| Study summary: |
|
OBJECTIVES:
Primary
- To compare the progression-free survival of women with estrogen- and/or
progesterone-receptor-positive stage IIIB-IV breast cancer treated with letrozole with
vs without bevacizumab as first-line treatment.
Secondary
- To compare the proportion of patients receiving letrozole with or without bevacizumab
who remain progression-free at 6 and 12 months.
- To compare the incidence of objective response (complete response [CR] + partial
response [PR]) in patients receiving letrozole with or without bevacizumab, as
determined by RECIST criteria, excluding patients with non-measurable disease.
- To compare the incidence of clinical benefit (CR + PR + stable disease ≥ 6 months) in
patients receiving letrozole with or without bevacizumab.
- To compare the duration of objective response in patients receiving letrozole with or
without bevacizumab.
- To compare the time to treatment failure, defined as the interval from randomization
until progression, toxicity, withdrawn consent, or going onto nonprotocol therapy, in
patients receiving letrozole with or without bevacizumab.
- To compare the overall survival of patients receiving letrozole with or without
bevacizumab, including the probability of survival until 36 months.
- To compare toxicity levels of bevacizumab in both the letrozole-treated patients and in
the tamoxifen-treated patients.
- To compare progression-free survival and overall survival of all patients receiving
endocrine therapy with and without bevacizumab (by combining both letrozole and
tamoxifen patient subgroups).
OUTLINE: This is a multicenter study. Patients are stratified according to planned endocrine
therapy (letrozole vs tamoxifen), disease measurability (no vs yes), and disease-free
interval from initial diagnosis to first progression (≤ 24 months vs > 24 months). Patients
are randomized to 1 of 2 treatment arms.NOTE: The placebo-controlled portion of the study
was canceled on 5-15-10
- Arm I: Patients receive oral endocrine therapy (tamoxifen citrate or letrozole) once
daily on days 1-21 and bevacizumab IV on day 1. Treatment repeats every 21 days in the
absence of disease progression or unacceptable toxicity.
- Arm II: Patients receive oral endocrine therapy (tamoxifen citrate or letrozole) once
daily on days 1-21. Treatment repeats every 21 days in the absence of disease
progression or unacceptable toxicity.
After completion of study therapy, patients are followed up every 6 months for the first 2
years and then annually for up to 3 years. |
| Criteria: |
|
DISEASE CHARACTERISTICS:
- Histologic confirmation of invasive cancer of the female breast in either the primary
or metastatic setting
- Stage IIIB disease not amenable to local therapy or stage IV disease
- Must have measurable or nonmeasurable disease by RECIST criteria, with radiologic
scans (CT scan of the chest/abdomen)
- Measurable disease is defined as lesions that can be accurately measured in at
least one dimension (longest diameter to be recorded) as ≥ 2.0 cm with
conventional techniques or as ≥ 1.0 cm with spiral CT scan
- Nonmeasurable disease is defined as all other lesions, including small lesions
(longest diameter < 2.0 cm with conventional techniques or < 1.0 cm with spiral
CT scan) and truly nonmeasurable lesions, including any of the following:
- Bone lesions
- Leptomeningeal disease
- Ascites
- Pleural/pericardial effusion
- Inflammatory breast disease
- Abdominal masses that are not confirmed and followed by imaging techniques
- Cystic lesions
- Baseline bone scans required for all patients for determination of metastatic bone
disease
- CT scan with bone windows required only for patients with bone metastases as the
only site of disease
- No known CNS metastases or leptomeningeal disease (screening with brain imaging is
not required for asymptomatic patients)
- Hormone receptor status: tumors (from either primary or metastatic sites) must
express estrogen receptor (ER) and/or progesterone receptor (PgR) in ≥ 1% of cells
PATIENT CHARACTERISTICS:
- Menopausal status: pre- or postmenopausal, meeting 1 of the following criteria:
- Age ≥ 55 years and one year or more of amenorrhea
- Age < 55 years and one year or more of amenorrhea, with an estradiol assay < 20
pg/ml
- Age < 55 with prior hysterectomy but intact ovaries, with an estradiol assay <
20 pg/ml
- Surgical menopause with bilateral oophorectomy
- Ovarian suppression on a luteinizing hormone-releasing hormone agonist
(goserelin acetate or leuprolide acetate)
- Premenopausal women must undergo ovarian suppression prior to beginning
protocol therapy
- Ovarian radiation is not permitted for induction of ovarian
suppression
- ECOG (Zubrod) performance status 0-1
- Life expectancy ≥ 12 weeks
- Granulocytes ≥ 1,000/μl
- Platelet count ≥ 100,000/μl
- Creatinine ≤ 2.0 mg/dL
- Bilirubin ≤ 1.5 times upper limit of normal (ULN) unless due to Gilbert's syndrome
- Transaminases (ALT, AST) ≤ 2.5 times ULN
- INR ≤ 1.6 unless on full dose warfarin
- Urinalysis ≤ 1+ protein
- Proteinuria ≥ 2 + at baseline must demonstrate < 1 g of protein/24 hr or
protein:creatinine ratio < 1 on 24-hour urine collection
- No "currently active" second malignancy other than nonmelanoma skin cancers
- Patients are not considered to have a "currently active" malignancy if they have
completed therapy and are considered by their physician to be at less than 30%
risk of relapse
- Taxane-related neurotoxicity must have resolved to sensory grade < 2
- No motor neuropathy of any grade
- No significant traumatic injury within 28 days prior to study registration
- No history of abdominal fistula, or intra-abdominal abscess within the past 6 months
- No history of GI perforation within the past 12 months
- No history of significant bleeding episodes (e.g., hemoptysis, upper or lower GI
bleeding) within the past 6 months
- No clinically significant cardiovascular disease, including any of the following:
- Uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg
and/or diastolic BP > 90 mm Hg on antihypertensive medications
- Prior history of hypertensive crisis or hypertensive encephalopathy
- Myocardial infarction or unstable angina within past 6 months
- New York Heart Association class II-IV congestive heart failure
- Symptomatic peripheral vascular disease
- Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
- Significant arterial thrombotic events
- No history of stroke or transient ischemic attack within the past 6 months
- History of seizures must be well controlled with standard medication
- No known allergies to imidazole drugs, (e.g., clotrimazole, ketoconazole, miconazole,
econazole, sulconazole, ticonazole, or terconazole) or compounds structurally similar
to bevacizumab (for patients treated with aromatase inhibitors)
- No known allergies to selective estrogen receptor modulators (e.g., tamoxifen,
raloxifene, or toremifene) or compounds structurally similar to bevacizumab (for
patients treated with tamoxifen)
- No serious, non-healing wound, ulcer, or bone fracture
- Not pregnant or nursing
- Negative pregnancy test
PRIOR CONCURRENT THERAPY:
- No prior endocrine therapy in the metastatic setting unless tamoxifen or an aromatase
inhibitor was initiated within 4 weeks prior to registration
- If prior endocrine therapy was initiated within the past 4 weeks, the patients
should remain on that chosen hormonal therapy (tamoxifen or aromatase inhibitor)
as the study therapy
- Patients who began therapy with anastrozole or exemestane must switch to
letrozole
- Prior endocrine therapy in the adjuvant setting allowed
- Prior treatment with ovarian suppression is allowed in either the adjuvant or
metastatic setting
- If medical ovarian suppression is being administered it can be initiated any
time prior to or at the start of protocol therapy, and continued throughout the
duration of the trial
- At least 28 days since surgical castration with bilateral oophorectomy
- At least 2 weeks since prior radiotherapy and all toxicities resolved
- At least 12 months since the completion of prior adjuvant or neoadjuvant chemotherapy
and all toxicities must have resolved
- No prior anti-VEGF or VEGFR tyrosine kinase inhibitor therapy
- May have received 1 prior chemotherapy regimen for metastatic disease
- More than 28 days since prior major surgical procedure or open biopsy and fully
recovered from any such procedure
- No core biopsy or other minor surgical procedure (except placement of a vascular
access device) within 7 days prior to study registration
- Prior palliative irradiation of a symptomatic lesion, or one that may produce
disability (e.g., unstable femur) prior to study initiation, provided other
measurable or non-measurable disease is present, is allowed
- Palliative radiotherapy may not be administered during protocol therapy
- Must not have anticipation of need for major surgical procedure during the course of
the study
- Concurrent full dose anticoagulation therapy is allowed for the treatment of prior
conditions such as venous thromboses or atrial fibrillation, but not for the
treatment of prior arterial thrombotic events
- Patients on full dose anticoagulants must be on a stable dose of warfarin and
have an in-range INR (usually between 2 and 3) or be on a stable dose of low
molecular weight heparin
- Concurrent antiplatelet agents, daily prophylactic aspirin, or anticoagulation for
atrial fibrillation allowed
- Concurrent treatment with bisphosphonates is allowed and recommended
- No concurrent hormones or other chemotherapeutic agents except for steroids given for
adrenal failure or chronic non-cancer related diseases, hormones administered for
non-disease-related conditions (e.g., insulin for diabetes), and intermittent use of
dexamethasone as an antiemetic in solid tumor protocols |