Brain Metastases In ErbB2-Positive Breast Cancer
Condition: Neoplasms, Breast
MeSH terms: Breast Neoplasms; Neoplasm Metastasis; Brain Neoplasms
Intervention: capecitabine; topotecan; lapatinib
Intervention description: capecitabine 2000mg/m2/day orally, Days 1-14, every 21 days; topotecan intravenous (IV, in the vien) 3.2mg/m2 Days 1, 8 and 15; every 28 days; lapatinib administered 1250mg once daily orally
Intervention MeSH terms: Capecitabine; Topotecan; Lapatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: brain metastases; ErbB2; lapatinib; Breast Cancer; HYCAMTIN; topotecan; capecitabine; metastatic breast cancer; TYKERB; XELODA

Summary:

      This study is for patients with ErbB2 overexpressing breast cancer that has spread to the
      brain and is still progressing there even after radiation treatment using WBRT (whole brain
      radiotherapy) or SRS (stereotactic radiosurgery) to the brain. The study will determine how
      safe and effective lapatinib is when given in combination with capecitabine to treat patients
      with ErbB2 overexpressing breast cancer that has spread to the brain. Lapatinib is an oral
      drug that will be taken every day. Tests for safety and efficacy will be performed regularly
      during the course of the study.
    

Eligibility criteria:

        Inclusion criteria:

        Subjects eligible for enrollment in the study must meet all of the following criteria:

          -  Signed written informed consent;

          -  Females or males age ≥ 18 years old;

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1;

          -  Life expectancy of at least 12 weeks;

          -  Subjects must have histologically or cytologically confirmed invasive breast cancer,
             with Stage IV disease;

          -  ErbB2 overexpressing breast cancer, defined as 3+ staining by immunohistochemistry
             (IHC), or 2+ staining by IHC in conjunction with ErbB 2 gene amplification by FISH, or
             ErbB 2 gene amplification by FISH alone (in subjects whose tumor blocks were not
             assessed by IHC). Subjects with tumors that are 2+ by IHC but negative or borderline
             by FISH assay are ineligible. For subjects with a history of more than one primary
             breast cancer, each breast cancer must be ErbB2 overexpressing to be eligible;

          -  ErbB2 overexpressing breast cancer, defined as 3+ staining by immunohistochemistry
             (IHC), or 2+ staining by IHC in conjunction with ErbB2 gene amplification by FISH, or
             ErbB2 gene amplification by FISH alone (in subjects whose tumor blocks were not
             assessed by IHC). ErbB2 gene amplification is defined by: > 6 ErbB2 gene
             copies/nucleus for test systems without an internal control probe or an ErbB2/CEP 17
             ratio of more than 2.2. Subjects with tumors that are 2+ by IHC but negative or
             borderline by FISH assay are ineligible. For subjects with a history of more than one
             primary breast cancer, each breast cancer must be ErbB2 overexpressing to be eligible;

          -  Prior treatment of brain metastases with WBRT and/or SRS;

          -  Unequivocal evidence of new and / or progressive lesions in the brain on an imaging
             study; Note: Subjects with progressive brain lesions are not required to meet RECIST
             criteria for CNS progression in order to be eligible for this study.

          -  Prior treatment with trastuzumab, either alone or in combination with chemotherapy is
             required. Trastuzumab will be discontinued at least 2 weeks prior to enrollment on
             study;

          -  Cardiac ejection fraction within institutional range of normal as measured by
             echocardiogram. Subjects who require cardiac medications (e.g. positive inotropic
             agents or afterload reducers) for normal ejection fraction are ineligible. MUGA scans
             will be accepted in cases where an echocardiogram cannot be performed or is
             inconclusive;

          -  At least 2 weeks since prior radiotherapy, last chemotherapy, immunotherapy, biologic
             therapy, or hormonal therapy for cancer, and sufficiently recovered or stabilized from
             side effects associated with prior therapy. Concurrent treatment with bisphosphonates
             is permitted;

          -  At least 3 weeks since major surgical procedures;

          -  Able to swallow and retain oral medications;

          -  Women of childbearing potential must have a negative serum pregnancy test at screening
             and must use an approved contraceptive method, if appropriate (for example,
             intrauterine device [IUD], birth control pills, or barrier device) beginning 2 weeks
             before the first dose of investigational product and for 28 days after the final dose
             of investigational product. Males able to father a child must practice adequate
             methods of birth control or practice complete abstinence from intercourse from the
             first dose of investigational treatment until one week after the final dose of
             investigational treatment.

          -  Subjects must complete all screening assessments as outlined in the protocol;

          -  Normal organ and marrow function as defined by these LABORATORY VALUES : ANC (absolute
             neutrophil count) ≥ 1.5 x 10^9/L; Hemoglobin ≥ 10 g/dL (after transfusion if needed);
             Platelets ≥ 100 x 10^9/L; Albumin ≥ 2.5 g/dL; Serum bilirubin ≤ 1.5x ULN unless due to
             Gilbert's syndrome; AST and ALT ≤ 5x ULN if documented liver metastases ≤ 3x ULN
             without liver metastases; Serum Creatinine ≤ 1.2 mg/dL or Calculated Creatinine
             Clearance1 ≥ 50 mL/min

        Exclusion Criteria:

        Subjects meeting any of the following criteria must not be enrolled in the study:

          -  Subjects who have had chemotherapy or radiotherapy within 2 weeks prior to entering
             the study or who have unresolved or unstable, serious toxicity from prior
             administration of another investigational drug and/or of prior cancer treatment;

          -  Concurrent treatment with an investigational agent or participation in another
             treatment clinical trial;

          -  Prior therapy with a topoisomerase 1 inhibitor;

          -  Prior lapatinib therapy;

          -  Prior therapy with capecitabine;

          -  Known dihydropyrimidine dehydrogenase (DPD) deficiency;

          -  ECOG Performance Status 2 or greater;

          -  Subjects receiving concurrent chemotherapy, radiation therapy, immunotherapy, biologic
             therapy (including an ErbB1 and/or ErbB2 inhibitor), or hormonal therapy for treatment
             of their cancer. Hormone therapy for ovarian suppression which has been used for > 6
             months, during which time there has been disease progression in the brain, is allowed.
             Concurrent treatment with bisphosphonates is allowed;

          -  Subjects with evidence of leptomeningeal carcinomatosis at screening;

          -  History of allergic reactions attributed to compounds of similar chemical composition
             (quinazolines) to lapatinib;

          -  History of allergic reactions attributed to compounds chemically related to
             capecitabine, fluorouracil or any excipients;

          -  Concurrent treatment with medications listed as Prohibited Medications;

          -  Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
             resection of the stomach or small bowel. Subjects with active, uncontrolled ulcerative
             colitis are also excluded;

          -  History of immediate or delayed hypersensitivity reaction to gadolinium contrast
             agents, or other contraindication to gadolinium contrast;

          -  Other known contraindication to MRI, such as a cardiac pacemaker, implanted cardiac
             defibrillator, brain aneurysm clips, cochlear implant, ocular foreign body, or
             shrapnel;

          -  Concurrent disease or condition that would make the subject inappropriate for study
             participation or any serious medical or psychiatric disorder that would interfere with
             the subject's safety;

          -  Anticoagulant therapy (other than coumadin or aspirin as catheter prophylaxis) at
             study entry;

          -  Dementia, altered mental status, or any psychiatric condition that would prohibit the
             understanding or rendering of informed consent, unless a legally acceptable
             representative could provide informed consent (if in accord with the policies of the
             local Ethics Committee);

          -  Pre-existing severe cerebral vascular disease, such as stroke involving a major
             vessel, CNS vasculitis, or malignant hypertension;

          -  Active cardiac disease, defined as one or more of the following:

          -  History of uncontrolled or symptomatic angina

          -  History of arrhythmias requiring medications, or clinically significant

          -  Myocardial infarction < 6 months from study entry

          -  Uncontrolled or symptomatic congestive heart failure

          -  Ejection fraction below the institutional normal limit

          -  Any other cardiac condition, which in the opinion of the treating physician, would
             make this protocol unreasonably hazardous for the patient;

          -  Uncontrolled infection;

          -  Pregnant or lactating females;

          -  History of other malignancy, except for curatively treated basal cell carcinoma or
             squamous cell carcinoma of the skin, or carcinoma in situ of the cervix. Subjects with
             other malignancies who have been disease-free for at least 5 years are eligible.

          -  Have current active hepatic or biliary disease (with exception of subjects with
             Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver
             disease per investigator assessment).