- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00016276
Combination Chemotherapy, Surgery, and Radiation Therapy With or Without Dexrazoxane and Trastuzumab in Treating Women With Stage III or Stage IV Breast Cancer
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 Overview
Status
Conditions
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 Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
-
-
Illinois
-
Chicago, Illinois, United States, 60606
- Cancer and Leukemia Group B
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / 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).
|
Correlative studies
Given IV
Other Names:
Given orally
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Undergo radiation therapy
Other Names:
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
|
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.
|
Correlative studies
Given IV
Other Names:
Given orally
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Undergo radiation therapy
Other Names:
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
|
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.
|
Correlative studies
Given IV
Other Names:
Given orally
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Undergo radiation therapy
Other Names:
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
|
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.
|
Correlative studies
Given IV
Other Names:
Given orally
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Undergo radiation therapy
Other Names:
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
|
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.
|
Correlative studies
Given IV
Other Names:
Given orally
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Undergo radiation therapy
Other Names:
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
|
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.
|
Correlative studies
Given IV
Other Names:
Given orally
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Undergo radiation therapy
Other Names:
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
|
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.
|
Correlative studies
Given IV
Other Names:
Given orally
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Undergo radiation therapy
Other Names:
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
|
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.
|
Correlative studies
Given IV
Other Names:
Given orally
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Undergo radiation therapy
Other Names:
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
At 24 weeks
|
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.
|
At 24 weeks
|
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.
|
At 24 weeks
|
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.
|
At 78 weeks
|
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.
|
Date of study entry to date of first relapse (local or distant) or death due to any cause, assessed up to 10 years
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
|
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
|
At 12 weeks
|
|
Clinical/radiographic response in the breast and axilla after paclitaxel with or without trastuzumab
Time Frame: At 24 weeks
|
At 24 weeks
|
|
Time to local/regional recurrence
Time Frame: Up to 10 years
|
Up to 10 years
|
|
Time to completion of treatment through radiotherapy
Time Frame: Up to 5 years
|
Up to 5 years
|
|
Rate of breast conservation for patients considered "candidates" prior to treatment
Time Frame: Up to 10 years
|
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.
|
Date of study entry to date of due to any cause, assessed up to 10 years
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Mark Graham, Cancer and Leukemia Group B
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Chemically-Induced Disorders
- Pathologic Processes
- Heart Diseases
- Cardiovascular Diseases
- Skin Diseases
- Neoplasms
- Neoplasms by Site
- Wounds and Injuries
- Breast Diseases
- Drug-Related Side Effects and Adverse Reactions
- Radiation Injuries
- Breast Neoplasms
- Inflammatory Breast Neoplasms
- Cardiotoxicity
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antirheumatic Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Tubulin Modulators
- Antimitotic Agents
- Mitosis Modulators
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Antineoplastic Agents, Hormonal
- Protective Agents
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Antineoplastic Agents, Phytogenic
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Cardiotonic Agents
- Antineoplastic Agents, Immunological
- Antibiotics, Antineoplastic
- Hormone Antagonists
- Bone Density Conservation Agents
- Estrogen Antagonists
- Selective Estrogen Receptor Modulators
- Estrogen Receptor Modulators
- Cyclophosphamide
- Paclitaxel
- Trastuzumab
- Doxorubicin
- Liposomal doxorubicin
- Tamoxifen
- Dexrazoxane
- Razoxane
Other Study ID Numbers
- NCI-2012-02380
- U10CA031946 (U.S. NIH Grant/Contract)
- CLB-49808
- CDR0000068617 (Registry Identifier: PDQ (Physician Data Query))
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Inflammatory Breast Cancer
-
Dana-Farber Cancer InstituteIncyte CorporationActive, not recruitingInflammatory Breast Cancer (IBC)United States
-
NYU Langone HealthCompletedBreast CancerUnited States
-
BerGenBio ASAMerck Sharp & Dohme LLCTerminatedTriple Negative Breast Cancer | Inflammatory Breast Cancer Stage IVSpain, United States, United Kingdom, Norway
-
National Cancer Institute (NCI)TerminatedAnatomic Stage IV Breast Cancer AJCC v8 | Metastatic Triple-Negative Breast Inflammatory CarcinomaUnited States
-
Hoffmann-La RocheActive, not recruitingInflammatory Breast Cancer | Early Breast Cancer | Locally Advanced Breast CancerCanada, Croatia, Spain, Argentina, Mexico, Korea, Republic of, Bosnia and Herzegovina, Brazil, Costa Rica, Turkey, Singapore, Bulgaria, South Africa, India, Peru, Kenya, Chile
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)Active, not recruitingAnatomic Stage IIIB Breast Cancer AJCC v8 | Anatomic Stage IIIC Breast Cancer AJCC v8 | Prognostic Stage IIIB Breast Cancer AJCC v8 | Prognostic Stage IIIC Breast Cancer AJCC v8 | Breast Inflammatory CarcinomaUnited States
-
M.D. Anderson Cancer CenterNovartis; Puma Biotechnology, Inc.; Celcuity IncRecruiting
-
Filipa Lynce, MDAstraZeneca; Daiichi Sankyo, Inc.RecruitingBreast Cancer | HER2-positive Breast Cancer | Invasive Breast Cancer | Inflammatory Breast Cancer Stage III | HER2 Low Breast AdenocarcinomaUnited States
-
National Cancer Institute (NCI)CompletedInflammatory Breast Cancer | Stage II Breast Cancer | Stage IIIA Breast Cancer | Stage IIIB Breast Cancer | Stage IIIC Breast CancerUnited States
-
Institut Paoli-CalmettesMSD France; OncodistinctRecruitingInflammatory Breast CancerFrance, Belgium
Clinical Trials on laboratory biomarker analysis
-
Children's Oncology GroupNational Cancer Institute (NCI)Completed
-
Alliance for Clinical Trials in OncologyNational Cancer Institute (NCI)Active, not recruitingLeukemia | Acute Lymphoblastic Leukemia | Acute Promyelocytic LeukemiaUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedUntreated Adult Acute Lymphoblastic Leukemia | Untreated Childhood Acute Lymphoblastic LeukemiaUnited States, Canada, Australia, New Zealand, Puerto Rico, Switzerland
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedChildhood Acute Lymphoblastic Leukemia in Remission | Recurrent Childhood Acute Lymphoblastic LeukemiaUnited States
-
Alliance for Clinical Trials in OncologyNational Cancer Institute (NCI)CompletedLung CancerUnited States
-
Alliance for Clinical Trials in OncologyNational Cancer Institute (NCI)Completed
-
Children's Oncology GroupNational Cancer Institute (NCI)WithdrawnClear Cell Renal Cell Carcinoma | Rhabdoid Tumor of the Kidney | Congenital Mesoblastic Nephroma | Childhood Kidney NeoplasmUnited States
-
Gynecologic Oncology GroupNational Cancer Institute (NCI)WithdrawnBreast Carcinoma | BRCA1 Mutation Carrier | BRCA2 Mutation CarrierUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedWilms Tumor and Other Childhood Kidney TumorsUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedChildhood Acute Monoblastic Leukemia (M5a) | Childhood Acute Monocytic Leukemia (M5b) | Childhood Acute Myeloblastic Leukemia Without Maturation (M1) | Childhood Acute Myelomonocytic Leukemia (M4) | Childhood Acute Myeloid Leukemia/Other Myeloid MalignanciesUnited States