Tamoxifen Citrate or Letrozole With or Without Bevacizumab in Treating Women With Stage III or Stage IV Breast Cancer

• Progression-free survival [ Time Frame: From randomization until disease progression or death, assessed up to 3 years ] [ Designated as safety issue: No ]
• Adverse events rate, especially for stroke, proteinuria, thrombosis, and hypertension in patients treated with tamoxifen citrate (As of 5/15/2011, patients only receive letrozole) [ Time Frame: Within 30 days of the last dose of investigational agent ] [ Designated as safety issue: Yes ]
  Graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Interpreted using P-values from the chi-square test (with one-sided alpha of 0.05).
• Occurrence of grade 3, 4, or 5 toxicity [ Time Frame: Assessed up to 3 years ] [ Designated as safety issue: Yes ]
  Graded using the NCI CTCAE version 4.0.

• Progression-free survival defined as the interval from randomization until disease progression or death, whichever occurs first in patients treated with letrozole [ Designated as safety issue: No ]
• Estimation of adverse events rate, especially for stroke, proteinuria, thrombosis, hypertension in patients treated with tamoxifen citrate [ Designated as safety issue: Yes ]
• Toxicity [ Designated as safety issue: Yes ]

• Objective tumor response as defined by RECIST criteria for patients with measurable disease [ Time Frame: Assessed up to 3 years ] [ Designated as safety issue: No ]
• Probability of being progression-free [ Time Frame: At 6 months ] [ Designated as safety issue: No ]
  Difference in proportions tested using the chi-square test.
• Probability of being progression-free [ Time Frame: At 12 months ] [ Designated as safety issue: No ]
  Difference in proportions tested using the chi-square test.
• Site of progression [ Time Frame: Assessed up to 3 years ] [ Designated as safety issue: No ]
• Treatment related toxicity [ Time Frame: Assessed up to 3 years ] [ Designated as safety issue: Yes ]
  Graded using the NCI CTCAE version 4.0. Tabulated by type, grade, and arm.
• Time-to-treatment failure [ Time Frame: From randomization until first disease progression, early termination of protocol therapy due to toxicity or withdrawn consent, or beginning non-protocol therapy, whichever occurs first, assessed up to 3 years ] [ Designated as safety issue: No ]
  Defined by RECIST criteria.
• Duration of tumor response [ Time Frame: From the time measurement criteria are met for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 3 years ] [ Designated as safety issue: No ]
  Defined by RECIST criteria.
• Overall survival (OS) [ Time Frame: Assessed up to 3 years ] [ Designated as safety issue: No ]
  Compared with a Kaplan-Meier analysis. 90% confidence interval will be calculated.
• Probability of surviving until 36 months [ Time Frame: At 36 months ] [ Designated as safety issue: No ]

• Objective tumor response as defined by RECIST criteria for those patients with measurable disease [ Designated as safety issue: No ]
• Probability of being progression-free at 6- and 12-months [ Designated as safety issue: No ]
• Site of progression [ Designated as safety issue: No ]
• Treatment-related toxicity [ Designated as safety issue: Yes ]
• Time to treatment failure [ Designated as safety issue: No ]
• Duration of tumor response [ Designated as safety issue: No ]
• Overall survival [ Designated as safety issue: No ]
• Probability of surviving until 36 months [ Designated as safety issue: No ]

This randomized phase III trial is studying giving tamoxifen citrate or letrozole together with bevacizumab to see how well it works compared with tamoxifen citrate or letrozole alone in treating women with stage III or stage IV breast cancer. Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen* or letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether giving hormone therapy is more effective with or without bevacizumab in treating advanced breast cancer

PRIMARY OBJECTIVES:

I. 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 OBJECTIVES:

I. To compare the proportion of patients receiving letrozole with or without bevacizumab who remain progression-free at 6 and 12 months.

II. 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.

III. To compare the incidence of clinical benefit (CR + PR + stable disease >= 6 months) in patients receiving letrozole with or without bevacizumab.

IV. To compare the duration of objective response in patients receiving letrozole with or without bevacizumab.

V. To compare the time to treatment failure, defined as the interval from randomization until progression, toxicity, withdrawn consent, or going onto non protocol therapy, in patients receiving letrozole with or without bevacizumab.

VI. To compare the overall survival of patients receiving letrozole with or without bevacizumab, including the probability of survival until 36 months.

V. To compare toxicity levels of bevacizumab in both the letrozole-treated patients and in the tamoxifen-treated* patients.

VI. 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). NOTE: *As of 5/15/2011, patients only receive letrozole.

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.

NOTE: As of 5/15/2011, patients only receive letrozole.

• Recurrent Breast Cancer
• Stage IIIB Breast Cancer
• Stage IV Breast Cancer

• Drug: tamoxifen citrate
  Oral once daily (not given after 5/15/2011)
  Other Names:

  • Nolvadex
  • TAM
  • tamoxifen
  • TMX
• Drug: letrozole
  Oral once daily
  Other Names:

  • CGS 20267
  • Femara
  • LTZ
• Biological: bevacizumab
  IV every 21 days
  Other Names:

  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF

• Experimental: Arm I (endocrine therapy with monoclonal antibody)
  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.
  Interventions:

  • Drug: tamoxifen citrate
  • Drug: letrozole
  • Biological: bevacizumab
• Active Comparator: Arm II (endocrine therapy)
  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.
  Interventions:

  • Drug: tamoxifen citrate
  • Drug: letrozole

Inclusion Criteria:

• 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

• 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 < 20pg/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-hoururine 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) NOTE: As of 5/15/2011, patients only receive letrozole.
• No serious, non-healing wound, ulcer, or bone fracture
• Not pregnant or nursing
• Negative pregnancy test

• 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. NOTE: As of 5/15/2011, patients only receive letrozole.
  • Patients who began therapy with tamoxifen (after 5/15/2011), 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 flow 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