First-Line Chemotherapy and Trastuzumab With or Without Bevacizumab in Treating Patients With Metastatic Breast Cancer That Overexpresses HER-2/NEU

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00520975
First received: August 24, 2007
Last updated: September 12, 2014
Last verified: July 2014

August 24, 2007
September 12, 2014
November 2007
September 2014   (final data collection date for primary outcome measure)
Progression-free survival [ Time Frame: From randomization to progression per RECIST, new second breast cancer primaries or to death from any cause without documentation of progression, whichever occurs first, assessed up to 10 years ] [ Designated as safety issue: No ]
This primary comparison will be performed using a one-sided log rank test stratified using an overall type I error of 2.5%.
Progression-free survival
Complete list of historical versions of study NCT00520975 on ClinicalTrials.gov Archive Site
  • Overall survival [ Time Frame: From randomization to death from any cause, assessed up to 10 years ] [ Designated as safety issue: No ]
    A truncated version of the Lan-Demets error spending rate function corresponding to the O'Brien-Fleming boundary will be used to control the overall type I error rate at a one-sided 0.025 level.
  • Quality of Life assessed using the Functional Assessment of Cancer Therapy (FACT)- Breast Symptom Index Questionnaire-8, FACT- General (G item GP5), FACT/Gynecologic Oncology Group-Neurotoxicity and FACT Fatigue [ Time Frame: Up to 60 months ] [ Designated as safety issue: No ]
    The Wilcoxon Rank Sum test will be used to compare the arms if the distributions of scores are not normally distributed. Longitudinal modeling will be used to look at changes in the scores over time between arms.
  • Congestive heart failure (CHF) rate [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
    Using a Fisher's exact test and a 10% one sided type I error rate, there is 81% power to detect a difference of 4% vs. 10% CHF rate.
  • Change in CTC levels over time [ Time Frame: Baseline to up to 12 weeks after treatment initiation ] [ Designated as safety issue: No ]
    Fisher's exact test will be used to test for differences between treatment groups with respect to the proportion of patients with blood will less than 5 CTCs at baseline and at follow up time points.
  • VEGF levels in breast tumor by immunohistochemistry assay [ Time Frame: Baseline ] [ Designated as safety issue: No ]
Overall survival
Not Provided
Not Provided
 
First-Line Chemotherapy and Trastuzumab With or Without Bevacizumab in Treating Patients With Metastatic Breast Cancer That Overexpresses HER-2/NEU
A Randomized Phase III Double-Blind Placebo-Controlled Trial of First-Line Chemotherapy and Trastuzumab With or Without Bevacizumab for Patients With HER-2/NEU Over-Expressing Metastatic Breast Cancer

This randomized phase III trial studies first-line chemotherapy and trastuzumab to compare how well they work when given with or without bevacizumab in treating patients with breast cancer that overexpresses human epidermal growth factor receptor 2 (HER-2/NEU) and has spread to other areas of the body. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as trastuzumab and bevacizumab, can block tumor growth in different ways. Bevacizumab may also stop the growth of breast cancer by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether giving first-line chemotherapy together with trastuzumab is more effective with or without bevacizumab in treating patients with metastatic breast cancer that overexpresses HER-2/NEU.

PRIMARY OBJECTIVES:

I. Evaluate efficacy of the addition of bevacizumab in patients eligible for first-line trastuzumab with chemotherapy for HER-2/NEU overexpressing metastatic breast cancer, by assessing the progression-free survival (PFS) after initiation of combination therapy.

SECONDARY OBJECTIVES:

I. Evaluate response rates (RR) in patients with measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST]), when applicable.

II. Evaluate overall survival (OS). III. Evaluate time to progression (TTP). IV. Evaluate the percent of patients who are progression-free (PPF) at 6 months.

V. Compare the toxicity of chemotherapy/trastuzumab to that of chemotherapy/trastuzumab in combination with bevacizumab.

VI. Compare breast cancer symptoms and treatment related symptoms between patients receiving chemotherapy and trastuzumab with or without bevacizumab.

VII. Evaluate whether PFS correlates with vascular endothelial growth factor (VEGF) levels in breast tumor tissue.

VIII. Analysis of circulating tumor cells and circulating endothelial cells (CEC).

IX. Serially enumerate circulating tumor cells (CTC) and CEC in patients on study and determine whether: the number of CTC and CEC decrease in responding patients; the extent of CTC and CEC decrease is greater in the experimental arm, Arm B versus the control arm, Arm A; enumeration of CTC and CEC in responding patients correlate with progression free survival (PFS).

X. Perform an exploratory analysis of phosphorylation status of v-akt murine thymoma viral oncogene homolog (akt)-2 in circulating tumor cells.

XI. Perform an exploratory analysis of reverse transcriptase (RT)-polymerase chain reaction (PCR) of CTC messenger ribonucleic acid (mRNA) to determine whether change in expression of selected downstream targets of bevacizumab therapy can serve as pharmacodynamic or surrogate markers of bevacizumab targeting and modulation.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A:

INDUCTION THERAPY: Patients receive trastuzumab intravenously (IV) over 30-90 minutes on days 1, 8, 15, and 22 and paclitaxel IV over 60 minutes with or without carboplatin IV over 60 minutes on days 1, 8, and 15. Patients also receive placebo IV over 30-90 minutes on day 1 and 15. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients receive trastuzumab IV over 30-90 minutes and placebo IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.

ARM B:

INDUCTION THERAPY: Patients receive trastuzumab and paclitaxel with or without carboplatin as in Arm A. Patients also receive bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients receive trastuzumab IV over 30-90 minutes and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 10 years.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
  • HER2-positive Breast Cancer
  • Male Breast Cancer
  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Biological: trastuzumab
    Given IV
    Other Names:
    • anti-c-erB-2
    • Herceptin
    • MOAB HER2
  • Drug: paclitaxel
    Given IV
    Other Names:
    • Anzatax
    • Asotax
    • TAX
    • Taxol
  • Drug: carboplatin
    Given IV
    Other Names:
    • Carboplat
    • CBDCA
    • JM-8
    • Paraplat
    • Paraplatin
  • Other: placebo
    Given IV
    Other Name: PLCB
  • 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: quality-of-life assessment
    Ancillary studies
    Other Name: quality of life assessment
  • Active Comparator: Arm A (chemotherapy and placebo)

    INDUCTION THERAPY: Patients receive trastuzumab IV over 30-90 minutes on days 1, 8, 15, and 22 and paclitaxel IV over 60 minutes with or without carboplatin IV over 60 minutes on days 1, 8, and 15. Patients also receive placebo IV over 30-90 minutes on day 1 and 15. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

    MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients receive trastuzumab IV over 30-90 minutes and placebo IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.

    Interventions:
    • Biological: trastuzumab
    • Drug: paclitaxel
    • Drug: carboplatin
    • Other: placebo
    • Other: laboratory biomarker analysis
    • Other: quality-of-life assessment
  • Experimental: Arm B (chemotherapy and bevacizumab)

    INDUCTION THERAPY: Patients receive trastuzumab and paclitaxel with or without carboplatin as in Arm A. Patients also receive bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

    MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients receive trastuzumab IV over 30-90 minutes and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.

    Interventions:
    • Biological: trastuzumab
    • Drug: paclitaxel
    • Drug: carboplatin
    • Biological: bevacizumab
    • Other: laboratory biomarker analysis
    • Other: quality-of-life assessment
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
489
Not Provided
September 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Histologically confirmed breast cancer that overexpresses HER-2/NEU with evidence of metastatic disease and/or chest wall recurrence prior to randomization
  • HER-2/NEU overexpression is defined as 3+ HER-2 positivity as measured by immunohistochemistry OR HER-2 gene amplification as measured by fluorescent in situ hybridization (FISH, e.g. Vysis), per American Society of Clinical Oncology guidelines

    • NOTE: representative diagnostic tissue must be submitted for central diagnostic review for confirmation of HER-2/NEU overexpression within two weeks following patient randomization
  • Evaluable (measurable or non-measurable) disease is allowed if confirmed within 4 weeks prior to randomization
  • Prior endocrine treatment in the adjuvant or metastatic setting is allowed, provided last dose given >= 2 weeks prior to randomization
  • Prior chemotherapy, trastuzumab, or bevacizumab for metastatic breast cancer is not allowed
  • Patients who have had a CUMULATIVE dose of doxorubicin of greater than 360 mg/m^2 or epirubicin of greater than 640 mg/m^2 in the adjuvant or neo-adjuvant setting at any time are not allowed
  • Radiation therapy is allowed provided last dose is given >= 3 weeks prior to randomization
  • Adjuvant trastuzumab therapy for breast cancer is allowed provided last dose was given >= 12 months prior to diagnosis of recurrence
  • Adjuvant or neoadjuvant taxane therapy for breast cancer is allowed provided last dose was given >= 12 months prior to diagnosis of recurrence
  • Adjuvant or neoadjuvant therapy with lapatinib is allowed provided last dose is given >= 4 weeks prior to diagnosis of recurrence
  • Patients with grade 2-4 neuropathy are not allowed
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Absolute neutrophil count >= 1,000/mm^3
  • Platelet count >= 100,000/mm^3
  • Total bilirubin =< 1.5 mg/dL
  • Aspartate aminotransferase (AST) =< 2 times upper limit of normal (ULN) (=< 5 times normal in patients with known liver involvement)
  • Serum creatinine =< 1.5 mg/dL
  • Urine protein: creatinine ratio =< 0.5 OR 24-hour urine protein < 1000 mg
  • International normalized ratio (INR) =< 1.5 X ULN
  • Partial thromboplastin time (PTT) =< 1.5 X ULN
  • Multi gated acquisition scan (MUGA) scan or echocardiogram (ECHO) within 6 weeks prior to randomization with an left ventricular ejection fraction (LVEF) above the institutional lower limit of normal
  • Patients must be able to understand and provide signed and dated written informed consent
  • Patients with a history or radiologic evidence of central nervous system (CNS) disease are not allowed
  • Major surgical procedure within 4 weeks prior to randomization is not allowed (except for non-operative biopsy, which would not be considered major surgery); treatment can not begin until seven (7) days after placement of a vascular access device
  • Clinically significant cardiovascular disease is not allowed, including:

    • History of cerebrovascular (CVA) within 6 months
    • Uncontrolled hypertension
    • Myocardial infarction or unstable angina within 6 months
    • New York Heart Association class II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris
    • Clinically significant peripheral vascular disease
  • Women must not be pregnant or breastfeeding; all females of childbearing potential must have a blood or urine test within 2 weeks prior to randomization to rule out pregnancy; women of childbearing potential and sexually active males must use an accepted and effective method of contraception
  • Patients on full-dose anticoagulants (e.g., warfarin) with PT/INR > 1.5 may be eligible provided that both of the following criteria are met:

    • The patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
    • The patient has not active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
  • Patients using any of the following drugs known to inhibit platelet function are not eligible: dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and cilostazol (Pletal)
  • Patients must not have a current non-healing wound or fracture
  • Patients must not have a hypersensitivity to paclitaxel or drugs using the vehicle Cremophor, Chinese hamster ovary cell products or other recombinant human antibodies
  • Patients must not have a serious medical or psychiatric illness that would prevent ability to safely participate or provide informed consent
  • Patients with a concurrent active malignancy except carcinoma in situ of the cervix or non-melanoma skin cancers (unless disease-free for at least 5 years at study entry) are not allowed
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00520975
NCI-2009-00504, NCI-2009-00504, CDR0000561762, E1105, E1105, U10CA180820, U10CA021115
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Ingrid Mayer ECOG-ACRIN Cancer Research Group
National Cancer Institute (NCI)
July 2014

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