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

The Study of Avastin (Bevacizumab) to Reverse Acquired Estrogen Independence in Metastatic Breast Cancer Patients Previously Responsive to Hormonal Therapy: A Phase II Trial

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).

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.

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.