Novel Capecitabine Dosing Schedule in Combination With Lapatinib, Based on the Norton-Simon Mathematical Method in Patients With HER2 Overexpressed/Amplified, Trastuzumab (Herceptin) -Refractory, Metastatic Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: capecitabine, lapatinib
Intervention description: Capecitabine 2,000mg twice daily for 7 days followed by a 7-day rest in combination with lapatinib 1,250mg orally daily. Cycle length is 28 days (+/- 2 days).Toxicity assessment will occur q2 weeks for the first 4 weeks, then q4 weeks(+/- 2 days). Radiographic response assessment will take place q12 weeks (+/- 1 week). LVEF assessment will be repeated q12 weeks (+/- 1 week).
Intervention MeSH terms: Capecitabine; Lapatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: CAPECITABINE; LAPATINIB

Summary:

      HER2 is a protein that sits on the surface of breast cancer cells in some people. Because you
      are one of these people, your breast cancer is called "HER2-positive." The HER2 protein is
      involved in the growth of your breast cancer. Certain drugs can interfere with the ability of
      the HER2 protein to cause breast cancer growth. Trastuzumab is one of these drugs. You must
      have already received trastuzumab as treatment for your breast cancer to be considered for
      this study.

      Other drugs are being studied in women with HER2-positive breast cancer. Lapatinib (Tykerb™)
      blocks signals that stimulate HER2-positive breast cancers to grow. The FDA approved
      lapatinib for use with capecitabine (Xeloda™) in patients who have metastatic breast cancer
      that has grown or spread after treatment with trastuzumab.

      Capecitabine was approved by the FDA in 1998 for treating metastatic breast cancer.
      Capecitabine is a pill that blocks the way cancer cells multiply and grow. Usually, this
      medicine is taken twice a day for fourteen days. Then, patients do not take the pill for
      seven days. With this schedule and dose, some patients have had side effects that interfered
      with their comfort. We have used mathematical models to recommend a new schedule of
      capecitabine. In animals, 7 days of treatment with capecitabine followed by a 7-day break was
      safer and more active against breast cancer. The purpose of this study is to find out what
      effect (both good and bad) capecitabine has on you and your breast cancer when given in this
      new schedule and combined with lapatinib.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients with a diagnosis of invasive adenocarcinoma of the breast confirmed by
             histology or cytology at MSKCC.

          -  Clinical evidence of metastatic breast cancer.

          -  HER2 overexpression and/or amplification as determined by immunohistochemistry (3+) or
             FISH (≥2.0).

          -  Progressive disease following treatment with trastuzumab for metastatic breast cancer
             or as adjuvant therapy (either single-agent or combination therapy)

          -  Prior therapy inclusion:

               -  No more than two prior chemotherapy regimens allowed for advanced stage disease

               -  No prior fluoropyrimidine in the metastatic setting. Adjuvant fluoropyrimidine is
                  permitted if >6 months prior to treatment on study.

               -  No restriction for prior hormonal therapy. No concurrent use of endocrine therapy
                  is permitted.

               -  No more than 450mg/m2 cumulative dose of prior doxorubicin

               -  At least 3 weeks since prior chemotherapy or radiation therapy

          -  Age ≥ or = to 18. Because no dosing or adverse event data are currently available on
             the use of lapatinib in patients <18 years of age, children are excluded from this
             study.

          -  Patients must be willing to discontinue sex hormonal therapy e.g., birth control
             pills, ovarian hormonal replacement therapy, etc., prior to enrollment. Women of
             childbearing potential must be willing to consent to using effective contraception
             while on treatment and for a reasonable period thereafter.

          -  Negative HCG pregnancy test for premenopausal women of reproductive capacity and for
             women less than 12 months after the menopause.

          -  Asymptomatic, central nervous system metastases are permitted if patients remain
             clinically stable after discontinuation of corticosteroids and anticonvulsants.

          -  ECOG performance status < or = to 2

          -  Life expectancy of greater than 12 weeks

        Patients must have normal organ and marrow function as defined below:

          -  leukocytes ≥ or = to 3,000/μL

          -  absolute neutrophil count ≥ or = 1,500/μL

          -  platelets ≥ or = 100,000/μL

          -  total bilirubin within normal institutional limits AST (SGOT)/ALT(SGPT) ≤ or = 2.5x
             institutional upper limit of normal serum creatinine within normal institutional
             limits

               -  Cardiac ejection fraction at or above the lower limit of normal of 50% as
                  measured by multigated radionuclide angiography (MUGA) scan. If LVEF is greater
                  than 70%, and ECHO should be performed as well. Baseline and on treatment scans
                  should be performed using the same modality and preferably at the same
                  institution.

               -  Ability to understand and the willingness to sign a written informed. consent
                  document.

               -  Able to swallow and retain oral medication.

        Exclusion Criteria:

          -  Patients may not be receiving any concurrent anticancer therapy or investigational
             agents with the intention of treating breast cancer.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to lapatinib or capecitabine.

          -  Known DPD deficiency.

          -  Uncontrolled inter-current illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, myocardial
             infarction within 6 months of study entry, uncontrolled cardiac arrhythmia, or
             psychiatric illness/social situations that would limit compliance with study
             requirements.

          -  Pregnant women are excluded from this study because lapatinib is member of the 4-
             anilinoquinazoline class of kinase inhibitors with the potential for teratogenic or
             abortifacient effects. Because there is an unknown but potential risk for adverse
             events in nursing infants secondary to treatment of the mother with lapatinib,
             breastfeeding should be discontinued if the mother is treated with lapatinib.

          -  HIV-positive patients receiving combination anti-retroviral therapy are excluded from
             the study because of possible pharmacokinetic interactions with lapatinib. Appropriate
             studies will be undertaken in patients receiving combination anti-retroviral therapy
             when indicated.

          -  Patients with GI tract disease resulting in an inability to take oral medication,
             malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures
             affecting absorption,uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative
             colitis).

          -  Concomitant requirement for medication classified as CYP3A4 inducers or inhibitors:

          -  Medications that inhibit or induce CYP3A4 are prohibited. Eligibility of patients
             receiving medications or substances known to affect, or with the potential to affect
             the activity or pharmacokinetics of lapatinib will be determined following review of
             their use by the Principal Investigator.

          -  Renal function as measured by creatinine clearance < 30ml/min

          -  Patients are permitted to participate in other non-therapeutic clinical trials while
             receiving treatment on this study (ie, experimental imaging, minor procedures
             necessary for tissue acquisition on study)