Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy With or Without Trastuzumab in Treating Women Who Have Undergone Surgery For Breast Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	18 to 70	NCI, Pharmaceutical / Industry	AVENTIS-TAX-GMA-302 UCLA-0102006, BCIRG-006, UAB-0106, UAB-F010326012, NCI-G01-1978, NCT00021255

Objectives

1. Compare disease-free survival in women with HER2-neu-expressing node-positive or high-risk node-negative operable breast cancer treated with adjuvant doxorubicin, cyclophosphamide, and docetaxel with or without trastuzumab (Herceptin) vs trastuzumab, docetaxel, and either carboplatin or cisplatin.
2. Compare overall survival of patients treated with these regimens.
3. Compare the toxic effects (including cardiac) of these regimens in these patients.
4. Compare quality of life of patients treated with these regimens.
5. Compare pathologic and molecular markers for predicting efficacy of these regimens in these patients.
6. Compare peripheral levels of shed HER2-neu extracellular domain with fluorescence in situ hybridization in predicting outcome in patients treated with these regimens.

Entry Criteria

Disease Characteristics:

• Histologically confirmed breast cancer
  • T1-3, N0-1, M0
  • HER2-neu gene amplification by fluorescence in situ hybridization



• Definitive surgery within the past 60 days comprising either mastectomy or breast-conserving surgery AND axillary lymph node involvement assessment
  • Surgical margins histologically free of invasive adenocarcinoma and/or ductal carcinoma in situ
  • Lobular carcinoma in situ not considered a positive margin



• Lymph node-positive disease, defined as invasive adenocarcinoma with at least 1 axillary lymph node showing evidence of tumor among 6 or more resected nodes

  OR




• High-risk lymph node-negative disease, defined as either no positive lymph nodes among 6 or more resected nodes or a negative sentinel node biopsy AND at least 1 of the following factors:
  • Tumor size greater than 2 cm
  • Estrogen and progesterone receptor status negative
  • Histologic and/or nuclear grade 2-3
  • Under 35 years of age



• No bilateral invasive breast cancer



• Hormone receptor status:
  • Estrogen and/or progesterone receptor status known

Prior/Concurrent Therapy:

Biologic therapy:

• No prior immunotherapy for breast cancer
• No other concurrent antitumor immunotherapy

Chemotherapy:

• No prior chemotherapy for breast cancer
• No prior anthracycline therapy
• No prior paclitaxel or docetaxel
• No prior platinum salts
• No other concurrent antitumor chemotherapy

Endocrine therapy:

• No prior hormonal therapy for breast cancer
• No concurrent hormonal therapy (e.g., raloxifene, tamoxifen, or other selective estrogen receptor modulators) for osteoporosis or prevention
• No concurrent ovarian hormone replacement therapy
• No concurrent chronic corticosteroids unless initiated more than 6 months prior to study and at low dose (no greater than 20 mg of methylprednisolone or equivalent)
• No other concurrent corticosteroids except for premedication, antiemesis, or acute hypersensitivity reaction

Radiotherapy:

• No prior radiotherapy for breast cancer

Surgery:

• See Disease Characteristics
• No concurrent antitumor surgery

Other:

• At least 30 days since prior participation in other clinical trial with investigational drugs
• No other concurrent investigational drugs
• No concurrent medications that alter cardiac conduction (e.g., digitalis, beta blockers, or calcium channel blockers) for cardiac arrhythmia, angina, or congestive heart failure
• No other concurrent anticancer therapy
• No concurrent bisphosphonates
• No concurrent amifostine
• No concurrent cardioprotectors (e.g., dexrazoxane)
• No concurrent aminoglycosides if receiving cisplatin

Patient Characteristics:

Age:

• 18 to 70

Sex:

• Female

Menopausal status:

• Not specified

Performance status:

• Karnofsky 80-100%

Life expectancy:

• Not specified

Hematopoietic:

• Neutrophil count at least 2,000/mm³
• Platelet count at least 100,000/mm³
• Hemoglobin at least 10 g/dL

Hepatic:

• Bilirubin no greater than upper limit of normal (ULN)
• AST and ALT no greater than 2.5 times ULN
• Alkaline phosphatase no greater than 5 times ULN
• If AST and/or ALT greater than 1.5 times ULN, then alkaline phosphatase must not be greater than 2.5 times ULN

Renal:

• Creatinine no greater than 2 mg/dL

  OR

• Creatinine clearance at least 60 mL/min

Cardiovascular:

• No documented myocardial infarction
• No angina pectoris requiring antianginal medication
• No history of congestive heart failure
• No grade 3 or 4 cardiac arrhythmia
• No clinically significant valvular heart disease
• No poorly controlled hypertension (diastolic greater than 100 mmHg)
• LVEF and EKG normal
• Cardiomegaly on chest x-ray or ventricular hypertrophy on EKG allowed, provided LVEF is at least lower limit of normal by MUGA scan or echocardiography within the past 3 months

Pulmonary:

• No symptomatic intrinsic lung disease resulting in dyspnea at rest

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective non-hormonal contraception
• No significant neurologic or psychiatric disorder (e.g., psychotic disorder, dementia, or seizures) that would preclude study
• No pre-existing motor or sensory neurotoxicity grade 2 or greater
• No active uncontrolled infection
• No active peptic ulcer
• No unstable diabetes mellitus
• No impaired hearing if receiving cisplatin
• No other malignancy within the past 10 years except curatively treated nonmelanoma skin cancer, carcinoma in situ of the cervix, ipsilateral ductal carcinoma in situ of the breast, or lobular carcinoma in situ of the breast

Expected Enrollment

A total of 3,150 patients (1,050 per treatment arm) will be accrued for this study within 2.5 years.

Outline

This is a randomized, multicenter study. Patients are stratified according to participating center, nodal status (node negative vs 1-3 positive nodes vs 4 or more positive nodes), and estrogen and/or progesterone receptor status (positive vs negative). Patients are randomized to one of three treatment arms.

• Arm I: Patients receive doxorubicin IV over 5-15 minutes and cyclophosphamide IV over 5-60 minutes on day 1 every 3 weeks for 4 courses. Beginning 3 weeks after the last course of doxorubicin and cyclophosphamide, patients receive docetaxel IV over 1 hour every 3 weeks for 4 courses.



• Arm II: Patients receive doxorubicin and cyclophosphamide as in arm I. Beginning 3 weeks after the last course of doxorubicin and cyclophosphamide, patients receive trastuzumab (Herceptin) IV over 30-90 minutes on days 1, 8, and 15. Patients also receive docetaxel IV over 1 hour on day 2 for the first course and on day 1 for all subsequent courses. Treatment repeats every 3 weeks for 4 courses. After completion of the last course, patients continue to receive trastuzumab once weekly until 1 year from date of initial trastuzumab dose.



• Arm III: Patients receive trastuzumab IV over 30-90 minutes on days 1, 8, and 15. Patients also receive docetaxel IV over 1 hour and either carboplatin IV over 30-60 minutes or cisplatin IV over at least 1 hour on day 2 for the first course and on day 1 for all subsequent courses. Treatment repeats every 3 weeks for a total of 6 courses. After completion of the last course, patients continue to receive trastuzumab once weekly until 1 year from date of initial trastuzumab dose.

Patients with estrogen and/or progesterone receptor-positive disease receive oral tamoxifen daily for 5 years beginning 3-4 weeks after the completion of chemotherapy.

Patients may undergo radiotherapy beginning 3-8 weeks after completion of chemotherapy.

Quality of life is assessed at baseline, before courses 1, 3, and 5 (and before course 7 on arms I and II), at 3-4 weeks after the last course of chemotherapy, every 3 months for 2 years, and then at relapse.

Patients are followed at 1 month, every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

Au HJ, Robert N, Eiermann W, et al.: BCIRG 006: quality of life (QoL) of patients (pts) treated with docetaxel and trastuzumab-based regimens in node positive and high risk node negative HER2 positive early breast cancer. [Abstract] Breast Cancer Res Treat 106 (1): A-3064, S147, 2007.

Robert NJ, Eiermann W, Pienkowski T, et al.: BCIRG 006: docetaxel and trastuzumab-based regimens improve DFS and OS over AC-T in node positive and high risk node negative HER2 positive early breast cancer patients: quality of life (QOL) at 36 months follow-up. [Abstract] J Clin Oncol 25 (Suppl 18): A-19647, 719s, 2007.

Slamon D, Eiermann W, Robert N, et al.: BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC->T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC->TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients. [Abstract] 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, Texas. A-52, 2006.

Press MF, Bernstein L, Sauter G, et al.: Topoisomerase II-alpha gene amplification as a predictor of responsiveness to anthracycline-containing chemotherapy in the Cancer International Research Group 006 clinical trial of trastuzumab (herceptin) in the adjuvant setting. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-1045, 2005.

Slamon D, Eiermann W, Robert N, et al.: Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-1, 2005.

Jahanzeb M: Adjuvant trastuzumab therapy for HER2-positive breast cancer. Clin Breast Cancer 8 (4): 324-33, 2008.[PUBMED Abstract]

Telli ML, Hunt SA, Carlson RW, et al.: Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility. J Clin Oncol 25 (23): 3525-33, 2007.[PUBMED Abstract]

Baselga J, Perez EA, Pienkowski T, et al.: Adjuvant trastuzumab: a milestone in the treatment of HER-2-positive early breast cancer. Oncologist 11 (Suppl 1): 4-12, 2006.[PUBMED Abstract]

Neyt M, Albrecht J, Cocquyt V: An economic evaluation of Herceptin in adjuvant setting: the Breast Cancer International Research Group 006 trial. Ann Oncol 17 (3): 381-90, 2006.[PUBMED Abstract]

Press MF, Sauter G, Bernstein L, et al.: Diagnostic evaluation of HER-2 as a molecular target: an assessment of accuracy and reproducibility of laboratory testing in large, prospective, randomized clinical trials. Clin Cancer Res 11 (18): 6598-607, 2005.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Sanofi-Aventis France

Linnea Chap, MD, Principal investigator		Ph: 310-206-6144; 888-798-0719

Registry Information
Official Title		Multicenter Phase III Randomized Trial Comparing Doxorubicin And Cyclophosphamide Followed By Docetaxel (AC-T) With Doxorubicin And Cyclophosphamide Followed By Docetaxel And Tastuzumab (AC-TH) And With Docetaxel, Platinum Salt And Trastuzumab (TCH) In The Treatment Of Node Positive And High Risk Node Negative Adjuvant Patients With Operable Breast Cancer Containing The HER2NEU Alteration
Trial Start Date		2001-09-10
Registered in ClinicalTrials.gov		NCT00021255
Date Submitted to PDQ		2001-05-24
Information Last Verified		2004-05-18
NCI Grant/Contract Number		CA16042