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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00601900
Recruitment Status : Active, not recruiting
First Posted : January 28, 2008
Results First Posted : August 23, 2016
Last Update Posted : March 8, 2023
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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Brief Summary:
This randomized phase III trial studies 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 IIIB or stage IV breast cancer. Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate or letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells. Immunotherapy with monoclonal antibodies, such as bevacizumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving hormone therapy is more effective with or without bevacizumab in treating advanced breast cancer.

Condition or disease Intervention/treatment Phase
Invasive Breast Carcinoma Recurrent Breast Carcinoma Stage III Breast Cancer AJCC v6 Stage IV Breast Cancer AJCC v6 and v7 Biological: Bevacizumab Other: Laboratory Biomarker Analysis Drug: Letrozole Other: Questionnaire Administration Drug: Tamoxifen Citrate Phase 3

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Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 394 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Endocrine Therapy With or Without Anti-VEGF Therapy: A Randomized, Phase III Trial of Endocrine Therapy Alone or Endocrine Therapy Plus Bevacizumab (NSC 704865) for Women With Hormone Receptor-Positive Advanced Breast Cancer
Actual Study Start Date : May 15, 2008
Actual Primary Completion Date : June 30, 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm I (endocrine therapy with monoclonal antibody)
Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21 and bevacizumab 15 mg/kg IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
 Biological: Bevacizumab
Given IV
Other Names:
  • ABP 215
  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF Monoclonal Antibody SIBP04
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab awwb
  • Bevacizumab Biosimilar ABP 215
  • Bevacizumab Biosimilar BEVZ92
  • Bevacizumab Biosimilar BI 695502
  • Bevacizumab Biosimilar CBT 124
  • Bevacizumab Biosimilar CT-P16
  • Bevacizumab Biosimilar FKB238
  • Bevacizumab Biosimilar GB-222
  • Bevacizumab Biosimilar HD204
  • Bevacizumab Biosimilar HLX04
  • Bevacizumab Biosimilar IBI305
  • Bevacizumab Biosimilar LY01008
  • Bevacizumab Biosimilar MIL60
  • Bevacizumab Biosimilar Mvasi
  • Bevacizumab Biosimilar MYL-1402O
  • Bevacizumab Biosimilar QL 1101
  • Bevacizumab Biosimilar QL1101
  • Bevacizumab Biosimilar RPH-001
  • Bevacizumab Biosimilar SCT501
  • Bevacizumab Biosimilar Zirabev
  • Bevacizumab-awwb
  • Bevacizumab-bvzr
  • BP102
  • BP102 Biosimilar
  • HD204
  • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
  • Mvasi
  • MYL-1402O
  • QL1101
  • Recombinant Humanized Anti-VEGF Monoclonal Antibody
  • rhuMab-VEGF
  • SCT501
  • SIBP 04
  • SIBP-04
  • SIBP04
  • Zirabev

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Letrozole
Given PO
Other Names:
  • CGS 20267
  • Femara

Other: Questionnaire Administration
Ancillary studies

Drug: Tamoxifen Citrate
Given PO
Other Names:
  • Apo-Tamox
  • Clonoxifen
  • Dignotamoxi
  • Ebefen
  • Emblon
  • Estroxyn
  • Fentamox
  • Gen-Tamoxifen
  • Genox
  • ICI 46,474
  • ICI-46474
  • Jenoxifen
  • Kessar
  • Ledertam
  • Lesporene
  • Nolgen
  • Noltam
  • Nolvadex
  • Nolvadex-D
  • Nourytam
  • Novo-Tamoxifen
  • Novofen
  • Noxitem
  • Oestrifen
  • Oncotam
  • PMS-Tamoxifen
  • Soltamox
  • TAM
  • Tamax
  • Tamaxin
  • Tamifen
  • Tamizam
  • Tamofen
  • Tamoxasta
  • Tamoxifeni Citras
  • Zemide
Active Comparator: Arm II (endocrine therapy)
Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
 Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Letrozole
Given PO
Other Names:
  • CGS 20267
  • Femara

Other: Questionnaire Administration
Ancillary studies

Drug: Tamoxifen Citrate
Given PO
Other Names:
  • Apo-Tamox
  • Clonoxifen
  • Dignotamoxi
  • Ebefen
  • Emblon
  • Estroxyn
  • Fentamox
  • Gen-Tamoxifen
  • Genox
  • ICI 46,474
  • ICI-46474
  • Jenoxifen
  • Kessar
  • Ledertam
  • Lesporene
  • Nolgen
  • Noltam
  • Nolvadex
  • Nolvadex-D
  • Nourytam
  • Novo-Tamoxifen
  • Novofen
  • Noxitem
  • Oestrifen
  • Oncotam
  • PMS-Tamoxifen
  • Soltamox
  • TAM
  • Tamax
  • Tamaxin
  • Tamifen
  • Tamizam
  • Tamofen
  • Tamoxasta
  • Tamoxifeni Citras
  • Zemide


Outcome Measures
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Primary Outcome Measures :
  1. Progression-free Survival [ Time Frame: From randomization until disease progression or death whichever occurs first, assessed up to 5 years ]
    The Primary Endpoint for this study was to compare the progression-free survival of letrozole therapy alone with the combination of letrozole therapy plus bevacizumab as first-line treatment in women with estrogen- and/or progesterone-receptor-positive advanced breast cancer. Progression-free survival (PFS) was defined as the time from randomization until disease progression or death, whichever occurs first. The median PFS was estimated using the Kaplan-Meier method. Progression was assessed per RECIST criteria, and defined as at least a 20% increase in the sum of the longest diameters of target lesions from baseline or the appearance of new lesions.


Secondary Outcome Measures :
  1. 12 Month Progression Free Survival Rate [ Time Frame: At 12 months ]
    The 12 month progression-free survival rate was defined as the proportion of patients who were alive progression-free 12 months after registration into the study.

  2. 6 Month Progression-Free Survival Rate [ Time Frame: At 6 months ]
    The 6 month progression-free survival rate was defined as the proportion of patients who were alive progression-free 6 months after registration into the study.

  3. Objective Response Rate [ Time Frame: Assessed up to 5 years ]
    Response was defined using RECIST criteria: Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions.

  4. Overall Survival (OS) [ Time Frame: Assessed up to 5 years ]
    OS is defined as the time from study entry to death from any cause. The median OS was estimated using the Kaplan-Meier method.

  5. 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 5 years ]
    Defined by RECIST criteria.

  6. Probability of Surviving Until 36 Months [ Time Frame: At 36 months ]
  7. Site of Progression [ Time Frame: Up to 5 years ]
  8. Time-to-treatment Failure [ Time Frame: Up to 5 years ]
    From randomization until first disease progression, early termination of protocol therapy due to toxicity or withdrawn consent, or going onto non-protocol therapy. Defined by RECIST criteria. The proportional hazards model will be used to compare the arms on time-to-treatment-failure

  9. Treatment Related Toxicity [ Time Frame: Up to 5 years ]
    Graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Tabulated by type, grade, and arm.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologic confirmation of invasive cancer of the female breast in either the primary or metastatic setting

    • Stage IV disease or stage IIIB disease (using American Joint Committee on Cancer [AJCC] criteria, 6th edition) not amenable to local therapy
  • Patients may not have a "currently active" second malignancy other than non-melanoma 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
  • Tumors (from either primary or metastatic sites) must express estrogen receptor (ER) and/or progesterone receptor (PgR) in >= 1% of cells will be considered positive

  • Postmenopausal women are eligible for this trial; before study registration, menopausal status must be defined according to the criteria below:

    • 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
    • For women age < 55 with prior hysterectomy but intact ovaries, with an estradiol assay < 20 pg/ml
    • Surgical menopause with bilateral oophorectomy (at least 28 days must elapse from surgery to time of study registration)
    • Ovarian suppression on a luteinizing hormone-releasing hormone (LH-RH) agonist
  • Premenopausal women who do not meet the postmenopausal criteria above are also eligible, but are required to undergo ovarian suppression; this can be initiated any time prior to or on day 1 of protocol therapy, regardless of chosen endocrine therapy, and will continue for the duration of protocol therapy

  • Patients must have measurable or non-measurable disease by RECIST criteria, with radiologic scans within 28 days of study registration

    • Measurable disease: 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 computed tomography (CT) scan
    • Non-measurable disease: all other lesions, including small lesions (longest diameter < 2.0 cm with conventional techniques or < 1.0 cm with spiral CT scan) and truly non-measurable lesions

    • Lesions that are considered non-measurable include 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

  • Prior endocrine therapy is not required

    • Prior endocrine therapy in the metastatic setting is not permitted (unless tamoxifen or an aromatase inhibitor was initiated within 4 weeks prior to registration to facilitate enrollment of patients who recently started first-line endocrine therapy for metastatic breast cancer); if prior letrozole therapy was initiated within the past 4 weeks, the patients should remain on letrozole as the study therapy; patients who began therapy with tamoxifen, anastrozole or exemestane must switch to letrozole to be eligible to participate in this study
    • Prior endocrine therapy in the adjuvant setting is permitted; there is no time restriction for how long the patient must be on the adjuvant endocrine therapy, nor is there a time restriction for how long the patient needs to be off prior adjuvant endocrine therapy before beginning protocol therapy on 40503
    • 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; surgical castration with bilateral oophorectomy must be performed at least 28 days prior to study registration (due to concerns of poor wound healing on bevacizumab)
  • Patients may not have received any prior anti-VEGF or VEGFR tyrosine kinase inhibitor therapy
  • Prior radiotherapy must have been completed and all toxicities resolved at least two weeks prior to registration
  • Chemotherapy in the adjuvant or neoadjuvant setting is permitted; at least twelve months prior to registration must have elapsed since the completion of adjuvant or neoadjuvant chemotherapy and all toxicities must have resolved; taxane-related neurotoxicity must have resolved to sensory grade < 2 and no motor neuropathy of any grade is allowed
  • Patients may have received one prior chemotherapy regimen for metastatic disease; the final dose of prior chemotherapy must have been administered at least 3 weeks prior to study registration
  • Treatment with bisphosphonates is allowed and recommended as per American Society of Clinical Oncology (ASCO) guidelines
  • Patients must not have had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study registration, and must have fully recovered from any such procedure
  • Patients must not have anticipation of need for major surgical procedure during the course of the study
  • Patients must not have had a core biopsy or other minor surgical procedure, within 7 days prior to study registration; placement of a vascular access device is allowed within 7 days of registration
  • Patients must not have a history of abdominal fistula, or intra-abdominal abscess within 6 months prior to study registration
  • Patients with a history of gastrointestinal (GI) perforation within 12 months prior to registration are not eligible
  • Patients with a history of significant bleeding episodes (e.g., hemoptysis, upper or lower GI bleeding) within 6 months prior to registration are not eligible

  • Patients must not have clinically significant cardiovascular disease that includes the following:

    • Uncontrolled hypertension defined as systolic blood pressure > 150 and/or diastolic blood pressure > 90 mmHg on antihypertensive medications or any prior history of hypertensive crisis or hypertensive encephalopathy
    • History of myocardial infarction or unstable angina within past 6 months
    • New York Heart Association (NYHA) grade 2 or greater congestive heart failure
    • Symptomatic peripheral vascular disease
    • Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or arterial thrombotic events
  • Full dose anticoagulation therapy is allowed for the treatment of prior conditions such as venous thrombosis 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 international normalized ratio (INR) (usually between 2 and 3) or be on a stable dose of low-molecular weight (LMW) heparin; patients receiving antiplatelet agents are eligible, as are patients on daily prophylactic aspirin or anticoagulation for atrial fibrillation
  • Patients may not have a history of stroke or transient ischemic attack within 6 months prior to study registration
  • Patients with a history of seizures must be well controlled with standard medication
  • Patients must not have known central nervous system (CNS) metastases or leptomeningeal disease (screening with brain imaging is not required for asymptomatic patients)
  • In aromatase inhibitor (AI)-treated patients: no known allergies to imidazole drugs, (e.g. clotrimazole, ketoconazole, miconazole, econazole, sulconazole, tioconazole, or terconazole) or compounds structurally similar to bevacizumab
  • In tamoxifen treated patients: no known allergies to selective estrogen receptor modulators (e.g. tamoxifen, raloxifene or toremifene) or compounds structurally similar to bevacizumab; for patients enrolled after Update #5, endocrine therapy will consist of letrozole only and this criterion will no longer apply
  • Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status =< 1
  • No serious, non-healing wound, ulcer, or bone fracture
  • Life expectancy of >= 12 weeks
  • All patients who are premenopausal (if not already receiving ovarian suppression therapy/surgical oophorectomy) must have a negative beta-human chorionic gonadotropin (beta-Hcg) prior to starting on study treatment; patients may not be pregnant or nursing at any time during the study; ovarian suppression is required in women of childbearing potential by the start of protocol therapy, and will continue for the duration of protocol therapy
  • Granulocytes >= 1,000/ul
  • Platelet count >= 100,000/ul
  • Creatinine =< 2.0 mg/dL
  • Bilirubin =< 1.5 times upper limit of normal (ULN) unless due to Gilbert's syndrome
  • Transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) =< 2.5 times ULN
  • International normalized ratio (INR) =< 1.6, unless on full dose warfarin
  • Beta-Hcg negative in premenopausal women

  • Urine protein =< 1+ or urine to plasma creatinine (UPC) < 1

    • Patients discovered to have >= 2+ proteinuria at baseline must undergo a 24-hour urine collection that must demonstrate < 1 g of protein/24 hr, or UPC ratio < 1 to allow participation in the study
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00601900


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Hope S Rugo Alliance for Clinical Trials in Oncology
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Layout table for additonal information
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00601900    
Other Study ID Numbers: NCI-2009-00477
NCI-2009-00477 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CALGB-40503
CDR0000584091
CALGB 40503/CTSU 40503
CALGB-40503 ( Other Identifier: Alliance for Clinical Trials in Oncology )
CALGB-40503 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
U10CA031946 ( U.S. NIH Grant/Contract )
First Posted: January 28, 2008    Key Record Dates
Results First Posted: August 23, 2016
Last Update Posted: March 8, 2023
Last Verified: November 2022
Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma
Breast Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Tamoxifen
Bevacizumab
Antineoplastic Agents, Immunological
Letrozole
Endothelial Growth Factors
Antibodies
Immunoglobulins
 Antibodies, Monoclonal
Immunoglobulin G
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Estrogen Antagonists
Hormone Antagonists