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Phase II Study of Cardiac Safety and Tolerability of an Adjuvant Chemotherapy Plus Trastuzumab With Lapatinib in Patients With Resected HER2 + Breast Cancer

Phase 2
18 Years
Not Enrolling
Breast Cancer, Cardiac Toxicity

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Trial Information

Phase II Study of Cardiac Safety and Tolerability of an Adjuvant Chemotherapy Plus Trastuzumab With Lapatinib in Patients With Resected HER2 + Breast Cancer



- 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

- 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


- 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

- 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

- 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.

Inclusion 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

- 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

- 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

- Rifamycin-class antibiotics (e.g., rifampin, rifabutin, or rifapentine)

- Anticonvulsants (e.g., phenytoin, carbamazepine, or barbiturates [e.g.,

- 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

- Modafinil

- Hypericum perforatum (St. John's wort)

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

- Antibiotics (e.g., clarithromycin, erythromycin, or troleandomycin)

- Antifungals (e.g., itraconazole, ketoconazole, fluconazole [> 150 mg daily], or

- 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

Type of Study:


Study Design:

Allocation: Randomized, Primary Purpose: Treatment

Outcome Measure:

Number of Patients With Congestive Heart Failure (CHF) While on Active Treatment

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Edith A. Perez, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Mayo Clinic in Florida


United States: Food and Drug Administration

Study ID:




Start Date:

March 2007

Completion Date:

Related Keywords:

  • Breast Cancer
  • Cardiac Toxicity
  • cardiac toxicity
  • male breast cancer
  • stage I breast cancer
  • stage II breast cancer
  • stage IIIA breast cancer
  • Breast Neoplasms



Mayo Clinic Cancer Research Consortium Rochester, Minnesota  55905