	Bevacizumab and Letrozole	Total
Arm/Group Description	brief exposure bevacizumab	brief exposure bevacizumab and letrozole	Total of all reporting groups
Overall Participants	3	2	5
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	2 66.7%	2 100%	4 80%
>=65 years	1 33.3%	0 0%	1 20%
Sex: Female, Male (Count of Participants)
Female	3 100%	2 100%	5 100%
Male	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients.

Arm/Group Title	Bevacizumab	Bevacizumab and Letrozole
Arm/Group Description	brief exposure bevacizumab	brief exposure bevacizumab and letrozole
Measure Participants	3	2
Complete Response	1 33.3%	0 0%
Partial Response	2 66.7%	1 50%
Progressive Disease	0 0%	0 0%
Stable Disease	0 0%	1 50%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients.

Arm/Group Title	Bevacizumab	Bevacizumab and Letrozole
Arm/Group Description	brief exposure bevacizumab	brief exposure bevacizumab and letrozole
Measure Participants	3	2
Performed at 14 weeks	2 66.7%	1 50%
Not Performed at 14 weeks	0 0%	0 0%
Performed at 14 weeks	1 33.3%	1 50%
Not Performed at 14 weeks	0 0%	0 0%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients.

Arm/Group Title	Bevacizumab	Bevacizumab and Letrozole
Arm/Group Description	brief exposure bevacizumab	brief exposure bevacizumab and letrozole
Measure Participants	3	2
CR	0 0%	0 0%
PR	2 66.7%	2 100%
PD	0 0%	0 0%
SD	1 33.3%	0 0%

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients.

Arm/Group Title	Bevacizumab	Bevacizumab and Letrozole
Arm/Group Description	brief exposure bevacizumab	brief exposure bevacizumab and letrozole
Measure Participants	3	2
CR	0 0%	0 0%
PR	1 33.3%	1 50%
PD	1 33.3%	1 50%
SD	1 33.3%	0 0%

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

These labs were never conducted as the study was terminated after 5 patients.

Arm/Group Title	Bevacizumab	Bevacizumab and Letrozole
Arm/Group Description	brief exposure bevacizumab	brief exposure bevacizumab and letrozole
Measure Participants	0	0

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All adverse events are presented in the adverse event module.

Arm/Group Title	Bevacizumab	Bevacizumab and Letrozole
Arm/Group Description	brief exposure bevacizumab	brief exposure bevacizumab and letrozole
Measure Participants	3	2
Any Grade 3 Adverse Events	0 0%	0 0%
Any Grade 4 Adverse Events	0 0%	0 0%

Adverse Events

Time Frame	Up to 18 weeks
Arm/Group Title	Bevacizumab		Bevacizumab and Letrozole
Arm/Group Description	brief exposure bevacizumab		brief exposure bevacizumab and letrozole
All Cause Mortality
	Bevacizumab		Bevacizumab and Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/2 (0%)
Serious Adverse Events
	Bevacizumab		Bevacizumab and Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Bevacizumab		Bevacizumab and Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		2/2 (100%)
Blood and lymphatic system disorders
BLOOD/BONE MARROW	0/3 (0%)	0	1/2 (50%)	3
HEMORRHAGE/BLEEDING	1/3 (33.3%)	1	0/2 (0%)	0
Cardiac disorders
CARDIAC GENERAL	2/3 (66.7%)	2	2/2 (100%)	4
Ear and labyrinth disorders
AUDITORY/EAR	0/3 (0%)	0	1/2 (50%)	1
Endocrine disorders
ENDOCRINE	1/3 (33.3%)	1	1/2 (50%)	4
Eye disorders
OCULAR/VISUAL	1/3 (33.3%)	1	2/2 (100%)	2
Gastrointestinal disorders
GASTROINTESTINAL	2/3 (66.7%)	9	2/2 (100%)	8
General disorders
CONSTITUTIONAL SYMPTOMS	2/3 (66.7%)	10	2/2 (100%)	8
PAIN	3/3 (100%)	17	2/2 (100%)	16
SYNDROMES	1/3 (33.3%)	1	0/2 (0%)	0
Immune system disorders
ALLERGY/IMMUNOLOGY	2/3 (66.7%)	4	0/2 (0%)	0
LYMPHATICS	1/3 (33.3%)	1	0/2 (0%)	0
Metabolism and nutrition disorders
METABOLIC/LABORATORY	3/3 (100%)	29	2/2 (100%)	20
Musculoskeletal and connective tissue disorders
MUSCULOSKELETAL/SOFT TISSUE	1/3 (33.3%)	2	1/2 (50%)	1
Nervous system disorders
NEUROLOGY	1/3 (33.3%)	1	1/2 (50%)	9
Renal and urinary disorders
RENAL/GENITOURINARY	1/3 (33.3%)	1	0/2 (0%)	0
Respiratory, thoracic and mediastinal disorders
PULMONARY/UPPER RESPIRATORY	1/3 (33.3%)	2	2/2 (100%)	5
Skin and subcutaneous tissue disorders
DERMATOLOGY/SKIN	2/3 (66.7%)	9	2/2 (100%)	3
Vascular disorders
VASCULAR	1/3 (33.3%)	1	0/2 (0%)	0

Limitations/Caveats

The data reported are summaries of the available data that were collected up until the time of study termination.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.