Combination Chemotherapy, Surgery, and Radiation Therapy With or Without Dexrazoxane and Trastuzumab in Treating Women With Stage III or Stage IV Breast Cancer - Full Text View

Sponsor:	Cancer and Leukemia Group B
Collaborator:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00016276

Purpose

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Chemoprotective drugs, such as dexrazoxane, may protect normal cells from the side effects of chemotherapy. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Radiation therapy uses high-energy x-rays to damage tumor cells. It is not yet known if chemotherapy combined with surgery and radiation therapy is more effective with or without dexrazoxane and trastuzumab in treating breast cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy, surgery, and radiation therapy with or without dexrazoxane and trastuzumab in treating women who have stage IIIA, stage IIIB or stage IV breast cancer.

Condition	Intervention	Phase
Breast Cancer Cardiac Toxicity	Biological: trastuzumab Drug: cyclophosphamide Drug: dexrazoxane hydrochloride Drug: doxorubicin hydrochloride Drug: paclitaxel Procedure: conventional surgery Radiation: radiation therapy	Phase III

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Active Control
Official Title:	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 IV Breast Cancer

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer Surgery

Drug Information available for: Cyclophosphamide ICRF 159 Razoxane Doxorubicin Dexrazoxane Doxorubicin hydrochloride Paclitaxel Myocet Dexrazoxane hydrochloride Trastuzumab

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Study Start Date:

May 2001

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Detailed Description:

OBJECTIVES:

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.
Determine whether addition of trastuzumab to paclitaxel therapy improves response at 24 weeks of therapy in these patients.
Determine whether addition of trastuzumab to paclitaxel therapy increases the rate of cardiotoxicity in these patients.
Determine whether addition of dexrazoxane to doxorubicin and cyclophosphamide compromises response in these patients.
Determine whether addition of dexrazoxane to doxorubicin and cyclophosphamide reduces the rate of cardiotoxicity in these patients.
Determine whether long-term trastuzumab after local therapy improves disease-free survival in these patients.
Determine whether long-term trastuzumab after local therapy increases the rate of cardiotoxicity in these patients.
Determine the occurrence of any grade 3 or higher toxicity, second malignancies, acute myelogenous leukemia, or myelodysplastic syndrome in patients treated with these regimens.
Determine the eventual rate of breast conservation in those patients considered candidates for breast conservation prior to neoadjuvant treatment.
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. Patient 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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed primary infiltrating adenocarcinoma of the breast
- Confirmed by core needle biopsy or incisional biopsy
- Amplification of HER-2 by FISH OR
- Overexpression (3+) of HER-2 by immunohistochemistry
- Staging criteria after complete clinical and radiographic staging:
  - T3, N1, M0 OR
  - Any T, N2 or N3, M0 OR
  - T4, any N, M0, including clinical or pathological inflammatory disease OR
  - 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

PATIENT CHARACTERISTICS:

Age:

18 and over

Sex:

Female

Menopausal status:

Not specified

Performance status:

Not specified

Life expectancy:

Not specified

Hematopoietic:

Granulocyte count at least 1,000/mm3
Platelet count at least 100,000/mm3

Hepatic:

Bilirubin no greater than upper limit of normal (ULN)
AST no greater than 2 times ULN

Renal:

Creatinine no greater than 1.5 times ULN

Cardiovascular:

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)

Other:

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

PRIOR CONCURRENT THERAPY:

Biologic therapy:

Not specified

Chemotherapy:

No prior chemotherapy
No other concurrent chemotherapy

Endocrine therapy:

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

Radiotherapy:

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

Surgery:

See Disease Characteristics
No prior sentinel lymph node biopsy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00016276

Show 52 Study Locations

Sponsors and Collaborators

Cancer and Leukemia Group B

National Cancer Institute (NCI)

Investigators

Study Chair:

Mark L. Graham, MD

UNC Lineberger Comprehensive Cancer Center

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Study ID Numbers:	CDR0000068617, CLB-49808
Study First Received:	May 6, 2001
Last Updated:	May 9, 2009
ClinicalTrials.gov Identifier:	NCT00016276 History of Changes
Health Authority:	United States: Federal Government

Keywords provided by National Cancer Institute (NCI):

stage IV breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
inflammatory breast cancer
cardiac toxicity

Additional relevant MeSH terms:

Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Cyclophosphamide
Antibiotics, Antineoplastic
Razoxane
Neoplasms by Site
Therapeutic Uses
Trastuzumab
Alkylating Agents
Breast Diseases
Skin Diseases
Mitosis Modulators

Breast Neoplasms
Antimitotic Agents
Cardiovascular Agents
Immunosuppressive Agents
Doxorubicin
Pharmacologic Actions
Neoplasms
Paclitaxel
Tubulin Modulators
Myeloablative Agonists
Antineoplastic Agents, Alkylating
Chelating Agents
Antirheumatic Agents
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on November 27, 2009