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Intermittent High-Dose Lapatinib in Tandem With Capecitabine for HER2 Overexpressed/Amplified Metastatic Breast Cancer With Central Nervous System (CNS) Metastases



The purpose of this study is to see if capecitabine can be taken safely with different doses of lapatinib in patients with HER-2 positive breast cancer involving brain (brain metastases) and/or in spinal fluid (leptomeningeal disease).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting


Phase 1

Trial Eligibility


Intermittent High-Dose <span class="go-doc-concept go-doc-intervention">Lapatinib</span> in Tandem With <span class="go-doc-concept go-doc-intervention">Capecitabine</span> for <span class="go-doc-concept go-doc-biomarker">HER2</span> <span class="go-doc-concept go-doc-keyword">Overexpressed</span>/<span class="go-doc-concept go-doc-keyword">Amplified</span> <span class="go-doc-concept go-doc-disease">Metastatic Breast Cancer</span> With Central Nervous System (<span class="go-doc-concept go-doc-disease">CNS</span>) Metastases


  • Brief Title: Intermittent High-Dose Lapatinib in Tandem With Capecitabine for HER2 Overexpressed/Amplified Metastatic Breast Cancer With Central Nervous System (CNS) Metastases
  • Official Title: Phase I Study of Intermittent High-Dose Lapatinib in Tandem With Capecitabine for HER2 Overexpressed/Amplified Metastatic Breast Cancer With Central Nervous System (CNS) Metastases
  • Clinical Trial IDs

    NCT ID: NCT02650752

    ORG ID: 15-278

    Trial Conditions

    Metastatic Breast Cancer

    Central Nervous System (CNS) Metastases

    Trial Interventions

    Drug Synonyms Arms
    Lapatinib in Tandem With Capecitabine Lapatinib in Tandem With Capecitabine

    Trial Purpose

    The purpose of this study is to see if capecitabine can be taken safely with different doses
    of lapatinib in patients with HER-2 positive breast cancer involving brain (brain
    metastases) and/or in spinal fluid (leptomeningeal disease).

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Lapatinib in Tandem With Capecitabine Experimental A minimum of one patient at each dose level will be enrolled. Patients will receive a 4 week treatment cycle consisting of lapatinib 3 day on/11 day off in tandem with capecitabine 7 day on/7 day off with lapatinib. Both drugs will be administered orally as outpatient. Safety, toxicity, and DLT will be assessed weekly during the cycle 1 (first 4 weeks). Each patient will be monitored during cycle 1 prior to enrolling the next patient to the next higher dose level. Dose escalation will take place if no DLT or less than two occurrences of grade 2 toxicity (except those listed below) is observed within a given patient. In the event that a second instance of separate grade 2 toxicity (except those listed below) is noted, the cohort will be expanded to 3 patients at the same dose level and the study will revert to the standard 3+3 design with 3 patients per cohort. There will be no intra-patient dose escalation. Lapatinib in Tandem With Capecitabine

    Eligibility Criteria

    Inclusion Criteria:

    - Age 18 years

    - Histologically-confirmed metastatic adenocarcinoma of the breast with either invasive
    primary tumor or metastatic tissue confirmation of HER2+ status as defined by
    immunohistochemistry (IHC) with score of 3+, or, if 2+ with confirmatory fluorescence
    in situ hybridization (FISH) ratio of 2.0

    - Received prior trastuzumab or chemotherapy for metastatic breast cancer except if
    patient has CNS as only site of metastatic disease.

    - Radiologic evidence of new and/or progressive parenchymal brain metastasis, or
    leptomeningeal disease (LMD) by magnetic resonance (MR) imaging of the brain and/or
    spine, or CSF cytology evidence of new LMD.

    - Life expectancy of >12 weeks.

    - ECOG Performance of 0 to 2

    - Non-escalating corticosteroid dose (not exceeding more than 16 mg daily of
    dexamethasone oral) for 5 days.

    - Prior therapy:

    - No limit to prior therapies with last anti-cancer treatment 2 weeks from
    initiation of protocol-based therapy provided all toxicities (other than
    alopecia) have resolved to Grade 1 or baseline. For lapatinib and IV
    trastuzumab and/or pertuzumab, no washout is required.

    - Patients with prior whole brain radiation therapy (WBRT) or stereotactic
    radiosurgery (SRS) are eligible, provided that there are new lesions not
    previously treated by SRS and 4 weeks have passed since radiation

    - Patients with prior cranial surgery are eligible, provided that there is
    evidence of residual disease and/or progression of disease and 4 weeks have
    passed since surgery.

    - Prior hormonal therapy for locally advanced or metastatic disease is allowed and
    can be continued. If everolimus is used in a combination with hormonal therapy,
    then, everolimus must be discontinued but hormonal therapy can be continued.

    - Continuation of intravenous (IV) trastuzumab is allowed for those patients
    already on IV trastuzumab therapy. Patients previously treated with intrathecal
    (IT) trastuzumab are allowed if there is evidence of progression as determined
    by treating physician and last dose administered is 4 weeks.

    - Prior capecitabine therapy is allowed, provided 6 months have passed since the
    last dose of capecitabine.

    - Cardiac ejection fraction at or above the lower limit of normal as measured by
    multigated radionuclide angiography (MUGA) scans or echocardiogram documented 3
    months prior to registration.

    - Adequate bone marrow, liver, and renal function as assessed by the following:

    - Granulocyte count 1,000/L for lapatinib and > 1,500/uL for capecitabine ,
    platelet count 100,000/L, and hemoglobin 8 g/dL

    - Serum bilirubin 1.5 mg/dL; AST, ALT, and alkaline phosphatase 2.5 ULN
    except for: Patients with hepatic metastases: ALT and AST 5 ULN; patients
    with hepatic and/or bone metastases: alkaline phosphatase 5 ULN and patients
    with Gilbert's disease: serum bilirubin < 5 mg/dL

    - Serum creatinine 1.5 mg/dL or creatinine clearance of 60 mL/min based on a
    24-hour urine collection

    - Women of childbearing potential must have a negative serum pregnancy test performed
    within 14 days prior to enrollment. Women of childbearing potential and men must
    agree to use adequate contraception prior to enrollment and for the duration of study

    - Patients must be able to swallow and retain oral medication.

    Exclusion Criteria:

    - Contraindications or history of allergic reaction to lapatinib or to capecitabine,
    known dihydropyrimidine dehydrogenase deficiency, or known hypersensitivity of

    - Craniotomy or any other major surgery, open biopsy, or significant traumatic injury
    within 4 weeks of enrollment.

    - Serious, non-healing wound, infection, ulcer, bone fracture, or uncontrolled seizures

    - Significant gastrointestinal disorder with diarrhea as a major symptom (example
    Crohn's disease, ulcerative colitis) or Grade 2 diarrhea of any etiology at
    baseline. Active hepatobiliary disease with the exception of patients with Gilbert's
    syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease
    as determined by investigator's assessment.

    - Significant medical co-morbidities as described below:

    - Cardiac disease:

    - Congestive heart failure >class II New York Heart Association (NYHA) or

    - Unstable angina (anginal symptoms at rest), or new-onset angina (begun within
    the last 3 months), or myocardial infarction within the 6 months prior to
    enrollment, or

    - Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

    - Known history of QTc prolongation or Torsades de Pointes

    - Grade 3 hypertension (SBP 160 mm Hg and/or DBP 100 mm Hg despite maximal medical

    - Thrombotic, embolic, venous, or arterial events such as a cerebrovascular accident
    including transient ischemic attacks within the past 6 months.

    - Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C

    - Previous or concurrent cancer that is distinct in primary site or histology from
    breast cancer within 5 years prior to enrollment EXCEPT cervical cancer in situ,
    treated non-melanoma skin cancers, superficial bladder tumors [Ta and Tis].

    - Concurrent medication:

    - Rivaroxaban and vitamin-K antagonists (e.g., warfarin), but enoxaparin is

    - No concurrent use of strong CYP3A4 inhibitor (e.g., ketoconazole, voriconazole,
    grapefruit) or inducers (e.g., phenytoin, carbamazepine, phenobarbital, St.
    John's Wort [Hypericum perforatum], dexamethasone at a dose of greater than 16
    mg daily, or rifampin [rifampicin], and/or rifabutin). 2 week washout period
    before enrollment required if any of strong inducer or inhibitors used (except
    for dexamethasone, dose needs to be 16mg or less daily). (Appendix H)

    - Use of concurrent cytochrome P450 enzyme-inducing anti-epileptic drugs (such as
    phenytoin, carbamazepine, or phenobarbital) is not allowed. (Anti-epileptic
    levetiracetam is allowed).

    - Concurrent anti-cancer therapy (chemotherapy, hormonal therapy, radiation therapy,
    surgery, immunotherapy, tumor embolization, or biologic therapy including pertuzumab,
    but except IV trastuzumab or hormonal therapy, if patient is already being treated
    with either of the two agents.)

    - Use of any investigational drug within 28 days or 5 half-lives, whichever is longer,
    preceding enrollment.

    - Women who are pregnant or breast-feeding.

    - Inability to comply with protocol and /or not willing or not available for follow-up
    assessments or any condition which in the investigator's opinion makes the patient
    unsuitable for the study participation.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Female

    Primary Outcome Measures

    maximum tolerated dose (MTD)

    Secondary Outcome Measures

    Trial Keywords