Combination Chemotherapy, Surgery, and Radiation Therapy With or Without Dexrazoxane and Trastuzumab in Treating Women With Stage III or Stage IV Breast Cancer
This study has been terminated.
(Administratively complete.)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00016276
First received: May 6, 2001
Last updated: January 15, 2013
Last verified: January 2013
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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. 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
| Condition | Intervention | Phase |
|---|---|---|
|
Cardiac Toxicity Inflammatory Breast Cancer Stage IIIA Breast Cancer Stage IIIB Breast Cancer Stage IV Breast Cancer |
Drug: dexrazoxane hydrochloride Drug: doxorubicin hydrochloride Drug: cyclophosphamide Drug: paclitaxel Biological: trastuzumab Procedure: therapeutic conventional surgery Radiation: radiation therapy Drug: tamoxifen citrate Other: laboratory biomarker analysis |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| 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 IIIA, IIIB OR REGIONAL STAGE IV BREAST CANCER |
Resource links provided by NLM:
Genetics Home Reference related topics:
breast cancer
Drug Information available for:
Cyclophosphamide
Tamoxifen
Doxorubicin
Dexrazoxane
Doxorubicin hydrochloride
Paclitaxel
Tamoxifen citrate
Dexrazoxane hydrochloride
Trastuzumab
U.S. FDA Resources
Further study details as provided by National Cancer Institute (NCI):
Primary Outcome Measures:
- Median number of positive axillary lymph nodes [ Time Frame: At 24 weeks ] [ Designated as safety issue: No ]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.
- Pathologic complete response (CR) rate in the breast and axilla [ Time Frame: At 24 weeks ] [ Designated as safety issue: No ]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.
- Cardiac toxicity, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0 [ Time Frame: At 24 weeks ] [ Designated as safety issue: Yes ]Assessment will use exact binomial comparison of two proportions.
- Cardiac toxicity, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0 [ Time Frame: At 78 weeks ] [ Designated as safety issue: Yes ]Assessment will use exact binomial comparison of two proportions.
- Disease-free survival [ Time Frame: Date of study entry to date of first relapse (local or distant) or death due to any cause, assessed up to 10 years ] [ Designated as safety issue: No ]Proportional hazards regression models will be used.
Secondary Outcome Measures:
- Occurrence of grade 3 or higher late cardiac or neurological toxicity, or secondary acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
- Clinical/radiographic response in the breast and axilla after doxorubicin hydrochloride and cyclophosphamide with or without dexrazoxane hydrochloride [ Time Frame: At 12 weeks ] [ Designated as safety issue: No ]
- Clinical/radiographic response in the breast and axilla after paclitaxel with or without trastuzumab [ Time Frame: At 24 weeks ] [ Designated as safety issue: No ]
- Time to local/regional recurrence [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
- Time to completion of treatment through radiotherapy [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
- Rate of breast conservation for patients considered "candidates" prior to treatment [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
- Overall survival [ Time Frame: Date of study entry to date of due to any cause, assessed up to 10 years ] [ Designated as safety issue: No ]Proportional hazards regression models will be used.
| Enrollment: | 396 |
| Study Start Date: | May 2001 |
| Primary Completion Date: | March 2005 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Arm I (chemoprotection, monoclonal antibody, radiotherapy)
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).
|
Drug: dexrazoxane hydrochloride
Given IV
Other Names:
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: paclitaxel
Given IV
Other Names:
Biological: trastuzumab
Given IV
Other Names:
Procedure: therapeutic conventional surgery
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
Radiation: radiation therapy
Undergo radiation therapy
Other Names:
Drug: tamoxifen citrate
Given orally
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Experimental: Arm II (chemoprotection, radiotherapy, surgery, trastuzumab)
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.
|
Drug: dexrazoxane hydrochloride
Given IV
Other Names:
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: paclitaxel
Given IV
Other Names:
Biological: trastuzumab
Given IV
Other Names:
Procedure: therapeutic conventional surgery
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
Radiation: radiation therapy
Undergo radiation therapy
Other Names:
Drug: tamoxifen citrate
Given orally
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Experimental: Arm III (chemoprotection, monoclonal antibody, radiotherapy)
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.
|
Drug: dexrazoxane hydrochloride
Given IV
Other Names:
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: paclitaxel
Given IV
Other Names:
Biological: trastuzumab
Given IV
Other Names:
Procedure: therapeutic conventional surgery
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
Radiation: radiation therapy
Undergo radiation therapy
Other Names:
Drug: tamoxifen citrate
Given orally
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Experimental: Arm IV (chemoprotection, paclitaxel, surgery, radiotherapy)
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.
|
Drug: dexrazoxane hydrochloride
Given IV
Other Names:
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: paclitaxel
Given IV
Other Names:
Procedure: therapeutic conventional surgery
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
Radiation: radiation therapy
Undergo radiation therapy
Other Names:
Drug: tamoxifen citrate
Given orally
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Experimental: Arm V (combination chemo, radiotherapy, long term trastuzumab)
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.
|
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: paclitaxel
Given IV
Other Names:
Biological: trastuzumab
Given IV
Other Names:
Procedure: therapeutic conventional surgery
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
Radiation: radiation therapy
Undergo radiation therapy
Other Names:
Drug: tamoxifen citrate
Given orally
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Experimental: Arm VI (combination chemo, paclitaxel, surgery, radiotherapy)
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.
|
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: paclitaxel
Given IV
Other Names:
Biological: trastuzumab
Given IV
Other Names:
Procedure: therapeutic conventional surgery
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
Radiation: radiation therapy
Undergo radiation therapy
Other Names:
Drug: tamoxifen citrate
Given orally
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Experimental: Arm VII (combination chemo, monoclonal antibody, radiotherapy)
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.
|
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: paclitaxel
Given IV
Other Names:
Biological: trastuzumab
Given IV
Other Names:
Procedure: therapeutic conventional surgery
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
Radiation: radiation therapy
Undergo radiation therapy
Other Names:
Drug: tamoxifen citrate
Given orally
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Experimental: Arm VIII (combination chemotherapy, paclitaxel, radiotherapy)
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.
|
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: paclitaxel
Given IV
Other Names:
Procedure: therapeutic conventional surgery
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
Radiation: radiation therapy
Undergo radiation therapy
Other Names:
Drug: tamoxifen citrate
Given orally
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
Show Detailed Description Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Female |
| Accepts Healthy Volunteers: | No |
Criteria
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
Contacts and Locations More Information
No publications provided
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT00016276 History of Changes |
| Other Study ID Numbers: | NCI-2012-02380, CLB-49808, U10CA031946, CDR0000068617 |
| Study First Received: | May 6, 2001 |
| Last Updated: | January 15, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Breast Neoplasms Inflammatory Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Cyclophosphamide Trastuzumab Doxorubicin Razoxane Tamoxifen Paclitaxel Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs |
Pharmacologic Actions Antirheumatic Agents Therapeutic Uses Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Myeloablative Agonists Antibiotics, Antineoplastic Cardiovascular Agents Chelating Agents Antineoplastic Agents, Hormonal Selective Estrogen Receptor Modulators Estrogen Receptor Modulators Hormone Antagonists |
ClinicalTrials.gov processed this record on May 19, 2013