Breast Cancer Clinical Trial

Doxorubicin and Cyclophosphamide Followed By Trastuzumab, Paclitaxel, and Lapatinib in Treating Patients With Early-Stage HER2-Positive Breast Cancer That Has Been Removed By Surgery


RATIONALE: Drugs used in chemotherapy, such as doxorubicin, cyclophosphamide, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy together with trastuzumab and lapatinib after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This randomized phase II trial is studying the side effects and how well giving doxorubicin together with cyclophosphamide followed by trastuzumab, paclitaxel, and lapatinib works in treating patients with early-stage HER2-positive breast cancer that has been removed by surgery.

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Full Description



Determine the cardiac safety of adjuvant therapy comprising doxorubicin hydrochloride and cyclophosphamide followed by paclitaxel, trastuzumab (Herceptin®), and lapatinib ditosylate in patients with resected early-stage HER2-positive breast cancer.


Determine the adverse event profile of this regimen in these patients.
Determine the cumulative incidence of cardiac events in patients treated with this regimen.
Determine the LVEF in patients treated with this regimen.
Determine the disease-free and overall survival of patients treated with this regimen.
Compare selected quality-of-life (QOL) questionnaires in these patients.
Evaluate QOL of patients treated with this regimen.
Determine the cumulative incidence of pulmonary events in patients treated with this regimen.


Compare Veridex CellSearch system vs quantitative reverse transcriptase polymerase chain reaction for detecting circulating tumor cells.
Determine the relationship between serum levels of HER1 and HER2 and response to treatment.
Evaluate cardiac markers (i.e., troponin-T, troponin-I, brain natriuretic peptide, and creatine kinase MB isoenzyme) at baseline.
Determine the association between abnormal levels of cardiac markers and incidence of cardiac adverse events.
Evaluate patterns of 500 metabolites in plasma in patients treated with this regimen and determine the association between metabolite patterns/molecular signatures and cardiotoxicity.
Determine the time course of these molecular signatures and evaluate whether they are accurate predictors of cardiotoxicity that precede other evidence of cardiotoxicity (e.g., changes in left ventricular function seen by echocardiogram or MUGA scan).
Compare metabolic signatures of cardiotoxicity with known laboratory evidence of cardiac damage (e.g., troponins or brain natriuretic peptide) in terms of sensitivity and specificity.

OUTLINE: This is a randomized, pilot, multicenter study. Patients are stratified according to educational level (less than high school vs high school or GED vs formal education beyond high school).

Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 2-3 weeks for 4 courses. Patients then receive paclitaxel IV over 60 minutes and trastuzumab (Herceptin®) IV over 90 minutes on days 1, 8, and 15 and oral lapatinib ditosylate on days 1-21. Treatment with paclitaxel, trastuzumab, and lapatinib repeats every 3 weeks for up to 4 courses. Patients then receive trastuzumab IV over 30-90 minutes on day 1 and oral lapatinib ditosylate on days 1-21. Treatment with trastuzumab and lapatinib ditosylate repeats every 3 weeks for up to 12 courses.

Patients complete Linear Anologue Self Assessment (LASA) and Symptoms Distress Scale (SDS) questionnaires, including fatigue, diarrhea, and rash assessment, at baseline, after 2-3, 5-6, and 18 months of treatment, and 5 years after completion of treatment. Patients are also randomized to 1 of 2 arms to complete additional quality of life questionnaires at these same time points.

Arm I: Patients complete EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires.
Arm II: Patients complete FACT-B questionnaire. Blood samples are acquired periodically throughout and at the completion of study treatment. Samples are analyzed for circulating tumor cells by Veridex CellSearch system, quantitative reverse transcriptase polymerase chain reaction, and liquid chromatography with tandem mass spectrometry, soluble HER1- and HER2-receptor concentrations, circulating cardiac markers, and metabolic markers for possible correlation with cardiac events.

After completion of study treatment, patients are followed periodically for up to 10 years.

PROJECTED ACCRUAL: A total of 109 patients will be accrued for this study.

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Eligibility Criteria


Histologically confirmed diagnosis of early-stage breast cancer

HER2 positive by immunohistochemistry (IHC) (3+) or fluorescent in situ hybridization (FISH)

Ductal carcinoma in situ (DCIS) components should not be counted in the determination of degree of IHC staining or FISH amplification

No locally advanced tumors (i.e., T4) at diagnosis, including the following:

Tumors fixed to chest wall
Peau d'orange
Skin ulcerations or nodules
Clinical inflammatory changes (e.g., diffuse brawny cutaneous induration with an erysipeloid edge)

Has undergone mastectomy or lumpectomy with axillary node or sentinel node dissection within the past 84 days

Patients who have undergone a mastectomy must meet the following criteria:

No evidence of gross or microscopic tumor (i.e., invasive DCIS) at the surgical resection margins noted in final surgery or pathology reports

Patients with close margins are eligible
Radiation therapy is required for 4 or more positive lymph nodes and must be started after completion of chemotherapy

Patients who have undergone a lumpectomy with axillary node or sentinel node dissection must meet the following criteria:

No evidence of invasive cancer or DCIS at the surgical resection margins
No gross residual adenopathy
Planning to undergo radiation therapy to the breast with or without regional lymphatics after completion of chemotherapy

No active hepatic or biliary disease

Patients with liver metastases, stable chronic liver disease, Gilbert's syndrome, or asymptomatic gallstones are eligible

Hormone receptor status:

Estrogen receptor and progesterone receptor status known


Male or female
Menopausal status not specified
ECOG performance status 0-2
Absolute neutrophil count ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Hemoglobin ≥ 10.0 g/dL
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST and ALT ≤ 2.5 times ULN
Alkaline phosphatase ≤ 2.5 times ULN
Creatinine normal OR creatinine clearance ≥ 60 mL/min
LVEF ≥ 50% by MUGA scan or echocardiogram
Able to complete questionnaire(s) by themselves or with assistance
Able and willing to provide blood and tissue samples
No known sensitivity to benzyl alcohol
No sensory neuropathy ≥ grade 2

No active cardiac disease, including any of the following:

Myocardial infarction within the past 6 months
Prior or concurrent congestive heart failure
Prior or concurrent arrhythmia or cardiac valvular disease requiring medications or that is clinically significant
Uncontrolled hypertension, defined as diastolic blood pressure (BP) >100 mm Hg or systolic BP > 200 mm Hg on 2 separate occasions ≥ 14 days apart
Clinically significant pericardial effusion
Prior or concurrent uncontrolled or symptomatic angina
Other cardiac condition that, in the opinion of the treating physician, would put the patient at hazardous risk
No history of allergic reactions attributed to compounds of similar chemical or biologic composition as lapatinib ditosylate

No uncontrolled intercurrent illness including, but not limited to, the following:

Ongoing or active infection
Psychiatric illness or social situations that would preclude study compliance

Able to swallow and retain oral medication

No history of gastrointestinal (GI) disease resulting in an inability to take oral medication, including any of the following:

Malabsorption syndrome
Requirement for IV alimentation
Prior surgical procedures affecting absorption
Uncontrolled inflammatory GI disease (e.g., Crohn's disease or ulcerative colitis)
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 6 months after completion of study treatment


See Disease Characteristics
No prior chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer
No primary breast radiation therapy as part of breast-conserving treatment
No prior anthracycline or taxane therapy for any malignancy
No prior epidermal growth factor receptor-targeting therapies (e.g., gefitinib, cetuximab, erlotinib hydrochloride, rituximab, trastuzumab [Herceptin®], lapatinib ditosylate, panitumumab, or nimotuzumab)

At least 14 days since prior and no concurrent CYP3A4 inducers, including the following:

Rifamycin-class antibiotics (e.g., rifampin, rifabutin, or rifapentine)
Anticonvulsants (e.g., phenytoin, carbamazepine, or barbiturates [e.g., phenobarbital])
Antiretrovirals (e.g., efavirenz or nevirapine)

Glucocorticoids (e.g., oral cortisone, hydrocortisone, prednisone, methylprednisolone, or dexamethasone)

Daily oral dexamethasone ≤ 1.5 mg (or equivalent) allowed
Hypericum perforatum (St. John's wort)

At least 7 days since prior and no concurrent CYP3A4 inhibitors, including the following:

Antibiotics (e.g., clarithromycin, erythromycin, or troleandomycin)
Antifungals (e.g., itraconazole, ketoconazole, fluconazole [> 150 mg daily], or voriconazole)
Antiretrovirals and protease inhibitors (e.g., delaviridine, nelfinavir, amprenavir, ritonavir, indinavir, saquinavir, or lopinavir)
Calcium channel blockers (e.g., verapamil or diltiazem)
Antidepressants (e.g., nefazodone or fluvoxamine)
Gastrointestinal agents (e.g., cimetidine or aprepitant)
Grapefruit and grapefruit juice
At least 6 months since prior and no concurrent amiodarone
No herbal or alternative medicines or supplements ≥ 14 days before, during, and for 30 days after completion of study treatment

No concurrent hormonal agents (e.g., birth control pills, ovarian hormonal replacement therapy, or raloxifene)

Adjuvant hormonal agents (e.g., tamoxifen, aromatase inhibitors) allowed after completion of chemotherapy as part of treatment for breast cancer
No concurrent antiretroviral therapy for HIV-positive patients
No concurrent digitalis or beta-blockers for congestive heart failure
No concurrent arrhythmia or angina pectoris medication
No other concurrent investigational agents or anticancer therapies, including cytotoxic agents or immunotherapy

Study is for people with:

Breast Cancer


Phase 2

Estimated Enrollment:


Study ID:


Recruitment Status:



Mayo Clinic

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There is 1 Location for this study

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Mayo Clinic Cancer Research Consortium
Rochester Minnesota, 55905, United States

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Study is for people with:

Breast Cancer


Phase 2

Estimated Enrollment:


Study ID:


Recruitment Status:



Mayo Clinic

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