Cardiac ToxicityPhase 3NCT00016276
Combination Chemotherapy, Surgery, and Radiation Therapy With or Without Dexrazoxane and Trastuzumab in Treating Women With Stage III or Stage IV Breast Cancer
A Phase 3 study testing dexrazoxane hydrochloride, doxorubicin hydrochloride and cyclophosphamide in people with Cardiac Toxicity and Inflammatory Breast Cancer, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Cardiac Toxicity, Inflammatory Breast Cancer, Stage IIIA Breast Cancer
- What is being tested?
- dexrazoxane hydrochloride, doxorubicin hydrochloride and cyclophosphamide
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 396 participants
- Where
- 1 siteUnited States
- Study dates
- May 2001to Mar 2005
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 41Show fewer
- 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
Who cannot join
None listed.
Trial locations and contacts
1 site in 1 country.
United States1 site
Cancer and Leukemia Group B
Chicago, Illinois, 60606
About this study
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
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
Read the 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.
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.
- 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.
- 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.
- Conditions
- Cardiac Toxicity, Inflammatory Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IV Breast Cancer
- Being tested
- dexrazoxane hydrochloride, doxorubicin hydrochloride, cyclophosphamide, paclitaxel, trastuzumab
- Medical subject headings
- Cardiotoxicity, Inflammatory Breast Neoplasms, Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
dexrazoxane hydrochlorideDrug
Also called Cardioxane, Savene, Totect, Zinecard
Given IV
Also called ADM, ADR, Adria, Adriamycin PFS
Given IV
cyclophosphamideDrug
Also called CPM, CTX, Cytoxan, Endoxan
Given IV
paclitaxelDrug
Also called Anzatax, Asotax, TAX, Taxol
Given IV
trastuzumabBiological
Also called anti-c-erB-2, Herceptin, MOAB HER2
Given IV
therapeutic conventional surgeryProcedure or surgery
Undergo breast conservation surgery, modified radical mastectomy, or mastectomy
radiation therapyRadiation
Also called irradiation, radiotherapy, therapy, radiation
Undergo radiation therapy
tamoxifen citrateDrug
Also called Nolvadex, TAM, tamoxifen, TMX
Given orally
laboratory biomarker analysisOther
Correlative studies
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: doxorubicin hydrochloride; Drug: cyclophosphamide; Drug: paclitaxel; Procedure: therapeutic conventional surgery; Radiation: radiation therapy; Drug: tamoxifen citrate; Other: laboratory biomarker analysis |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: At 78 weeks
Disease-free survival
Proportional hazards regression models will be used.
Measured: 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)
Measured: Up to 10 years
Clinical/radiographic response in the breast and axilla after doxorubicin hydrochloride and cyclophosphamide with or without dexrazoxane hydrochloride
Measured: At 12 weeks
Clinical/radiographic response in the breast and axilla after paclitaxel with or without trastuzumab
Measured: At 24 weeks
Time to local/regional recurrence
Measured: Up to 10 years
Time to completion of treatment through radiotherapy
Measured: Up to 5 years
Rate of breast conservation for patients considered "candidates" prior to treatment
Measured: Up to 10 years
Overall survival
Proportional hazards regression models will be used.
Measured: Date of study entry to date of due to any cause, assessed up to 10 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Sep 2003 (estimated)
- Study startMay 2001
- Primary completionMar 2005
Why it stopped: Administratively complete.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Cardiac ToxicityStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 396 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Mark Graham, Principal investigator, Cancer and Leukemia Group B
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00016276
- Sponsor's protocol ID
- NCI-2012-02380
- Other IDs
- CLB-49808, U10CA031946, CDR0000068617
- Status last verified
- Jan 2013
- First submitted
- 6 May 2001
- Last updated
- 16 Jan 2013
- Results posted
- No
Study at a glance
From the registry record, last updated by the sponsor on 16 Jan 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00016276
- Acronym / sponsor ID
- NCI-2012-02380
- Conditions
- Cardiac Toxicity, Inflammatory Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IV Breast Cancer
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Administratively complete.
- Enrolment
- 396 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- May 2001
- Primary completion
- Mar 2005 (actual)
- First posted
- 4 Sep 2003 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
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.
- 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.
- 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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 8
| Arm | Type | Receives |
|---|---|---|
| Arm I (chemoprotection, monoclonal antibody, radiotherapy) | Experimental | 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 analysisPatients 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 (chemoprotection, radiotherapy, surgery, trastuzumab) | Experimental | 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 analysisPatients 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 (chemoprotection, monoclonal antibody, radiotherapy) | Experimental | 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 analysisPatients 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 (chemoprotection, paclitaxel, surgery, radiotherapy) | Experimental | Drug: dexrazoxane hydrochloride, Drug: doxorubicin hydrochloride, Drug: cyclophosphamide, Drug: paclitaxel, Procedure: therapeutic conventional surgery, Radiation: radiation therapy, Drug: tamoxifen citrate, Other: laboratory biomarker analysisPatients 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 (combination chemo, radiotherapy, long term trastuzumab) | Experimental | Drug: doxorubicin hydrochloride, Drug: cyclophosphamide, Drug: paclitaxel, Biological: trastuzumab, Procedure: therapeutic conventional surgery, Radiation: radiation therapy, Drug: tamoxifen citrate, Other: laboratory biomarker analysisPatients 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 (combination chemo, paclitaxel, surgery, radiotherapy) | Experimental | Drug: doxorubicin hydrochloride, Drug: cyclophosphamide, Drug: paclitaxel, Biological: trastuzumab, Procedure: therapeutic conventional surgery, Radiation: radiation therapy, Drug: tamoxifen citrate, Other: laboratory biomarker analysisPatients 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 (combination chemo, monoclonal antibody, radiotherapy) | Experimental | Drug: doxorubicin hydrochloride, Drug: cyclophosphamide, Drug: paclitaxel, Biological: trastuzumab, Procedure: therapeutic conventional surgery, Radiation: radiation therapy, Drug: tamoxifen citrate, Other: laboratory biomarker analysisPatients 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 (combination chemotherapy, paclitaxel, radiotherapy) | Experimental | Drug: doxorubicin hydrochloride, Drug: cyclophosphamide, Drug: paclitaxel, Procedure: therapeutic conventional surgery, Radiation: radiation therapy, Drug: tamoxifen citrate, Other: laboratory biomarker analysisPatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (41 listed)
- Histologically confirmed primary infiltrating adenocarcinoma of the breast
- 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)
Key exclusion criteria (0 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| dexrazoxane hydrochlorideAlso: Cardioxane, Savene, Totect, ZinecardGiven IV | Drug | 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 hydrochlorideAlso: ADM, ADR, Adria, Adriamycin PFSGiven IV | Drug | 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) |
| cyclophosphamideAlso: CPM, CTX, Cytoxan, EndoxanGiven IV | Drug | 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) |
| paclitaxelAlso: Anzatax, Asotax, TAX, TaxolGiven IV | Drug | 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) |
| trastuzumabAlso: anti-c-erB-2, Herceptin, MOAB HER2Given IV | Biological | 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 surgeryUndergo breast conservation surgery, modified radical mastectomy, or mastectomy | Procedure or surgery | 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 therapyAlso: irradiation, radiotherapy, therapy, radiationUndergo radiation 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 citrateAlso: Nolvadex, TAM, tamoxifen, TMXGiven orally | Drug | 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 analysisCorrelative studies | Other | 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) |
Primary outcome
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.
7 secondary outcomes
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
Results and safety
The study was stopped early (reason given: Administratively complete.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Jan 2013.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mark Graham principal investigator
Cancer and Leukemia Group B
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing dexrazoxane hydrochloride, doxorubicin hydrochloride and cyclophosphamide in people with Cardiac Toxicity and Inflammatory Breast Cancer, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 41 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 16 Jan 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Administratively complete.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Median number of positive axillary lymph nodes (time frame: At 24 weeks). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Jan 2013.