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Bevacizumab in Treating Patients With Metastatic Breast Cancer That Overexpresses HER-2/NEU

This study has been terminated.
(Closed early due to slow accrual)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00520975
First received: August 24, 2007
Last updated: December 12, 2016
Last verified: December 2016
  Purpose
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, may interfere with the ability of tumor cells to grow and spread. 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.

Condition Intervention Phase
Breast Carcinoma
Recurrent Breast Carcinoma
Stage IV Breast Cancer
Biological: Bevacizumab
Drug: Carboplatin
Drug: Paclitaxel
Other: Placebo
Biological: Trastuzumab
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Progression-free Survival [ Time Frame: assessed every 3 months for patients within 2 years of registration, every 6 months for patients 3-5 years from registration and then yearly for up to10 years ]
    Progression-free survival (PFS) was defined as time from date of randomization to first disease progression, new second breast primaries, or to death from any cause, whichever occurred first, otherwise cases were censored at date last documented to be free of progression. Disease progression was defined using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Kaplan-Meier method was used to estimate the median PFS.


Secondary Outcome Measures:
  • Overall Survival [ Time Frame: assessed every 3 months for patients within 2 years of registration, every 6 months for patients 3-5 years from registration and then yearly for up to10 years ]
    Overall survival (OS) is defined as the time from randomization until death (event), or censored at last date known alive. Kaplan-Meier method was used to estimate the median OS.

  • Proportion of Progression-free at 6 Months [ Time Frame: assessed at baseline, at 3 and 6 months after study entry ]
    Disease progression was defined using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Proportion of progression-free at 6 months was calculated using the Kaplan-Meier method.

  • Overall Response Rate [ Time Frame: assessed at baseline, every 12 weeks while on treatment, then very 3 months if patient is <2 years from study entry, every 6 months if 2-5 years from study entry, and annually if 6-10 years from study entry until disease progression ]
    Overall response rate is defined as number of patients with complete response (CR) or partial response (PR) divided by all randomized patients. Responses are evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline. CR is defined as disappearance of all target and non-target lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameters), and/or persistence of one or more non-target lesion(s).

  • Number of Patients Experiencing Congestive Heart Failure [ Time Frame: assessed every 3 months while on treatment and at 3 months post treatment ]
    Clinical congestive heart failure (CHF) was assessed using Left Ventricular Ejection Fraction (LVEF) and symptom information via the Cardiac Toxicity Form as well as symptom information collected via the Adverse Event Form. Clinical CHF was defined as symptomatic decline in LVEF to below the lower limit of normal (LLN) or symptomatic diastolic dysfunction.


Other Outcome Measures:
  • Change in Fatigue Level Between Baseline and Cycle 6 Induction [ Time Frame: assessed at baseline and at cycle 6 induction prior to starting maintenance therapy ]
    Fatigue level was measured using Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue subscale. Participants indicated their level of fatigue across 13 items, each item on a 5-point Likert scale ranging from 0 (not at all) to 4(very much). Total score per patient was calculated by taking the reverse of each item (unless specified not to), taking the sum of those items, multiplying the sum by the number of items in the scale, and then dividing that number by the number of answered items. Total score ranged from 0 to 52 with higher scores representing less fatigue.

  • Change in FACT/NCCN Breast Symptom Index (FBSI) Between Baseline and Cycle 6 Induction [ Time Frame: assessed at baseline and at cycle 6 induction prior to starting maintenance therapy ]
    Participants indicated their level of breast symptoms across 8 items using the Functional Assessment of Cancer Therapy/National Comprehensive Cancer Network (FACT/NCCN) FBSI scale, each item on a 5-point Likert scale ranging from 0 (not at all) to 4(very much). Total score per patient, ranged from 0 to 32 with higher scores representing fewer symptoms.

  • Change in Neurotoxicity Level Between Baseline and Cycle 6 Induction [ Time Frame: assessed at baseline and at cycle 6 induction prior to starting maintenance therapy ]
    Participants indicated their level of neurotoxicity symptoms across 4 items using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) scale, each item on a 5-point Likert scale ranging from 0 (not at all) to 4(very much). Total score per patient ranged from 0 to 16 with higher scores representing fewer neurotoxic symptoms.

  • Change in Level of Experiencing Side Effects Between Baseline and Cycle 6 Induction [ Time Frame: assessed at baseline and at cycle 6 induction prior to starting maintenance therapy ]
    Participants indicated their level of experiencing side effects across 1 item (Functional Assessment of Cancer Therapy [FACT] item G5) on a 5-point Likert scale ranging from 0 (not at all) to 4(very much). Total score per patient, ranged from 0 to 4 with a higher score representing better quality of life (QOL).

  • Number of Circulating Tumor Cells at Baseline [ Time Frame: assessed at baseline prior to starting protocol therapy ]
    Number of circulating tumor cells per 7.5mL blood were counted prior to starting protocol therapy

  • VEGF Levels in Breast Tumor by Immunohistochemistry Assay (Tumor Sample Has Not Been Analyzed Yet, no Results Could be Reported) [ Time Frame: assessed at baseline ]
    Tissue sections from the primary or metastatic paraffin blocks were subjected to VEGF immunohistochemistry (IHC). The VEGF cytoplasmic staining intensity was evaluated semiquantitavely using a classification from 0 to 3, with 0 representing lack of staining, 1 = low staining intensity, 2 = intermediate staining intensity and 3 = strong staining intensity. The fraction of positively staining cells will be determined as well (0 = lack of staining, 1 ≤ 1% cell staining, 2 = 1 - 10% cell staining, 3 = 10 - 50% cell staining, 4 = 50 - 90% cells staining and 5 ≤ 90% cells staining) (48). Staining intensity score zero and fraction of positively staining cells of ≤ 1% (scores zero and 1) will be considered as absence of staining and therefore negative overexpression of VEGF.


Enrollment: 96
Study Start Date: November 2007
Study Completion Date: October 2015
Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

Drug: Carboplatin
Given IV
Other Names:
  • CBDCA
  • JM-8
  • Paraplatin
  • NSC-241240
Drug: Paclitaxel
Given IV
Other Names:
  • Taxol
  • NSC 125973
Other: Placebo
Given IV
Other Names:
  • placebo therapy
  • sham therapy
Biological: Trastuzumab
Given IV
Other Names:
  • Anti-HER2 Monoclonal Antibody
  • Herceptin
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.

Biological: Bevacizumab
Given IV
Other Names:
  • Anti-VEGF Humanized Monoclonal Antibody
  • Avastin
Drug: Carboplatin
Given IV
Other Names:
  • CBDCA
  • JM-8
  • Paraplatin
  • NSC-241240
Drug: Paclitaxel
Given IV
Other Names:
  • Taxol
  • NSC 125973
Biological: Trastuzumab
Given IV
Other Names:
  • Anti-HER2 Monoclonal Antibody
  • Herceptin

  Show Detailed Description

  Eligibility

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

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
  • 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
  • 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
  • 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
  • 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 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

Exclusion Criteria:

  • Prior chemotherapy, trastuzumab, or bevacizumab for metastatic breast cancer
  • 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
  • Patients with grade 2-4 neuropathy
  • Patients with a history or radiologic evidence of central nervous system (CNS) disease
  • Patients have a current non-healing wound or fracture
  • Patients have a hypersensitivity to paclitaxel or drugs using the vehicle Cremophor, Chinese hamster ovary cell products or other recombinant human antibodies
  • Patients have a serious medical or psychiatric illness that would prevent ability to safely participate or provide informed consent
  • Patients using any of the following drugs known to inhibit platelet function are not eligible: dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and cilostazol (Pletal)
  • Clinically significant cardiovascular disease, 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
  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: NCT00520975

  Show 373 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Ingrid Mayer ECOG-ACRIN Cancer Research Group
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00520975     History of Changes
Other Study ID Numbers: NCI-2009-00504
NCI-2009-00504 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
E1105 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
U10CA180794 ( US NIH Grant/Contract Award Number )
U10CA023318 ( US NIH Grant/Contract Award Number )
Study First Received: August 24, 2007
Results First Received: October 5, 2016
Last Updated: December 12, 2016
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.

Keywords provided by National Cancer Institute (NCI):
Trastuzumab
Bevacizumab
Metastatic Breast Cancer
HER2/NEU

Additional relevant MeSH terms:
Breast Neoplasms
Carcinoma
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Bevacizumab
Paclitaxel
Albumin-Bound Paclitaxel
Trastuzumab
Carboplatin
Antibodies, Monoclonal
Antibodies
Immunoglobulins
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunologic Factors

ClinicalTrials.gov processed this record on May 25, 2017