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: April 9, 2014
Last verified: April 2014
  Purpose

This randomized phase III trial is studying first-line chemotherapy and trastuzumab to compare how well they work when given with or without bevacizumab in treating patients with metastatic breast cancer that overexpresses HER-2/NEU. 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 or by stopping them from dividing. Monoclonal antibodies, such as trastuzumab and 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 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
HER2-positive Breast Cancer
Male Breast Cancer
Recurrent Breast Cancer
Stage IV Breast Cancer
Biological: trastuzumab
Drug: paclitaxel
Drug: carboplatin
Other: placebo
Biological: bevacizumab
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, 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: 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%.


Secondary Outcome Measures:
  • 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 FBSI-8, FACT-G item GP5, FACT/GOGNtx, 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.


Estimated Enrollment: 489
Study Start Date: November 2007
Estimated Primary Completion Date: September 2014 (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.

Biological: trastuzumab
Lead intervention, 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
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: trastuzumab
Lead intervention, 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
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF

  Hide Detailed Description

Detailed Description:

PRIMARY OBJECTIVE:

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 (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 VEGF levels in breast tumor tissue. VIII. Analysis of Circulating Tumor Cells and Circulating Endothelial Cells (CEC).

IX. Serially enumerate 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 akt-2 in circulating tumor cells.

XI. Perform an exploratory analysis of RT-PCR of CTC mRNA to determine whether change in expression of selected down stream targets of bevacizumab therapy can serve as pharmacodynamic or surrogate markers of bevacizumab targeting and modulation.

OUTLINE: This is a multicenter study. Patients are stratified according to prior treatment with adjuvant trastuzumab (Herceptin) (yes vs no), prior treatment with neoadjuvant or adjuvant taxane (yes vs no), disease-free interval (> 24 months vs =< 24 months), and planned treatment with carboplatin (yes vs no). 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 periodically for 10 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • ECOG performance status of 0 or 1
  • Histologically confirmed breast cancer that overexpresses HER-2/NEU
  • HER-2/NEU overexpression is defined as 3+ HER-2 positivity as measured by immunohistochemistry OR HER-2 gene amplification as measured by FISH
  • Evidence of metastatic disease and/or chest wall recurrence
  • Evaluable (measurable or non-measurable) disease is allowed if confirmed within 4 weeks prior to study randomization
  • No history or radiologic evidence of CNS disease
  • Platelet count >= 100,000/mm^3
  • Total bilirubin =< 1.5 mg/dL
  • 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 < 1,000 mg
  • INR =< 1.5 times ULN
  • PTT =< 1.5 times ULN
  • LVEF above the lower limit of normal by MUGA scan or ECHO
  • No grade 2-4 neuropathy
  • No unstable angina pectoris
  • No serious cardiac arrhythmia requiring medication
  • No clinically significant peripheral vascular disease
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No current non-healing wound or fracture
  • No hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies, paclitaxel, or drugs using the vehicle Cremophor
  • No serious medical or psychiatric illness that would preclude study participation
  • No other active malignancy within the past 5 years except carcinoma in situ of the cervix or nonmelanoma skin cancer
  • Adjuvant or neoadjuvant taxane therapy for breast cancer is allowed provided last dose was given >= 12 months prior to diagnosis of recurrence
  • No prior chemotherapy, trastuzumab, or bevacizumab for metastatic breast cancer
  • No prior cumulative dose of doxorubicin hydrochloride > 360 mg/m2 or epirubicin hydrochloride > 640 mg/m2 (in the neoadjuvant or adjuvant setting)
  • More than 4 weeks since prior major surgical procedure (except for non-operative biopsy)
  • More than 7 days since prior placement of a vascular access device
  • Concurrent full-dose anticoagulants (e.g., warfarin) with PT/INR > 1.5 allowed provided the following criteria are met:
  • 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
  • No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
  • No concurrent local radiotherapy for pain control or life-threatening situations
  • No concurrent drugs known to inhibit platelet function, including the following:

    • dipyridamole,
    • ticlopidine,
    • clopidogrel,
    • cilostazol
  • Adjuvant trastuzumab (Herceptin) therapy for breast cancer is allowed provided last dose was given >= 12 months prior to diagnosis of recurrence
  • Adjuvant or neoadjuvant therapy with lapatinib ditosylate is allowed provided last dose was given >= 4 weeks prior to diagnosis of recurrence
  • Absolute neutrophil count >= 1,000/mm^3
  • No clinically significant cardiovascular disease
  • No cerebrovascular accident within the past 6 months
  • No myocardial infarction or unstable angina within the past 6 months
  • No New York Heart Association class II-IV congestive heart failure
  • No uncontrolled hypertension
  • Endocrine treatment in the adjuvant or metastatic setting is allowed, provided last dose given >= 2 weeks prior to randomization
  • More than 3 weeks since prior radiotherapy
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00520975

  Show 375 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Ingrid Mayer Eastern Cooperative Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00520975     History of Changes
Other Study ID Numbers: NCI-2009-00504, NCI-2009-00504, E1105, CDR0000561762, E1105, E1105, U10CA021115
Study First Received: August 24, 2007
Last Updated: April 9, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Breast Neoplasms, Male
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Antibodies
Antibodies, Monoclonal
Trastuzumab
Bevacizumab
Carboplatin
Paclitaxel
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on April 16, 2014