Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy and Paclitaxel Plus Trastuzumab in Treating Women With Palpable Breast Cancer That Can Be Removed by Surgery

Basic Trial Information

Special Category: CTSU trial

Objectives

Primary

1. To compare the pathologic complete response rate (pCR) within the breast of patients with breast cancer receiving neoadjuvant combination chemotherapy comprising fluoroucacil, epirubicin hydrochloride, and cyclophosphamide followed by paclitaxel and trastuzumab vs neoadjuvant paclitaxel with trastuzumab (Herceptin®) followed by combination chemotherapy comprising fluoroucacil, epirubicin hydrochloride, cyclophosphamide, and trastuzumab.

Secondary

1. To estimate and compare the cardiotoxicity in patients receiving these regimens.
2. To compare the combined pCR rate in the breast and ipsilateral axilla obtained with the two regimens evaluated in this study.
3. To compare the clinical response rates of the two regimens evaluated in this study.
4. To compare the non-cardiac toxicity of the two regimens evaluated in this study.
5. To compare breast conservation rates achieved with the two regimens evaluated in this study.
6. To evaluate disease-free survival and overall survival at 5 years post-randomization.
7. To correlate pCR rate with potential molecular markers of response.

Entry Criteria

Disease Characteristics:

• Diagnosis of invasive adenocarcinoma by core needle biopsy
  • Fine needle aspiration allowed provided primary tumor size < 2 cm and lymph node metastases are present
  • Excisional biopsy of the primary tumor allowed provided biopsy-positive lymph nodes are present

• Primary tumor ≥ 2 cm and/or ≥ 1 biopsy-positive lymph node

• HER2-positive disease
  • Confirmation by fluorescent in situ hybridization (FISH) requires gene amplification
  • Confirmation by immunohistochemistry (IHC) requires a strongly positive (3+) staining intensity score

• Ductal carcinoma in situ (DCIS) or synchronous DCIS of the contralateral breast regardless of prior therapy allowed
  • Synchronous invasive breast cancer not allowed

• Ipsilateral DCIS treated by local excision with or without hormonal therapy allowed
  • Those treated with radiation therapy are not allowed

• No definitive clinical or radiologic evidence of metastatic disease

• No prior history of invasive breast cancer

• Hormone receptor status known

Prior/Concurrent Therapy:

• No prior surgical axillary staging procedure
  • Prior non-excisional biopsy of an axillary node allowed
• No prior treatment for this breast cancer
  • Hormonal therapy allowed if had been given for up to a total of 28 days anytime after diagnosis and before study entry
  • Hormonal therapy must stop at or before study entry and be re-started, if indicated, following surgery
• No prior therapy with anthracyclines or taxanes for any malignancy
• No other investigational agents within the past 30 days
• No concurrent sex hormonal therapy (e.g., birth control pills, ovarian hormonal replacement therapy)
• No concurrent therapy with any hormonal agent such as raloxifene, tamoxifen, or other selective estrogen receptor modulator (SERM), either for osteoporosis or breast cancer prevention

Patient Characteristics:

• Menopausal status not specified
• ECOG performance status of 0 -1
• Absolute neutrophil count ≥ 1,200/mm³
• Platelet count ≥ 100,000/mm³
• Total bilirubin normal unless the patient has a grade 1 bilirubin elevation (normal to 1.5 times upper limit of normal [ULN]) resulting from Gilbert disease or similar syndrome due to slow conjugation of bilirubin
• Alkaline phosphatase ≤ 2.5 times ULN
• AST ≤ 1.5 times ULN
• Creatinine normal
• LVEF ≥ 55 by MUGA or ECHO within the past 3 months
• Patients with either skeletal pain or alkaline phosphatase that is > ULN but ≤ 2.5 times ULN allowed if bone scans fail to demonstrate metastatic disease
  • Suspicious findings on bone scan must be confirmed as benign by x-ray, MRI, or biopsy
• Prior non-breast malignancies allowed if disease-free for 5 years since completion of initial treatment regimen and deemed by their physician to be at low risk for recurrence
  • Patients who had the following cancers are eligible if diagnosed and treated within the past 5 years:
    • Carcinoma in situ of the cervix
    • Colon carcinoma in situ
    • Melanoma in situ
    • Basal cell and squamous cell carcinoma of the skin
• No cardiac disease that would preclude the use of epirubicin hydrochloride or trastuzumab (Herceptin®) including any of the following:
  • Active cardiac disease
  • Angina pectoris that requires the use of antianginal medication
  • Cardiac arrhythmia requiring medication
  • Severe conduction abnormality
  • Clinically significant valvular disease
  • Cardiomegaly on chest x-ray
  • Ventricular hypertrophy on EKG
  • Patient’s with poorly controlled hypertension ( i.e., diastolic greater than 100 mm/Hg)
    • Patients with hypertension that is well controlled on medication are eligible
  • History of cardiac disease
  • Myocardial infarction documented as a clinical diagnosis or by EKG or any other tests
  • Documented congestive heart failure
  • Documented cardiomyopathy
• No sensory or motor neuropathy ≥ grade 2, as defined by the NCI’s CTCAE v3.0
• Women of reproductive potential must agree to use an effective non-hormonal method of contraception during therapy
• Women of child bearing potential must have a negative urine or serum pregnancy test within 2 weeks of registration
• Not pregnant or nursing
• No psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements
• No non-malignant systemic disease (e.g., cardiovascular, renal, hepatic) that would preclude treatment with either of the treatment regimens

Expected Enrollment

Outcomes

Pathologic complete response within the breast

Combined pathologic complete response rate in the breast and axillary lymph nodes
Cardiac event rate during treatment and follow-up
LVEF by MUGA or ECHO at baseline and 3 and 6 months
Method of definitive surgery
Adverse events by CTCAE version 3.0
Disease-free and overall survival at 5 years

Outline

Patients are stratified by clinical tumor size (breast tumor size < 2 cm and nodal metastases < 2 cm vs breast tumor size < 2 cm and nodal metastases ≥ 2 cm vs breast tumor size 2-4 cm [any nodal status] vs breast tumor size ≥ 4 cm [any nodal status]), age (< 50 vs ≥ 50) and hormone receptor status (estrogen receptor [ER]- and progesterone receptor [PgR]-negative vs ER- and/or PgR-positive). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive FEC comprising fluoroucacil IV, epirubicin hydrochloride IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. Beginning 21 days after completion of FEC, patients receive paclitaxel IV once weekly and trastuzumab (Herceptin®) IV once weekly for 12 weeks. Within 6 weeks after completion of paclitaxel and trastuzumab, patients undergo surgery. Beginning 3-4 weeks after surgery, patients receive trastuzumab IV once every 3 weeks for up to 52 weeks.

• Arm II: Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after completion of paclitaxel and trastuzumab, patients receive FEC comprising fluoroucacil IV, epirubicin IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. Patients also receive trastuzumab IV once weekly for an additional 12 weeks. Within 6 weeks after completion of FEC and trastuzumab, patients undergo surgery. Beginning 3-4 weeks after surgery, patients receive trastuzumab as in arm I.

After completion of study therapy, patients are followed every 3 months for 1 year and then every 6 months for 4 years.

Trial Contact Information

Trial Lead Organizations

American College of Surgeons Oncology Group

Aman Buzdar, MD, Protocol chair		Ph: 713-792-2817; 800-392-1611
Kelly Hunt, MD, Protocol co-chair		Ph: 713-792-7216; 800-392-1611 Email: khunt@mdanderson.org

Registry Information
Official Title		A Randomized Phase III Trial Comparing a Neoadjuvant Regimen of FEC-75 Followed by Paclitaxel Plus Trastuzumab with a Neoadjuvant Regimen of Paclitaxel Plus Trastuzumab Followed by FEC-75 Plus Trastuzumab in Patients with HER-2 Positive Operable Breast Cancer
Trial Start Date		2007-07-02
Trial Completion Date		2008-06-01 (estimated)
Registered in ClinicalTrials.gov		NCT00513292
Date Submitted to PDQ		2007-07-02
Information Last Verified		2011-12-16
NCI Grant/Contract Number		CA12027

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