Stage IIIA Breast Cancer AJCC v7 Clinical Trial
Official title:
Phase III Trial of Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Paclitaxel With or Without Trastuzumab as Adjuvant Treatment for Women With HER-2 Over-Expressing or Amplified Node Positive or High-Risk Node Negative Breast Cancer
This randomized phase III trial studies doxorubicin hydrochloride, cyclophosphamide, paclitaxel, and trastuzumab to see how well they work compared to combination chemotherapy alone in treating women with breast cancer that is human epidermal growth factor receptor 2 (HER2)-positive and has spread to the lymph nodes or high-risk and has not spread to the lymph nodes. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known whether combination chemotherapy is more effective with or without trastuzumab in treating breast cancer.
PRIMARY OBJECTIVES:
I. To compare the combination of doxorubicin hydrochloride and cyclophosphamide (AC) followed
by weekly paclitaxel with the combination of AC followed by the combination of weekly
paclitaxel and trastuzumab in terms of disease free survival (DFS). (Stage I) II. To compare
the combination of AC followed by weekly paclitaxel with the combination of AC followed by
the combination of weekly paclitaxel and trastuzumab in terms of the rate of cardiac events.
(Stage I) III. To compare the combination AC followed by weekly paclitaxel with the
sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of
DFS. (Stage II) IV. To compare the sequential schedule of the combination of AC, weekly
paclitaxel, and trastuzumab with the combination of AC followed by the combination of weekly
paclitaxel and trastuzumab in terms of DFS. (Stage II) V. To compare the combination AC
followed by weekly paclitaxel with the sequential schedule of the combination of AC, weekly
paclitaxel, and trastuzumab in terms of the rate of cardiac events. (Stage II)
SECONDARY OBJECTIVES:
I. To compare the combination of AC followed by weekly paclitaxel with the sequential
schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of overall
survival (OS).
II. To compare the combination AC followed by weekly paclitaxel with the combination of AC
followed by the combination of weekly paclitaxel and trastuzumab in terms of OS.
III. To compare the sequential schedule of the combination AC, weekly paclitaxel, and
trastuzumab with the combination of AC followed by the combination of weekly paclitaxel and
trastuzumab in terms of OS.
TERTIARY OBJECTIVES:
I. To determine whether higher levels of shed ECD (extracellular domain) or autoantibodies to
human epidermal growth factor receptor (HER)-2 and HER-1 measured in the serum prior to
treatment are prognostic for DFS and survival.
II. To determine the concordance of central review of HER-2 overexpression as measured by the
HercepTest (DAKO) and Vysis fluorescence in situ hybridization (FISH).
III. For each treatment arm, levels of brain natriuretic peptide (BNP), troponin-T (TnT),
troponin-I (cTnI), tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and
interleukin-6 (IL-6), CD40 ligand, and troponin levels will be compared and contrasted.
IV. To determine whether genetic markers are prognostic for cardiac adverse events associated
with treatment.
OUTLINE: Patients are randomized to 1 of 3 treatment arms.
ARM I*: Patients receive doxorubicin hydrochloride intravenously (IV) and cyclophosphamide IV
over 20-30 minutes on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then
receive paclitaxel IV over 1 hour beginning on day 1 of week 13 and continuing weekly for 12
courses in the absence of disease progression or unacceptable toxicity. NOTE: *Patients who
completed paclitaxel on or after October 25, 2004 may receive trastuzumab for a maximum of 52
weeks either concurrently with paclitaxel or following completion of paclitaxel treatment.
ARM II*: Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in
arm I. Patients then receive trastuzumab IV over 30-90 minutes beginning on day 1 of week 25
and continuing weekly for 52 courses in the absence of disease progression or unacceptable
toxicity. NOTE: *Patients who completed paclitaxel on or after October 25, 2004 may receive
trastuzumab for a maximum of 52 weeks either concurrently with paclitaxel or following
completion of paclitaxel treatment.
ARM III: Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I.
Patients then receive paclitaxel IV over 1 hour and trastuzumab IV over 30-90 minutes
beginning on day 1 of week 13 and continuing weekly for 12 courses. Patients then receive
trastuzumab IV over 30 minutes beginning on day 1 of week 25 and continuing weekly for 40
courses in the absence of disease progression or unacceptable toxicity.
Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All
postmenopausal estrogen receptor (ER)- or progesterone receptor (PR)-positive patients
receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later
than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase
inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive
tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until
they have received a total of 5 years of adjuvant hormonal therapy.
After completion of study treatment, patients are followed up every 3 months for 1 year,
every 6 months for 4 years, and then annually for 15 years or until disease progression.
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