Clinical trial NCT00436566: 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
Official title: Phase II Study of Cardiac Safety and Tolerability of an Adjuvant Chemotherapy Plus Trastuzumab With Lapatinib in Patients With Resected HER2 + Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Cardiac Toxicity
Keywords: cardiac toxicity
male breast cancer
stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-02-19
Enrollment: 122
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed description: OBJECTIVES:

Primary

* 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.

Secondary

* 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.

Tertiary

* 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.

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

Primary outcomes:
measure: Number of Patients With Congestive Heart Failure (CHF) While on Active Treatment
timeFrame: 6 months
Secondary outcomes:
measure: Adverse Event Profile as Measured by NCI CTCAE v 3.0
timeFrame: 5 years
measure: Cumulative Incidence (CI) of Cardiac Events
timeFrame: 5 years
measure: Number of Patients Who Experience >= 10 Percent Drop in Left Ventricular Ejection Fraction (LVEF)
timeFrame: 5 years
measure: Percentage of Participants With Disease-Free Survival (DFS)
timeFrame: 5 years
measure: Percentage of Participants With Overall Survival (OS)
timeFrame: 5 years
measure: Change in Overall LINEAR ANALOGUE SELF ASSESSMENT (LASA) and Change in Symptom Distress Scale (SDS) Overall QOL
timeFrame: 5 years
measure: Proportion of Patients Experienced a Significant Decline in LINEAR ANALOGUE SELF ASSESSMENT (LASA) and a Overall Symptom Distress Scale (SDS) QOL Measurements
timeFrame: 5 years
measure: Incidence of Pulmonary Events
timeFrame: 5 years
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic Cancer Research Consortium
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Edith A. Perez, MD
role: STUDY_CHAIR
affiliation: Mayo Clinic
name: Donald W. Northfeld, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic in Rochester
name: James N. Ingle, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: McCullough A, Dueck A, Chen B, et al.: HER-2 central confirmatory testing using ASCO/CAP guidelines for trastuzumab/lapatinib trial MCCR RC0639. [Abstract] J Clin Oncol 27 (Suppl 15): A-e11527, 2009.
citation: Palmieri FM, Dueck AC, Johnson DB, et al.: Cardiac safety of lapatinib given concurrently with paclitaxel and trastuzumab as part of adjuvant therapy for patients with HER2+ breast cancer: Pilot data from the Mayo Clinic Cancer Research Consortium Trial RC0639. [Abstract] 32nd Annual San Antonio Breast Cancer Symposium, December 9-13, 2009, San Antonio, Texas. A-3086, 2009.
citation: Johnson BS, Dueck AC, Dakhil SR, et al.: Tolerability of lapatinib given concurrently with paclitaxel and trastuzumab as part of adjuvant therapy in patients with resected HER2+ breast cancer: initial safety data from the Mayo Clinic Cancer Research Consortium trial RC0639. [Abstract] 31st Annual San Antonio Breast Cancer Symposium, December 10-14, 2008, San Antonio, Texas. A-2109, 2008.