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.