Study of Avastin (Bevacizumab) to Reverse Acquired Estrogen Independence in Previously Hormone Responsive Metastatic Breast Ca.

• Sponsor: University of Alabama at Birmingham (Other)
• Overall Status: Completed
• CT.gov ID: NCT00240071
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 30
• Location: 1
• Arm: 1
• Duration (Months): 66
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if acquired hormone therapy resistance can be reversed by Avastin (Bevacizumab), as measured by time to disease progression and evaluate toxicity of the combination of hormone treatment plus Avastin (Bevacizumab).

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Avastin; Drug: Hormonal therapy	Phase 2

Detailed Description

This is a single institution, open-label study designed to evaluate safety and efficacy of Avastin (Bevacizumab) combined with an endocrine agent in patients with estrogen and/or progesterone receptor positive metastatic breast carcinoma who have acquired resistance to at least one hormonal agent. Patients will be treated with the same hormonal agent that was used previously assuming that the patient had a partial or complete response (for at least 6 months) followed by a clear disease progression using the Response Evaluation Criteria in solid Tumors (RECIST Criteria). Patients with stable disease for a prolonged time (for at least 6 months) will be also eligible to enter in the trial. Patients who have not had interval studies to evaluate disease response will be considered eligible if they have remained clinically stable (i.e. stable performance status (PS), no increasing pain) and on the same hormone for at least 6 months, and now they have signs and symptoms of clinical progression (i.e. elevated tumor markers, increasing bone pain, worsening performance status). Patients must have histologically confirmed measurable and/or evaluable metastatic breast cancer with positive estrogen and/or progesterone receptors. Patients can have up to an 8-12 week break in therapy (discontinuation of hormonal therapy) and still remain eligible for the study as long as the documentation of disease progression is determined before the 8-12 week break in hormonal therapy.

The type and dose of the hormonal agent that will be used in this trial will be the same one that the patient used before progression. Hormonal therapy may include any estrogen deprivation reagent such as Tamoxifen, Anastrazole, Exemestane, Letrozole, or Fulvestrant. All patients will receive Avastin (Bevacizumab) 15 mg/kg IV every three weeks. Based on statistical evaluations, 30 patients will be enrolled. The first evaluation of efficacy will be done at week 6; patients with objective response or stable disease will continue therapy with re-staging every 6 weeks until evidence of disease progression. Patients with progression of disease will be taken off study (see appendix A). PET scan will be done at baseline and only in the first evaluation (6 weeks) to obtain early "metabolic response data" that will be correlated with objective response and time to disease progression (PET data on week 6 will not be used to evaluate response and to make therapeutic decisions). PET "metabolic response" will be defined as a >20% reduction in Standardized Uptake Value (SUV). Safety will be assessed by the recording of adverse events, serious adverse events, laboratory test results, and changes in vital signs. A positive response to Avastin (Bevacizumab) (reversal of hormonal resistance) will be defined as an objective response or stable disease of ≥ 3 months duration. All concomitant medication must be documented. Additionally, any diagnostic, therapeutic or surgical procedure performed during the study period, should be recorded including the date, indication, description of the procedure(s) and any clinical findings.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Study of Avastin (Bevacizumab) to Reverse Acquired Estrogen Independence in Metastatic Breast Cancer Patients Previously Responsive to Hormonal Therapy: A Phase II Trial
• Study Start Date: Oct 1, 2005
• Actual Primary Completion Date: Mar 1, 2009
• Actual Study Completion Date: Apr 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Avastin The patient will continue the same hormonal therapy used prior to study enrollment but will combine it with Avastin.

Drug: Avastin; All patients will received Avastin 15 mg/kg IV every three weeks. The first evaluation will be done at Week 6. Patients with objective response or stable disease will continue therapy with restaging every 6 weeks until evidence of disease progression. Patients with progression of disease will be taken off study.; Other Names: Bevacizumab ; Drug: Hormonal therapy; aromatase inhibitor (letrozole 2.5mg/d PO, anastrazole 1mg/d PO, or exemestane 25mg/d PO)or Selective Estrogen Receptor Modulator (SERM) (tamoxifen 20mg/d PO); Other Names: Femara (letrozole) Arimidex (anastrazole) Aromasin (exemestane) Nolvadex (tamoxifen)

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [From date of registration until disease progression or death, whichever occurs first]

   Progression free survival is defined as time from date of registration until the date of first documented disease progression or date of death from any cause, whichever occurs first.

Secondary Outcome Measures

1. Objective Response Rate (Defined as the Rate of Complete and Partial Responses). [From date of registration until disease progression or death, whichever occurs first]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 80 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have cytologically or histologically proven breast cancer which is estrogen receptor or progesterone receptor positive and is locally advanced and /or metastatic.

• Give written informed consent prior to study specific screening procedures, with the understanding that the patient has the right to withdraw from the study at any time, without prejudice (Appendix E).

• Be female and greater than or equal to 19 years of age (age limit required by the State of Alabama). Women of childbearing potential must have a negative pregnancy test and must be willing to consent to using effective contraception while on treatment and for a reasonable period thereafter. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

• Be ambulatory (outpatient) and have an Eastern Cooperative Oncology Group (ECOG) PS <2 (Appendix B).

• Previous treatment: Patients must have responded to first or second line hormonal therapy (Partial and complete response greater than 6 months using RECIST criteria. Patients with stable disease for more than 6 months will be eligible) and became resistant to the hormonal agent. They must remain on the current hormone therapy to which they initially responded but now are resistant.

• Clear documentation of acquired hormonal resistance.

• Evaluable disease will be considered eligible, but measurable disease according to RECIST criteria will be preferable (Appendix C). The target lesion(s) must not have been previously irradiated (newly arising lesions in previously irradiated areas are acceptable).

• Patients must have adequate organ and marrow function as defined as follows: absolute neutrophil count > 1,500/mm3, hemoglobin > 8.0 g/dl, platelets > 75,000/mm3, total bilirubin < 2 mg/dl, serum creatinine < 2 mg/dl, transaminases (AST, ALT) may be up to 2.5 x institutional upper limit of normal for patients with no liver metastases and up to 5 x institutional upper normal limit for patients with documented liver metastases. In addition < 1 gr of protein in 24 hr urine collection and urine protein/creatinine ratio < 1.0

• Prior chemotherapy does not exclude patients from study as long as the current therapy was hormonal therapy alone.

• Patients with de novo hormone therapy resistance will not be eligible.

• No life threatening parenchymal disease or rapidly progressing disease warranting cytotoxic chemotherapy.

• No history of brain metastases.

• No history of thrombosis during the previous year, including transient ischemic attack.

• Hypertension must be controlled (< 150/100 mmHg).

• Ejection Fraction > 50%.

Exclusion Criteria:

• Patients who are "de novo" resistant to hormone therapy.

• Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than this Genentech-sponsored bevacizumab cancer study.

• Blood pressure of >150/100 mmHg

• Unstable angina

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

• History of myocardial infarction within 6 months

• History of stroke within 6 months

• Clinically significant peripheral vascular disease

• History of a bleeding disorder

• Presence of central nervous system or brain metastases

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during the course of the study

• Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 0

• Pregnant (positive pregnancy test) or lactating

• Urine protein: creatinine ratio greater than or equal to 1.0 at screening. Patients demonstrating > 1 gr of protein in 24 hr urine collection within 4 weeks prior to study entry will not participate in the trial.

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0

• Serious, non-healing wound, ulcer, or bone fracture

• Unwilling or unable to comply with the protocol for the duration of the study.

• Psychiatric illness/social situations that would limit compliance with study requirements.

• Previously radiated area(s) must not be the only site of disease.

• History of another malignancy within the last five years except cured basal cell carcinoma of skin and carcinoma in-situ of uterine cervix.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294

Sponsors and Collaborators

• University of Alabama at Birmingham
• Genentech, Inc.

Investigators

• Principal Investigator: Carla Falkson, MD, University of Alabama at Birmingham

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Carla Falkson, MD, Professor, University of Alabama at Birmingham
• ClinicalTrials.gov Identifier: NCT00240071
• Other Study ID Numbers: F050103001; UAB 0461
• First Posted: Oct 17, 2005
• Last Update Posted: Oct 30, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by Carla Falkson, MD, Professor, University of Alabama at Birmingham: Breast cancer; Metastatic breast cancer; Hormonal therapy; Bevacizumab
• Additional relevant MeSH terms: Breast Neoplasms; Tamoxifen; Bevacizumab; Letrozole; Exemestane

Study Results

Participant Flow

Recruitment Details	Recruitment started October 2005 - until March 2009. Kirklin Clinic at University of Alabama at Birmingham (UAB), Birmingham, Alabama (AL) and Georgia Cancer Center, Atlanta, Georgia (GA)
Pre-assignment Detail	The purpose of this study is to determine if acquired hormone therapy resistance can be reversed by Avastin (Bevacizumab), as measured by time to disease progression and evaluate toxicity of the combination of hormone treatment plus Avastin.

Arm/Group Title	Avastin(Bevacizumab) Plus Hormonal Therapy
Arm/Group Description	Avastin (Bevacizumab)15mg/m2 IV every 3 weeks plus various daily oral hormonal therapies.
Period Title: Overall Study
STARTED	30
COMPLETED	27
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Avastin(Bevacizumab) Plus Hormonal Therapy
Arm/Group Description	Avastin (Bevacizumab)15mg/m2 IV every 3 weeks plus various daily oral hormonal therapies.
Overall Participants	30
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	19 63.3%
>=65 years	11 36.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.7 (16)
Sex: Female, Male (Count of Participants)
Female	30 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	30 100%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	Progression free survival is defined as time from date of registration until the date of first documented disease progression or date of death from any cause, whichever occurs first.
Time Frame	From date of registration until disease progression or death, whichever occurs first

Outcome Measure Data

Analysis Population Description

All participants entered onto study (intention to treat) (ITT) were analyzed.

Arm/Group Title	Avastin (Bevacizumab) Plus Hormone
Arm/Group Description	All patients received Avastin (Bevacizumab) 15 mg/kg IV every three weeks as well as continuing with hormonal therapy they previously were taking.
Measure Participants	30
Median (95% Confidence Interval) [days]	125.5

2. Secondary Outcome

Title	Objective Response Rate (Defined as the Rate of Complete and Partial Responses).
Time Frame	From date of registration until disease progression or death, whichever occurs first

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Avastin
Arm/Group Description	The patient will continue the same hormonal therapy used prior to study enrollment but will combine it with Avastin. Avastin: All patients will received Avastin 15 mg/kg IV every three weeks. The first evaluation will be done at Week 6. Patients with objective response or stable disease will continue therapy with restaging every 6 weeks until evidence of disease progression. Patients with progression of disease will be taken off study. Hormonal therapy: aromatase inhibitor (letrozole 2.5mg/d PO, anastrazole 1mg/d PO, or exemestane 25mg/d PO)or Selective Estrogen Receptor Modulator (SERM) (tamoxifen 20mg/d PO)
Measure Participants	30
Number [participants]	0 0%

Adverse Events

Time Frame	1245 days
Arm/Group Title	Avastin(Bevacizumab) Plus Hormonal Therapy
Arm/Group Description	Avastin (Bevacizumab)15mg/m2 IV every 3 weeks plus various daily oral hormonal therapies.
All Cause Mortality
	Avastin(Bevacizumab) Plus Hormonal Therapy
	Affected / at Risk (%)	# Events
Total	0/30 (0%)
Serious Adverse Events
	Avastin(Bevacizumab) Plus Hormonal Therapy
	Affected / at Risk (%)	# Events
Total	7/30 (23.3%)
Gastrointestinal disorders
Grade III diarrhea	1/30 (3.3%)
General disorders
Grade III fatigue	2/30 (6.7%)
Grade III syncope	2/30 (6.7%)
Metabolism and nutrition disorders
Hyperkalemia	1/30 (3.3%)
Musculoskeletal and connective tissue disorders
Knee and foot pain	1/30 (3.3%)
Nervous system disorders
Grade III neuropathy	1/30 (3.3%)
Respiratory, thoracic and mediastinal disorders
Grade III dyspnea on exertion	2/30 (6.7%)
Skin and subcutaneous tissue disorders
Grade III leg ulcer	1/30 (3.3%)
Vascular disorders
Grade III hypertension	4/30 (13.3%)
Other (Not Including Serious) Adverse Events
	Avastin(Bevacizumab) Plus Hormonal Therapy
	Affected / at Risk (%)	# Events
Total	24/30 (80%)
Blood and lymphatic system disorders
Anemia	2/30 (6.7%)
Ear and labyrinth disorders
Epistaxis	4/30 (13.3%)
Dizziness	2/30 (6.7%)
Gastrointestinal disorders
Diarrhea	3/30 (10%)
Transaminitits	4/30 (13.3%)
Nausea and vomiting	8/30 (26.7%)
GI Bleeding	2/30 (6.7%)
Mucositis	4/30 (13.3%)
Change in taste	2/30 (6.7%)
General disorders
Fatigue	6/30 (20%)
Anorexia	2/30 (6.7%)
Weight loss	4/30 (13.3%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	7/30 (23.3%)
Arthralgias	2/30 (6.7%)
Nervous system disorders
Headache	2/30 (6.7%)
Renal and urinary disorders
Proteinuria	10/30 (33.3%)
Acute Renal Failure	2/30 (6.7%)
Respiratory, thoracic and mediastinal disorders
Hoarsness of voice	3/30 (10%)
Cough	3/30 (10%)
Skin and subcutaneous tissue disorders
Skin rash	2/30 (6.7%)
Vascular disorders
Hypertension	4/30 (13.3%)

Limitations/Caveats

A Phase II trial.

More Information

Certain Agreements

Principal Investigators are NOT 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.