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

This study has been completed.
Sponsor:
Collaborator:
Information provided by:
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT00436566
First received: February 15, 2007
Last updated: November 20, 2012
Last verified: November 2012
  Purpose

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.


Condition Intervention Phase
Breast Cancer
Cardiac Toxicity
Biological: trastuzumab
Drug: cyclophosphamide
Drug: doxorubicin hydrochloride
Drug: lapatinib ditosylate
Drug: paclitaxel
Genetic: gene expression analysis
Genetic: reverse transcriptase-polymerase chain reaction
Other: fluorophotometry
Other: laboratory biomarker analysis
Other: mass spectrometry
Procedure: adjuvant therapy
Procedure: quality-of-life assessment
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Number of Patients With Congestive Heart Failure (CHF) While on Active Treatment [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Adverse Event Profile as Measured by NCI CTCAE v 3.0 [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
    Maximum grade for each type of adverse event will be recorded for each patient.

  • Cumulative Incidence (CI) of Cardiac Events [ Time Frame: 5 years ] [ Designated as safety issue: No ]

    Evaluable patients included those completed the AC phase of their treatment regimen; with post AC cardiac evaluation indicates they are eligible to begin treatment with PTL; and those have begun their post-AC therapy.

    Cardiac events: symptomatic congestive heart failure (CHF), cardiac death and other cardiac events (NCI Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3)


  • Number of Patients Who Experience >= 10 Percent Drop in Left Ventricular Ejection Fraction (LVEF) Between Two Time Points [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Disease-free Survival (DFS) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    DFS was defined as the time from registration to the earliest date of documentation of any local, regional, or distant recurrence of breast cancer (BC); the development of a contralateral BC or second primary other than squamous or basal cell carcinoma of the skin, carcinoma in situ of the cervix, or lobular carcinoma in situ of the breast; or death from any cause without the documentation of one of these events. Participants were followed for a maximum of 5 years from randomization. The median OS with 95%CI was estimated using the Kaplan Meier method.

  • Overall Survival (OS) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    OS was defined as the time from registration to death of any cause. Participants were followed for a maximum of 5 years from randomization. The median OS with 95%CI was estimated using the Kaplan Meier method.

  • Comparison of Selected Quality-of-life Questionnaires [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Quality-of-life [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Incidence of Pulmonary Events [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    Pulmonary events to be included were grade 3 and higher pulmonary adverse events at least possibly related to study treatment, which occur at any time after post-AC treatment is begun, but prior to documentation of a breast cancer recurrence, contralateral breast cancer, secondary primary cancer, non-pulmonary death, or pulmonary death not related to study treatment.


Enrollment: 122
Study Start Date: March 2007
Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)
  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00436566

Locations
United States, Minnesota
Mayo Clinic Cancer Research Consortium
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
Investigators
Study Chair: Edith A. Perez, MD Mayo Clinic in Florida
Principal Investigator: Donald W. Northfeld, MD Mayo Clinic in Arizona
Principal Investigator: James N. Ingle, MD Mayo Clinic in Rochester
  More Information

Additional Information:
Publications:
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.
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.
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.

Responsible Party: Edith A. Perez, Mayo Clinic in Florida
ClinicalTrials.gov Identifier: NCT00436566     History of Changes
Other Study ID Numbers: CDR0000533793, P30CA015083, RC0639, 06-004049
Study First Received: February 15, 2007
Results First Received: October 22, 2012
Last Updated: November 20, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Mayo Clinic:
cardiac toxicity
male breast cancer
stage I breast cancer
stage II breast cancer
stage IIIA breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Cyclophosphamide
Doxorubicin
Lapatinib
Liposomal doxorubicin
Paclitaxel
Trastuzumab
Alkylating Agents
Antibiotics, Antineoplastic
Antimitotic Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antineoplastic Agents, Phytogenic
Antirheumatic Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Protein Kinase Inhibitors
Therapeutic Uses
Topoisomerase II Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on October 30, 2014