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Phase III Trial of Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Paclitaxel With or Without Trastuzumab as Adjuvant Treatment for Women With HER-2 Overexpressing Node Positive or High-Risk Node Negative Breast Cancer


Phase 3
18 Years
N/A
Open (Enrolling)
Female
Stage I Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer

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Trial Information

Phase III Trial of Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Paclitaxel With or Without Trastuzumab as Adjuvant Treatment for Women With HER-2 Overexpressing Node Positive or High-Risk Node Negative Breast Cancer


PRIMARY OBJECTIVES:

I. Compare the disease-free survival of women with HER-2-overexpressing node-positive or
high-risk node-negative breast cancer treated with doxorubicin plus cyclophosphamide
followed by paclitaxel with or without trastuzumab (Herceptin).

II. Compare the cardiotoxic effects of these regimens in these patients.

SECONDARY OBJECTIVES:

I. Compare the overall survival of patients treated with these regimens.

TERTIARY OBJECTIVES:

I. Determine whether higher levels of shed extracellular domain or autoantibodies to HER-2
and HER-1 measured in the serum prior to treatment are prognostic for disease-free and
overall survival in these patients.

II. Determine whether the concordance of HER-2 overexpression is associated with
disease-free and overall survival in this patient population.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to nodal
status (0 vs 1-3 positive nodes by axillary nodal dissection vs 4-9 positive nodes by
axillary nodal dissection vs at least 10 positive nodes by axillary nodal dissection vs
positive sentinel node with no or negative axillary nodal dissection vs negative sentinel
node with no axillary nodal dissection vs node negative by axillary nodal dissection) and
receptor status (estrogen receptor [ER] or progesterone receptor [PR] positive vs other).
Patients are randomized to 1 of 3 treatment arms.

ARM I*: Patients receive doxorubicin 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, cyclophosphamide, and paclitaxel as in arm I.
Patients then receive trastuzumab (Herceptin®) 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 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 ER- or 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.

Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then
annually for 15 years or until disease progression.


Inclusion Criteria:



- Histologically confirmed operable adenocarcinoma of the breast, meeting 1 of the
following criteria:

- Node-positive disease, meeting the following criteria:

- One or more positive lymph nodes (T1-3, pN1-2, M0)

- No cN2 disease

- pN2 disease allowed

- One positive lymph node by sentinel node biopsy or at least 6 axillary
nodes must be examined on axillary node dissection with at least 1
positive lymph node

- Metaplastic carcinoma allowed

- High-risk node-negative disease, meeting the following criteria:

- Node-negative as determined by 1 of the following:

- Negative sentinel node biopsy

- No positive lymph nodes found among at least 6 axillary nodes examined
on axillary node dissection

- Tumor must be greater than 2.0 cm if estrogen-receptor (ER)- and
progesterone-receptor (PR)-positive disease is present OR greater than 1.0
cm if ER and PR negative

- HER-2 positive

- Fluorescent in situ hybridization (FISH) must show gene amplification

- IHC assay must show a strong positive (3+) staining score

- Ductal carcinoma in situ (DCIS) components must not be counted in determination
of the degree of IHC staining or FISH amplification

- No locally advanced (T4) tumors at diagnosis, including:

- Tumors fixed to chest wall

- Peau d'orange

- Skin ulcerations/nodules

- Clinical inflammatory changes (diffuse brawny cutaneous induration with an
erysipeloid edge)

- No bilateral invasive carcinoma or DCIS (metachronous or synchronous)

- Unilateral invasive carcinoma and previous metachronous or synchronous DCISof
the contralateral breast treated with mastectomy allowed

- No prior breast cancer except lobular carcinoma in situ (LCIS)

- No more than 84 days since prior mastectomy or axillary or sentinel node dissection

- No gross or microscopic disease at margins

- No significant pericardial effusion

- Hormone receptor status:

- ER/PR status known

- Female

- Any status

- Absolute neutrophil count at least 1,500/mm^3

- Platelet count at least 100,000/mm^3

- Bilirubin no greater than 1.5 times upper limit of normal (ULN)

- AST no greater than 2 times ULN

- LVEF normal

- No prior myocardial infarction or congestive heart failure

- No prior arrhythmia or cardiovalvular disease that requires medications or is
clinically significant

- No uncontrolled hypertension (diastolic blood pressure [BP] greater than 100 mm Hg
and systolic BP greater than 200 mm Hg)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective barrier contraception during and for 2 months
after study participation

- No active unresolved infection

- No known sensitivity to benzyl alcohol

- No grade 2 or greater neuropathy

- No other prior malignancy within the past 5 years except:

- Effectively treated squamous cell or basal cell skin cancer

- Carcinoma in situ of the cervix treated with surgery only

- LCIS of the ipsilateral or contralateral breast treated with surgery and/or
tamoxifen only

- No prior biologic therapy or immunotherapy for breast cancer

- No prior chemotherapy for breast cancer

- No prior anthracycline or taxane

- Prior tamoxifen or any other hormonal therapy for breast cancer allowed if
administered for no more than 4 weeks

- Prior tamoxifen or raloxifene for chemoprevention (e.g., Breast Cancer Prevention
Trial) or for other indications (e.g., prior LCIS) allowed

- No concurrent tamoxifen or raloxifene

- No concurrent hormonal therapy (e.g., birth control pills or hormone replacement
therapy)

- No prior radiotherapy for breast cancer

- See Disease Characteristics

- No concurrent digitalis or beta-blockers for congestive heart failure

- No concurrent medications for cardiac arrhythmias or angina pectoris

- No concurrent cardioprotective drugs

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Duration of disease-free survival (DFS)

Outcome Description:

Will be estimated using the Kaplan-Meier method.

Outcome Time Frame:

Time from registration to first adverse event, assessed up to 15 years

Safety Issue:

No

Principal Investigator

Edith Perez

Investigator Role:

Principal Investigator

Investigator Affiliation:

North Central Cancer Treatment Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-01849

NCT ID:

NCT00005970

Start Date:

May 2000

Completion Date:

Related Keywords:

  • Stage I Breast Cancer
  • Stage II Breast Cancer
  • Stage IIIA Breast Cancer
  • Breast Neoplasms

Name

Location

North Central Cancer Treatment GroupRochester, Minnesota  55905