Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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: September 12, 2014
Last verified: September 2014

January 18, 2008
September 12, 2014
May 2008
June 2014   (final data collection date for primary outcome measure)
  • 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.
  • 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 ]
Complete list of historical versions of study NCT00601900 on ClinicalTrials.gov Archive Site
  • 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. The proportional hazards model will be used to compare the arms on time-to-treatment-failure.
  • 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 ]
  • 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 ]
  • 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 cutpoints 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.
Not Provided
 
Tamoxifen Citrate or Letrozole With or Without Bevacizumab in Treating Women With Stage III or Stage IV Breast Cancer
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

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 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, may help control breast cancer by stopping the growth of blood vessels 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 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.

SECONDARY OBJECTIVES:

I. To compare the proportion of patients receiving letrozole alone, who remain progression-free at 6 and 12 months, to those receiving letrozole plus bevacizumab.

II. To compare the incidence of objective response (complete response [CR] + partial response [PR]) in patients receiving letrozole with and without bevacizumab, as determined by Response Evaluation Criteria in Solid Tumors (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 and without bevacizumab.

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

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bevacizumab; time to treatment failure is defined as the interval from randomization until progression, toxicity, withdrawn consent or going onto non-protocol therapy.

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

V. To compare toxicity levels between the bevacizumab arm and the arm without 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).

TERTIARY OBJECTIVES:

I. To compare baseline and changes in serial levels of circulating endothelial cells and circulating tumor cells in patients treated with endocrine therapy alone or endocrine therapy plus bevacizumab, and to explore the relationship of these markers with progression free survival.

II. To conduct proteomic analysis of longitudinal samples from patients with advanced-stage disease undergoing hormonal therapy to define new serum-based biomarkers related to disease activity.

III. To identify biologic correlates that will predict progression-free survival (PFS) and response to therapy.

IV. To conduct pharmacogenomic assessment of candidate variants in the vascular endothelial growth factor (VEGF), cytochrome P450 system (CYP) family 2, subfamily D, polypeptide 6 (2D6), and CYP family 19 (CYP19) genes and evaluate their association with PFS and other study outcomes.

V. To identify single nucleotide polymorphisms (SNPs) associated with progression free survival in the genome-wide approach (GWAS).

VI. To identify factors other than chronological age that predict the risk of grade 3, 4 or 5 toxicity with bevacizumab and endocrine therapy by means of functional age assessment measures; the factors to be studied include: functional status, comorbid medical conditions, cognitive function, psychological state, social support and nutritional status.

VII. To perform an exploratory analysis of the ability of the other factors included in the functional age assessment (either individual or in combination), to predict the risk of grade 3, 4 or 5 toxicity.

VIII. To evaluate longitudinal changes in the parameters of the factors described in objective VI while on therapy.

OUTLINE: 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 endocrine therapy* (tamoxifen citrate or letrozole) orally (PO) once daily (QD) on days 1-21 and bevacizumab intravenously (IV) over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: 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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Estrogen Receptor-positive Breast Cancer
  • Progesterone Receptor-positive Breast Cancer
  • Recurrent Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IV Breast Cancer
  • 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
  • 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.
    Interventions:
    • Drug: tamoxifen citrate
    • Drug: letrozole
    • Biological: bevacizumab
    • Other: laboratory biomarker analysis
    • Other: questionnaire administration
  • 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.
    Interventions:
    • Drug: tamoxifen citrate
    • Drug: letrozole
    • Other: laboratory biomarker analysis
    • Other: questionnaire administration
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
394
June 2014
June 2014   (final data collection date for primary outcome measure)

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 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
    • 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 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, 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 =< 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
  • 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
Female
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States,   Puerto Rico
 
NCT00601900
NCI-2009-00477, NCI-2009-00477, CALGB 40503/CTSU 40503, CDR0000584091, CALGB 40503, CALGB-40503, U10CA031946, U10CA180821
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Maura Dickler Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP