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

NCT00016276 | Terminated Phase 3

• 4 other identifiers: NCI-2012-02380CLB-49808U10CA031946CDR0000068617
• Study Type: interventional
• Target: 396
• Locations: 1 country
• Sites: 1

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

Conditions

Cardiac Toxicity; Inflammatory Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IV Breast Cancer

Outcome Measures

Primary Outcomes (5)

• Median number of positive axillary lymph nodes

  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.

  At 24 weeks

• Pathologic complete response (CR) rate in the breast and axilla

  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.

  At 24 weeks

• Cardiac toxicity, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0

  Assessment will use exact binomial comparison of two proportions.

  At 24 weeks

• Cardiac toxicity, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0

  Assessment will use exact binomial comparison of two proportions.

  At 78 weeks

• Disease-free survival

  Proportional hazards regression models will be used.

  Date of study entry to date of first relapse (local or distant) or death due to any cause, assessed up to 10 years

Secondary Outcomes (7)

• Occurrence of grade 3 or higher late cardiac or neurological toxicity, or secondary acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS)

  Up to 10 years

• Clinical/radiographic response in the breast and axilla after doxorubicin hydrochloride and cyclophosphamide with or without dexrazoxane hydrochloride

  At 12 weeks

• Clinical/radiographic response in the breast and axilla after paclitaxel with or without trastuzumab

  At 24 weeks

• Time to local/regional recurrence

  Up to 10 years

• Time to completion of treatment through radiotherapy

  Up to 5 years

Study Arms (8)

Arm I (chemoprotection, monoclonal antibody, radiotherapy)

EXPERIMENTAL

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; Drug: doxorubicin hydrochloride; Drug: cyclophosphamide; Drug: paclitaxel; Biological: trastuzumab; Procedure: therapeutic conventional surgery; Radiation: radiation therapy; Drug: tamoxifen citrate; Other: laboratory biomarker analysis

Arm II (chemoprotection, radiotherapy, surgery, trastuzumab)

EXPERIMENTAL

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; Drug: doxorubicin hydrochloride; Drug: cyclophosphamide; Drug: paclitaxel; Biological: trastuzumab; Procedure: therapeutic conventional surgery; Radiation: radiation therapy; Drug: tamoxifen citrate; Other: laboratory biomarker analysis

Arm III (chemoprotection, monoclonal antibody, radiotherapy)

EXPERIMENTAL

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; Drug: doxorubicin hydrochloride; Drug: cyclophosphamide; Drug: paclitaxel; Biological: trastuzumab; Procedure: therapeutic conventional surgery; Radiation: radiation therapy; Drug: tamoxifen citrate; Other: laboratory biomarker analysis

Arm IV (chemoprotection, paclitaxel, surgery, radiotherapy)

EXPERIMENTAL

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; Drug: doxorubicin hydrochloride; Drug: cyclophosphamide; Drug: paclitaxel; Procedure: therapeutic conventional surgery; Radiation: radiation therapy; Drug: tamoxifen citrate; Other: laboratory biomarker analysis

Arm V (combination chemo, radiotherapy, long term trastuzumab)

EXPERIMENTAL

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; Drug: cyclophosphamide; Drug: paclitaxel; Biological: trastuzumab; Procedure: therapeutic conventional surgery; Radiation: radiation therapy; Drug: tamoxifen citrate; Other: laboratory biomarker analysis

Arm VI (combination chemo, paclitaxel, surgery, radiotherapy)

EXPERIMENTAL

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; Drug: cyclophosphamide; Drug: paclitaxel; Biological: trastuzumab; Procedure: therapeutic conventional surgery; Radiation: radiation therapy; Drug: tamoxifen citrate; Other: laboratory biomarker analysis

Arm VII (combination chemo, monoclonal antibody, radiotherapy)

EXPERIMENTAL

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; Drug: cyclophosphamide; Drug: paclitaxel; Biological: trastuzumab; Procedure: therapeutic conventional surgery; Radiation: radiation therapy; Drug: tamoxifen citrate; Other: laboratory biomarker analysis

Arm VIII (combination chemotherapy, paclitaxel, radiotherapy)

EXPERIMENTAL

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; Drug: cyclophosphamide; Drug: paclitaxel; Procedure: therapeutic conventional surgery; Radiation: radiation therapy; Drug: tamoxifen citrate; Other: laboratory biomarker analysis

Interventions

dexrazoxane hydrochloride DRUG

Given IV

Also known as: Cardioxane, Savene, Totect, Zinecard

Arm I (chemoprotection, monoclonal antibody, radiotherapy); Arm II (chemoprotection, radiotherapy, surgery, trastuzumab); Arm III (chemoprotection, monoclonal antibody, radiotherapy); Arm IV (chemoprotection, paclitaxel, surgery, radiotherapy)

doxorubicin hydrochloride DRUG

Given IV

Also known as: ADM, ADR, Adria, Adriamycin PFS, Adriamycin RDF

Arm I (chemoprotection, monoclonal antibody, radiotherapy); Arm II (chemoprotection, radiotherapy, surgery, trastuzumab); Arm III (chemoprotection, monoclonal antibody, radiotherapy); Arm IV (chemoprotection, paclitaxel, surgery, radiotherapy); Arm V (combination chemo, radiotherapy, long term trastuzumab); Arm VI (combination chemo, paclitaxel, surgery, radiotherapy); Arm VII (combination chemo, monoclonal antibody, radiotherapy); Arm VIII (combination chemotherapy, paclitaxel, radiotherapy)

cyclophosphamide DRUG

Given IV

Also known as: CPM, CTX, Cytoxan, Endoxan, Endoxana

Arm I (chemoprotection, monoclonal antibody, radiotherapy); Arm II (chemoprotection, radiotherapy, surgery, trastuzumab); Arm III (chemoprotection, monoclonal antibody, radiotherapy); Arm IV (chemoprotection, paclitaxel, surgery, radiotherapy); Arm V (combination chemo, radiotherapy, long term trastuzumab); Arm VI (combination chemo, paclitaxel, surgery, radiotherapy); Arm VII (combination chemo, monoclonal antibody, radiotherapy); Arm VIII (combination chemotherapy, paclitaxel, radiotherapy)

paclitaxel DRUG

Given IV

Also known as: Anzatax, Asotax, TAX, Taxol

Arm I (chemoprotection, monoclonal antibody, radiotherapy); Arm II (chemoprotection, radiotherapy, surgery, trastuzumab); Arm III (chemoprotection, monoclonal antibody, radiotherapy); Arm IV (chemoprotection, paclitaxel, surgery, radiotherapy); Arm V (combination chemo, radiotherapy, long term trastuzumab); Arm VI (combination chemo, paclitaxel, surgery, radiotherapy); Arm VII (combination chemo, monoclonal antibody, radiotherapy); Arm VIII (combination chemotherapy, paclitaxel, radiotherapy)

trastuzumab BIOLOGICAL

Given IV

Also known as: anti-c-erB-2, Herceptin, MOAB HER2

Arm I (chemoprotection, monoclonal antibody, radiotherapy); Arm II (chemoprotection, radiotherapy, surgery, trastuzumab); Arm III (chemoprotection, monoclonal antibody, radiotherapy); Arm V (combination chemo, radiotherapy, long term trastuzumab); Arm VI (combination chemo, paclitaxel, surgery, radiotherapy); Arm VII (combination chemo, monoclonal antibody, radiotherapy)

therapeutic conventional surgery PROCEDURE

Undergo breast conservation surgery, modified radical mastectomy, or mastectomy

Arm I (chemoprotection, monoclonal antibody, radiotherapy); Arm II (chemoprotection, radiotherapy, surgery, trastuzumab); Arm III (chemoprotection, monoclonal antibody, radiotherapy); Arm IV (chemoprotection, paclitaxel, surgery, radiotherapy); Arm V (combination chemo, radiotherapy, long term trastuzumab); Arm VI (combination chemo, paclitaxel, surgery, radiotherapy); Arm VII (combination chemo, monoclonal antibody, radiotherapy); Arm VIII (combination chemotherapy, paclitaxel, radiotherapy)

radiation therapy RADIATION

Undergo radiation therapy

Also known as: irradiation, radiotherapy, therapy, radiation

Arm I (chemoprotection, monoclonal antibody, radiotherapy); Arm II (chemoprotection, radiotherapy, surgery, trastuzumab); Arm III (chemoprotection, monoclonal antibody, radiotherapy); Arm IV (chemoprotection, paclitaxel, surgery, radiotherapy); Arm V (combination chemo, radiotherapy, long term trastuzumab); Arm VI (combination chemo, paclitaxel, surgery, radiotherapy); Arm VII (combination chemo, monoclonal antibody, radiotherapy); Arm VIII (combination chemotherapy, paclitaxel, radiotherapy)

tamoxifen citrate DRUG

Given orally

Also known as: Nolvadex, TAM, tamoxifen, TMX

Arm I (chemoprotection, monoclonal antibody, radiotherapy); Arm II (chemoprotection, radiotherapy, surgery, trastuzumab); Arm III (chemoprotection, monoclonal antibody, radiotherapy); Arm IV (chemoprotection, paclitaxel, surgery, radiotherapy); Arm V (combination chemo, radiotherapy, long term trastuzumab); Arm VI (combination chemo, paclitaxel, surgery, radiotherapy); Arm VII (combination chemo, monoclonal antibody, radiotherapy); Arm VIII (combination chemotherapy, paclitaxel, radiotherapy)

laboratory biomarker analysis OTHER

Correlative studies

Arm I (chemoprotection, monoclonal antibody, radiotherapy); Arm II (chemoprotection, radiotherapy, surgery, trastuzumab); Arm III (chemoprotection, monoclonal antibody, radiotherapy); Arm IV (chemoprotection, paclitaxel, surgery, radiotherapy); Arm V (combination chemo, radiotherapy, long term trastuzumab); Arm VI (combination chemo, paclitaxel, surgery, radiotherapy); Arm VII (combination chemo, monoclonal antibody, radiotherapy); Arm VIII (combination chemotherapy, paclitaxel, radiotherapy)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

Cancer and Leukemia Group B

Chicago, Illinois, 60606, United States

Location

MeSH Terms

Conditions

Cardiotoxicity; Inflammatory Breast Neoplasms; Breast Neoplasms

Interventions

Dexrazoxane; Razoxane; Doxorubicin; Cyclophosphamide; Paclitaxel; Taxes; Trastuzumab; Radiotherapy; Radiation; Tamoxifen

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Radiation Injuries; Wounds and Injuries; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Diketopiperazines; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Diterpenes; Terpenes; Economics; Health Care Economics and Organizations; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Therapeutics; Physical Phenomena; Stilbenes; Benzylidene Compounds; Benzene Derivatives

Study Officials

• Mark Graham

  Cancer and Leukemia Group B

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 6, 2001
• First Posted: September 4, 2003
• Study Start: May 1, 2001
• Primary Completion: March 1, 2005
• Last Updated: January 16, 2013

Record last verified: 2013-01

Locations

US (1)