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

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ClinicalTrials.gov Identifier: NCT00016276

Recruitment Status : Terminated (Administratively complete.)

First Posted : September 4, 2003

Last Update Posted : January 16, 2013

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

National Cancer Institute (NCI)

Study Description

Brief Summary:

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 or disease	Intervention/treatment	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

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Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	396 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (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
Study Start Date :	May 2001
Actual Primary Completion Date :	March 2005

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Breast cancer

MedlinePlus related topics: Breast Cancer

Drug Information available for: Dexrazoxane Dexrazoxane hydrochloride Trastuzumab

Genetic and Rare Diseases Information Center resources: Inflammatory Breast Cancer

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
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: Cardioxane Savene Totect Zinecard Drug: doxorubicin hydrochloride Given IV Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF Drug: cyclophosphamide Given IV Other Names: CPM CTX Cytoxan Endoxan Endoxana Drug: paclitaxel Given IV Other Names: Anzatax Asotax TAX Taxol Biological: trastuzumab Given IV Other Names: anti-c-erB-2 Herceptin MOAB HER2 Procedure: therapeutic conventional surgery Undergo breast conservation surgery, modified radical mastectomy, or mastectomy Radiation: radiation therapy Undergo radiation therapy Other Names: irradiation radiotherapy therapy, radiation Drug: tamoxifen citrate Given orally Other Names: Nolvadex TAM tamoxifen TMX 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: Cardioxane Savene Totect Zinecard Drug: doxorubicin hydrochloride Given IV Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF Drug: cyclophosphamide Given IV Other Names: CPM CTX Cytoxan Endoxan Endoxana Drug: paclitaxel Given IV Other Names: Anzatax Asotax TAX Taxol Biological: trastuzumab Given IV Other Names: anti-c-erB-2 Herceptin MOAB HER2 Procedure: therapeutic conventional surgery Undergo breast conservation surgery, modified radical mastectomy, or mastectomy Radiation: radiation therapy Undergo radiation therapy Other Names: irradiation radiotherapy therapy, radiation Drug: tamoxifen citrate Given orally Other Names: Nolvadex TAM tamoxifen TMX 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: Cardioxane Savene Totect Zinecard Drug: doxorubicin hydrochloride Given IV Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF Drug: cyclophosphamide Given IV Other Names: CPM CTX Cytoxan Endoxan Endoxana Drug: paclitaxel Given IV Other Names: Anzatax Asotax TAX Taxol Biological: trastuzumab Given IV Other Names: anti-c-erB-2 Herceptin MOAB HER2 Procedure: therapeutic conventional surgery Undergo breast conservation surgery, modified radical mastectomy, or mastectomy Radiation: radiation therapy Undergo radiation therapy Other Names: irradiation radiotherapy therapy, radiation Drug: tamoxifen citrate Given orally Other Names: Nolvadex TAM tamoxifen TMX 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: Cardioxane Savene Totect Zinecard Drug: doxorubicin hydrochloride Given IV Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF Drug: cyclophosphamide Given IV Other Names: CPM CTX Cytoxan Endoxan Endoxana Drug: paclitaxel Given IV Other Names: Anzatax Asotax TAX Taxol Procedure: therapeutic conventional surgery Undergo breast conservation surgery, modified radical mastectomy, or mastectomy Radiation: radiation therapy Undergo radiation therapy Other Names: irradiation radiotherapy therapy, radiation Drug: tamoxifen citrate Given orally Other Names: Nolvadex TAM tamoxifen TMX 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: ADM ADR Adria Adriamycin PFS Adriamycin RDF Drug: cyclophosphamide Given IV Other Names: CPM CTX Cytoxan Endoxan Endoxana Drug: paclitaxel Given IV Other Names: Anzatax Asotax TAX Taxol Biological: trastuzumab Given IV Other Names: anti-c-erB-2 Herceptin MOAB HER2 Procedure: therapeutic conventional surgery Undergo breast conservation surgery, modified radical mastectomy, or mastectomy Radiation: radiation therapy Undergo radiation therapy Other Names: irradiation radiotherapy therapy, radiation Drug: tamoxifen citrate Given orally Other Names: Nolvadex TAM tamoxifen TMX 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: ADM ADR Adria Adriamycin PFS Adriamycin RDF Drug: cyclophosphamide Given IV Other Names: CPM CTX Cytoxan Endoxan Endoxana Drug: paclitaxel Given IV Other Names: Anzatax Asotax TAX Taxol Biological: trastuzumab Given IV Other Names: anti-c-erB-2 Herceptin MOAB HER2 Procedure: therapeutic conventional surgery Undergo breast conservation surgery, modified radical mastectomy, or mastectomy Radiation: radiation therapy Undergo radiation therapy Other Names: irradiation radiotherapy therapy, radiation Drug: tamoxifen citrate Given orally Other Names: Nolvadex TAM tamoxifen TMX 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: ADM ADR Adria Adriamycin PFS Adriamycin RDF Drug: cyclophosphamide Given IV Other Names: CPM CTX Cytoxan Endoxan Endoxana Drug: paclitaxel Given IV Other Names: Anzatax Asotax TAX Taxol Biological: trastuzumab Given IV Other Names: anti-c-erB-2 Herceptin MOAB HER2 Procedure: therapeutic conventional surgery Undergo breast conservation surgery, modified radical mastectomy, or mastectomy Radiation: radiation therapy Undergo radiation therapy Other Names: irradiation radiotherapy therapy, radiation Drug: tamoxifen citrate Given orally Other Names: Nolvadex TAM tamoxifen TMX 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: ADM ADR Adria Adriamycin PFS Adriamycin RDF Drug: cyclophosphamide Given IV Other Names: CPM CTX Cytoxan Endoxan Endoxana Drug: paclitaxel Given IV Other Names: Anzatax Asotax TAX Taxol Procedure: therapeutic conventional surgery Undergo breast conservation surgery, modified radical mastectomy, or mastectomy Radiation: radiation therapy Undergo radiation therapy Other Names: irradiation radiotherapy therapy, radiation Drug: tamoxifen citrate Given orally Other Names: Nolvadex TAM tamoxifen TMX Other: laboratory biomarker analysis Correlative studies

Outcome Measures

Primary Outcome Measures :

Median number of positive axillary lymph nodes [ Time Frame: At 24 weeks ]
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 ]
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 ]
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 ]
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 ]
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 ]
Clinical/radiographic response in the breast and axilla after doxorubicin hydrochloride and cyclophosphamide with or without dexrazoxane hydrochloride [ Time Frame: At 12 weeks ]
Clinical/radiographic response in the breast and axilla after paclitaxel with or without trastuzumab [ Time Frame: At 24 weeks ]
Time to local/regional recurrence [ Time Frame: Up to 10 years ]
Time to completion of treatment through radiotherapy [ Time Frame: Up to 5 years ]
Rate of breast conservation for patients considered "candidates" prior to treatment [ Time Frame: Up to 10 years ]
Overall survival [ Time Frame: Date of study entry to date of due to any cause, assessed up to 10 years ]
Proportional hazards regression models will be used.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes 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

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To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00016276

Locations

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United States, Illinois
Cancer and Leukemia Group B
Chicago, Illinois, United States, 60606

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

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Principal Investigator:	Mark Graham	Cancer and Leukemia Group B

More Information

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Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00016276
Other Study ID Numbers:	NCI-2012-02380 CLB-49808 U10CA031946 ( U.S. NIH Grant/Contract ) CDR0000068617 ( Registry Identifier: PDQ (Physician Data Query) )
First Posted:	September 4, 2003 Key Record Dates
Last Update Posted:	January 16, 2013
Last Verified:	January 2013

Additional relevant MeSH terms:

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Breast Neoplasms Inflammatory Breast Neoplasms Cardiotoxicity Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Heart Diseases Cardiovascular Diseases Pathologic Processes Drug-Related Side Effects and Adverse Reactions Chemically-Induced Disorders Radiation Injuries Wounds and Injuries Tamoxifen	Paclitaxel Razoxane Cyclophosphamide Doxorubicin Liposomal doxorubicin Trastuzumab Dexrazoxane Antineoplastic Agents, Phytogenic Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Immunosuppressive Agents Immunologic Factors

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