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A 2X2X2 Factorial Randomized Phase III Trial Of Multimodality Therapy Comparing 4 Cycles Of Doxorubicin And Cyclophosphamide With Or Without Dexrazoxane (AC+/-Z) Followed By 12 Weeks Of Weekly Paclitaxel With Or Without Trastuzumab (T+/-H) Followed By Local Therapy Followed By 40 Weeks Of Weekly Trastuzumab Or None In Women With HER-2+ STAGE IIIA, IIIB OR REGIONAL STAGE IV BREAST CANCER


Phase 3
18 Years
N/A
Not Enrolling
Female
Cardiac Toxicity, Inflammatory Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IV Breast Cancer

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Trial Information

A 2X2X2 Factorial Randomized Phase III Trial Of Multimodality Therapy Comparing 4 Cycles Of Doxorubicin And Cyclophosphamide With Or Without Dexrazoxane (AC+/-Z) Followed By 12 Weeks Of Weekly Paclitaxel With Or Without Trastuzumab (T+/-H) Followed By Local Therapy Followed By 40 Weeks Of Weekly Trastuzumab Or None In Women With HER-2+ STAGE IIIA, IIIB OR REGIONAL STAGE IV BREAST CANCER


OBJECTIVES:

I. Determine the time to locoregional recurrence, time to completion of treatment, and
overall survival in women with HER-2+ stage IIIA or IIIB or regional stage IV breast cancer
treated with doxorubicin and cyclophosphamide with or without dexrazoxane, followed by
paclitaxel with or without trastuzumab (Herceptin), followed by surgery and radiotherapy
with or without trastuzumab.

II. Determine whether addition of trastuzumab to paclitaxel therapy improves response at 24
weeks of therapy in these patients.

III. Determine whether addition of trastuzumab to paclitaxel therapy increases the rate of
cardiotoxicity in these patients.

IV. Determine whether addition of dexrazoxane to doxorubicin and cyclophosphamide
compromises response in these patients.

V. Determine whether addition of dexrazoxane to doxorubicin and cyclophosphamide reduces the
rate of cardiotoxicity in these patients.

VI. Determine whether long-term trastuzumab after local therapy improves disease-free
survival in these patients.

VII. Determine whether long-term trastuzumab after local therapy increases the rate of
cardiotoxicity in these patients.

VIII. Determine the occurrence of any grade 3 or higher toxicity, second malignancies, acute
myelogenous leukemia, or myelodysplastic syndrome in patients treated with these regimens.

IX. Determine the eventual rate of breast conservation in those patients considered
candidates for breast conservation prior to neoadjuvant treatment.

X. Determine the clinical response after doxorubicin and cyclophosphamide with or without
dexrazoxane and the clinical/mammographic/ultrasound response after paclitaxel with or
without trastuzumab, compared to the pathologic response at definitive surgery in these
patients.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified
according to stage (inflammatory vs noninflammatory inoperable stage III/ regional stage IV
vs operable stage III). Patients are randomized to 1 of 8 treatment arms.

Arm I: Patients receive dexrazoxane IV over 10-20 minutes, doxorubicin IV over 5-10 minutes,
and cyclophosphamide IV over 30 minutes on days 1, 22, 43, and 64. Patients receive
paclitaxel IV over 1 hour and trastuzumab (Herceptin) IV over 30-90 minutes on days 85, 92,
99, 106, 113, 120, 127, 134, 141, 148, 155, and 162. Approximately 1-2 weeks after
completion of neoadjuvant chemotherapy, patients undergo breast conservation surgery,
modified radical mastectomy, or mastectomy. Patients with unacceptable toxicity or
locoregional disease progression may undergo surgery prior to week 24 (i.e., completion of
neoadjuvant chemotherapy). Beginning 2-4 weeks after breast conservation surgery or 3-5
weeks after mastectomy, patients undergo radiotherapy daily 5 days a week for 6-8 weeks.
Patients receive long-term trastuzumab IV over 30-90 minutes weekly for 40 weeks beginning
on week 36 (day 254).

Arm II: Patients receive dexrazoxane, doxorubicin, and cyclophosphamide as in arm I.
Patients receive paclitaxel (without trastuzumab) as in arm I. Patients undergo surgery and
radiotherapy as in arm I. Patients receive long-term trastuzumab as in arm I.

Arm III: Patients receive dexrazoxane, doxorubicin, and cyclophosphamide as in arm I.
Patients receive paclitaxel and trastuzumab as in arm I. Patients undergo surgery and
radiotherapy as in arm I. Patients undergo observation only for 40 weeks after completion of
radiotherapy.

Arm IV: Patients receive dexrazoxane, doxorubicin, and cyclophosphamide as in arm I.
Patients receive paclitaxel as in arm II. Patients undergo surgery and radiotherapy as in
arm I. Patients undergo observation as in arm III.

Arm V: Patients receive doxorubicin and cyclophosphamide (without dexrazoxane) as in arm I.
Patients receive paclitaxel and trastuzumab as in arm I. Patients undergo surgery and
radiotherapy as in arm I. Patients receive long-term trastuzumab as in arm I.

Arm VI: Patients receive doxorubicin and cyclophosphamide as in arm V. Patients receive
paclitaxel as in arm II. Patients undergo surgery and radiotherapy as in arm I. Patients
receive long-term trastuzumab as in arm I.

Arm VII: Patients receive doxorubicin and cyclophosphamide as in arm V. Patients receive
paclitaxel and trastuzumab as in arm I. Patients undergo surgery and radiotherapy as in arm
I. Patients undergo observation as in arm III.

Arm VIII: Patients receive doxorubicin and cyclophosphamide as in arm V. Patients receive
paclitaxel as in arm II. Patients undergo surgery and radiotherapy as in arm I. Patients
undergo observation as in arm III.

Treatment continues in all arms in the absence of distant disease progression. Beginning
within 12 weeks of completion of neoadjuvant chemotherapy, hormone receptor-positive
patients may receive oral tamoxifen daily for 5 years.

Patients are followed every 6 months for 5 years and then annually for 5 years.

PROJECTED ACCRUAL: A total of 396 patients will be accrued for this study within 4 years.


Inclusion Criteria:



- Histologically confirmed primary infiltrating adenocarcinoma of the breast

- Confirmed by core needle biopsy or incisional biopsy

- Amplification of HER-2 by FISH

- Overexpression (3+) of HER-2 by immunohistochemistry

- Staging criteria after complete clinical and radiographic staging:

- T3, N1, M0

- Any T, N2 or N3, M0

- T4, any N, M0, including clinical or pathological inflammatory disease

- Regional stage IV disease with supraclavicular or infraclavicular lymph
nodes as only site of metastasis

- Measurable or evaluable disease

- Prior ductal carcinoma in situ of the ipsilateral breast allowed if treated with
excision only without mastectomy or radiation

- Metaplastic carcinoma allowed

- Synchronous bilateral primary disease allowed (provided at least 1 cancer meets
staging criteria)

- No dermal lymphatic involvement with clinical inflammatory changes

- Hormone receptor status:

- Estrogen receptor positive or negative

- Progesterone receptor positive or negative

- Female

- Granulocyte count at least 1,000/mm^3

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

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

- AST no greater than 2 times ULN

- Creatinine no greater than 1.5 times ULN

- LVEF normal by MUGA

- No uncontrolled or severe cardiovascular disease (e.g., myocardial infarction within
the past 6 months, congestive heart failure treated with medications, or uncontrolled
hypertension)

- No other currently active malignancy except nonmelanoma skin cancer

- Not pregnant or nursing

- Fertile patients must use effective contraception

- Patients taking tamoxifen must use effective nonhormonal contraception during and for
2 months after study

- No prior chemotherapy

- No other concurrent chemotherapy

- No more than 4 weeks of prior tamoxifen for disease

- Prior tamoxifen or raloxifene for longer than 4 weeks as chemoprevention allowed

- No concurrent tamoxifen or raloxifene

- No other concurrent hormonal therapy except for steroids for adrenal failure,
hormones for non-disease-related conditions (e.g., insulin for diabetes), or
intermittent dexamethasone as an antiemetic

- See Disease Characteristics

- No prior radiotherapy for index malignancy

- No prior radiotherapy to the ipsilateral breast, regional nodes, mediastinum, or
heart

- Prior radiotherapy to the contralateral breast for ductal carcinoma in situ or early
stage invasive breast cancer allowed provided earlier radiotherapy does not preclude
optimal delivery of study radiotherapy and criterion of low risk for metastasis from
first malignancy is met

- See Disease Characteristics

- No prior sentinel lymph node biopsy

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:

Median number of positive axillary lymph nodes

Outcome Description:

Compared in the Herceptin and no Herceptin groups and in the dexrazoxane versus no dexrazoxane groups using a chi-square test and a two-sample t test, respectively.

Outcome Time Frame:

At 24 weeks

Safety Issue:

No

Principal Investigator

Mark Graham

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cancer and Leukemia Group B

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-02380

NCT ID:

NCT00016276

Start Date:

May 2001

Completion Date:

Related Keywords:

  • Cardiac Toxicity
  • Inflammatory Breast Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IV Breast Cancer
  • Breast Neoplasms
  • Inflammatory Breast Neoplasms

Name

Location

Cancer and Leukemia Group BChicago, Illinois  60606