Trial record 2 of 113 for:    30607

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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00601900
First received: January 18, 2008
Last updated: July 23, 2014
Last verified: July 2014
  Purpose

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 citrate* 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.


Condition Intervention Phase
Recurrent Breast Cancer
Stage IIIB Breast Cancer
Stage IV Breast Cancer
Drug: tamoxifen citrate
Drug: letrozole
Biological: bevacizumab
Other: laboratory biomarker analysis
Other: questionnaire administration
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Progression-free survival [ Time Frame: From randomization until disease progression or death, assessed up to 5 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 5 years ] [ Designated as safety issue: Yes ]
    Graded using the NCI CTCAE version 4.0.


Secondary Outcome Measures:
  • Objective tumor response as defined by RECIST criteria for patients with measurable disease [ Time Frame: Assessed up to 5 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 5 years ] [ Designated as safety issue: No ]
  • Treatment related toxicity [ Time Frame: Assessed up to 5 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 5 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 5 years ] [ Designated as safety issue: No ]
    Defined by RECIST criteria.

  • Overall survival (OS) [ Time Frame: Assessed up to 5 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 ]

Other Outcome Measures:
  • PFS predicted by CTCs and CECs measured at baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Descriptive statistics and proportional hazards regression modeling will be examined. A variety of functional forms, including untransformed values, logarithms, and cut points will be used, as will regression trees and loess plots within test/validation samples to explore cutpoints.

  • Longitudinal aspect of CTC and CEC levels [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    A multivariate proportional hazards model that relates various functional forms of CTC and CEC levels to the hazard of progression. The mixed linear model will be used to test for arm differences in changes in CTCs and CECs across time.

  • Correlation of PIK3CA with CECs [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The association of PIK3CA with dichotomous markers will be assessed with contingency tables and the chi-square test. A variety of functional forms will be considered through the use of cutpoints, loess plots and restricted cubic splines.

  • Correlation of PIK3CA with CTCs [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The association of PIK3CA with dichotomous markers will be assessed with contingency tables and the chi-square test. A variety of functional forms will be considered through the use of cutpoints, loess plots and restricted cubic splines.

  • Correlation of PIK3CA with VEGF [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The association of PIK3CA with continuous markers such as VEGF will be assessed by using the logistic regression model to examine the functional form of the association. A variety of functional forms will be examined through the use of cutpoints, loess plots and restricted cubic splines.

  • Correlation of PIK3CA with CD31 [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The association of PIK3CA with continuous markers will be assessed by using the logistic regression model to examine the functional form of the association. A variety of functional forms will be examined through the use of cutpoints, loess plots and restricted cubic splines.

  • Correlation of PIK3CA with AR [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The association of PIK3CA with continuous markers will be assessed by using the logistic regression model to examine the functional form of the association. A variety of functional forms will be examined through the use of cutpoints, loess plots and restricted cubic splines.

  • Correlation of PIK3CA with Luminal subtype [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The association of PIK3CA with continuous markers will be assessed by using the logistic regression model to examine the functional form of the association. A variety of functional forms will be examined through the use of cutpoints, loess plots and restricted cubic splines.

  • Improvement in PFS due to bevacizumab depends on the VEGF gene [ Time Frame: Assessed up to 3 years ] [ Designated as safety issue: No ]
    This will be investigated in the framework of a two-way multiplicative log-linear Cox model with factors drug (P=control or B=bevacizumab) and VEGF gene (1=CT/TT or 2=CC).

  • Identify SNPs associated with PFS [ Time Frame: Assessed up to 3 years ] [ Designated as safety issue: No ]
    Logistic regression models and conditional inference trees (or more generally conditional random forests) will be used to construct multi-variable models based on the SNPs identified as interesting. This model also allows for inclusion of other potentially relevant clinical demographic variables.

  • Association between each CNV marker and the clinical adverse event (AE) endpoint [ Time Frame: Assessed up to 3 years ] [ Designated as safety issue: No ]
    This will be assessed using the Wilcoxon two-sample test. Regression methods, as in the case of the SNP markers, will be employed to construct multivariable models based on the CVN markers.

  • Associations between the occurrence of grade 3, 4, or 5 toxicity and clinical factors [ Time Frame: Baseline to 3 years ] [ Designated as safety issue: No ]
    To account for multiple comparisons in the primary objective, a Bonferroni correction will be applied to a two-sided Type I error of 0.05. For the continuous factors (Medical Outcome Study [MOS] Physical Functioning, Karnofsky Performance Status Rated Healthcare Professional, Timed "Up and Go", Older American Resources and Services [OARS] Physical Health Section), logistic regression will be used to determine the odds ratio of toxicity.


Enrollment: 394
Study Start Date: May 2008
Study Completion Date: June 2014
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (endocrine therapy with monoclonal antibody)
Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: tamoxifen citrate
Given PO
Other Names:
  • Nolvadex
  • TAM
  • tamoxifen
  • TMX
Drug: letrozole
Given PO
Other Names:
  • CGS 20267
  • Femara
  • LTZ
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Other: laboratory biomarker analysis
Correlative studies
Other: questionnaire administration
Ancillary studies
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.
Drug: tamoxifen citrate
Given PO
Other Names:
  • Nolvadex
  • TAM
  • tamoxifen
  • TMX
Drug: letrozole
Given PO
Other Names:
  • CGS 20267
  • Femara
  • LTZ
Other: laboratory biomarker analysis
Correlative studies
Other: questionnaire administration
Ancillary studies

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders 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
  • Must have measurable or nonmeasurable disease by RECIST criteria, with radiologic scans

    • 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
    • Nonmeasurable 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 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
  • 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 VEGF receptor (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 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 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, ticonazole, 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 toremilfene) 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 0-1
  • 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/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 (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
  • Urinalysis =< 1+ protein 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
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00601900

  Show 466 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Maura Dickler Cancer and Leukemia Group B
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00601900     History of Changes
Other Study ID Numbers: NCI-2009-00477, NCI-2009-00477, CDR0000584091, CALGB-40503, CALGB 40503, CALGB-40503, P30CA014236, U10CA031946
Study First Received: January 18, 2008
Last Updated: July 23, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Antibodies
Antibodies, Monoclonal
Citric Acid
Tamoxifen
Letrozole
Bevacizumab
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Anticoagulants
Hematologic Agents
Therapeutic Uses
Chelating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Bone Density Conservation Agents
Estrogen Antagonists
Aromatase Inhibitors
Enzyme Inhibitors
Angiogenesis Inhibitors

ClinicalTrials.gov processed this record on July 23, 2014