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
Condition: Breast Cancer; Cardiac Toxicity
MeSH terms: Breast Neoplasms; Cardiotoxicity
Intervention: trastuzumab; cyclophosphamide; doxorubicin hydrochloride; lapatinib ditosylate; paclitaxel; gene expression analysis; reverse transcriptase-polymerase chain reaction; fluorophotometry; laboratory biomarker analysis; mass spectrometry; adjuvant therapy; quality-of-life assessment
Intervention MeSH terms: Paclitaxel; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Trastuzumab; Lapatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Enrollment: 122.0
Sex: All
Minimum age: 18 Years
Maximum age: 120 Years
Healthy volunteers: No
Keywords: cardiac toxicity; male breast cancer; stage I breast cancer; stage II breast cancer; stage IIIA breast cancer

Summary:

      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.
    

Eligibility criteria:

        DISEASE CHARACTERISTICS:

          -  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

        PATIENT CHARACTERISTICS:

          -  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

        PRIOR CONCURRENT THERAPY:

          -  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

               -  Modafinil

               -  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