Lapatinib in Stage IV Melanoma With ERBB4 Mutations
Condition: Malignant Melanoma
MeSH terms: Melanoma
Intervention: Lapatinib
Intervention description: 500 mg PO (orally) twice a day for 28 days (1 cycle). Up to 27 cycles allowed if response seen.
Intervention MeSH terms: Lapatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 34.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Lapatinib; Melanoma; ERBB4 Mutation; Malignant Melanoma; Skin Cancer

Summary:

      Background:

      - Studies of melanoma tumor samples have shown that tumor cells from approximately 20 percent
      of melanoma patients contain a specific mutation of a gene involved in making a protein
      called ERBB4, and that changes in this gene have been associated with cancer. Lapatinib, a
      drug that is currently approved for the treatment of breast cancer, has been shown in the
      laboratory to significantly slow the growth of melanoma cells that contain this specific
      ERBB4 gene mutation. Researchers are interested in determining whether lapatinib can be
      effective against melanoma in individuals who have the ERBB4 mutation.

      Objectives:

      - To evaluate the safety and effectiveness of lapatinib as a treatment for melanoma with
      ERBB4 mutation that has not responded to standard therapy.

      Eligibility:

      - Individuals at least 18 years of age who have stage 4 melanoma that has not responded to
      standard therapy.

      Design:

        -  Participants will be screened with a full physical examination and medical history, as
           well as tests of tumor tissue taken from previous surgeries or biopsies or from a new
           biopsy that will be conducted before the start of the study. Test results to determine
           eligibility will be available within about 2 weeks.

        -  Participants will take four lapatinib tablets daily (two in the morning, 1 hour before
           or after breakfast and two in the evening, 1 hour before or after dinner) during every
           28-day cycle of treatment. Participants will keep a medication diary to record tablets
           taken and any side effects from the medication.

        -  After the first 2 weeks, and every 2 to 4 weeks afterward for the first 12 weeks,
           participants will have clinic visits with blood samples and other tests to determine if
           lapatinib is causing their disease to shrink or be controlled. If the disease has not
           progressed, participants will continue to receive a new lapatinib supply every 28 days
           for up to 2 years (27 cycles), and will continue to have regular clinic visits to
           monitor the progress of treatment.

        -  When tumor tissue is easily accessible and can be easily biopsied, researchers will
           collect two additional biopsies, one after 2 weeks of treatment and one after 12 weeks
           of treatment....
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients must have histologically confirmed stage IV cutaneous melanoma.

          -  Patients must have measurable disease defined by Response Evaluation Criteria in Solid
             Tumors (RECIST) 1.1. Measurable disease is defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded). Each
             lesion must be greater than 10 mm when measured by computed tomography (CT), magnetic
             resonance imaging (MRI) or caliper measurement by clinical exam; or greater than 20 mm
             when measured by chest x-ray. Lymph nodes must be greater than 15 mm in short axis
             when measured by CT or MRI.

          -  Patients must have no more than two oncogenic somatic ERBB4 mutations detected in one
             of the 28 exons of the ERBB4 gene analyzed from the tumor and which is not present in
             the matched normal deoxyribonucleic acid (DNA) as confirmed by sequence analysis of
             tumor genomic DNA derived from any biopsy specimen obtained at the participating
             clinical sites. Sequence analysis will be performed at the National Institutes of
             Health (NIH) Clinical Molecular Profiling Core, a Clinical Laboratory Improvement
             Amendments (CLIA)-certified laboratory.

        Note: Patients with 3 or more mutations in their ERBB4 gene may have an increased
        resistance to lapatinib and are not eligible for lapatinib treatment

          -  Patients must not have had chemotherapy, molecular therapy with B-RAF, mouse embryonic
             fibroblast (MEK), or c-kit inhibitors, hormonal therapy, radiation therapy, or
             biological therapy for at least 4 weeks prior to starting study medication. Patients
             who received mitomycin C, nitrosoureas, anti-cytotoxic T-lymphocyte antigen 4
             (CTLA-4), or carboplatin must be 6 weeks from the last administration of therapy.
             Patients must have recovered from any acute toxicity related to prior therapy or
             surgery, to a grade 1 or less unless specified.

          -  Patients with no more than 3 intracranial metastases, which have been definitively
             treated by surgery or radiation therapy may be eligible for study provided there is no
             evidence of active disease for at least 2 months and no requirement for anticonvulsant
             therapy or steroids following treatment.

          -  Age greater than or equal to 18 years.

        Note: Because no dosing or adverse event data are currently available on the use of
        lapatinib in patients less than 18 years of age, children are excluded from this study but
        will be eligible for future pediatric single-agent trials, if applicable.

          -  Life expectancy of greater than 3 months.

          -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1
             (Karnofsky greater than or equal to 70%).

          -  Patients must have normal organ and marrow function as defined below:

               -  absolute neutrophil count greater than or equal to 1,500/mcL

               -  platelets greater than or equal to 100,000/mcL

               -  total bilirubin within normal institutional limits

               -  Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
                  (SGOT))/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase
                  (SGPT)) less than or equal to 3 times institutional upper limit of normal

               -  creatinine less than or equal to institutional upper limit of normal

        OR

        --creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients with
        creatinine levels above institutional normal.

          -  Patients must be willing to return to the Clinic for follow-up visits.

          -  Women of childbearing potential must have a negative beta-human chorionic gonadotropin
             (HCG) (serum or urine) within 14 days prior to study treatment and must be willing to
             practice effective birth control to prevent pregnancy while receiving treatment and
             for four months after treatment is discontinued. All males of child fathering
             potential must also be willing to practice effective birth control.

        Note: Lapatinib is a tyrosine kinase inhibitor 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. Should a woman become pregnant or
        suspect she is pregnant while she or her partner is participating in this study, the
        patient should inform the treating physician immediately.

          -  Ability to understand and the willingness to sign the Informed Consent Document.

          -  Patients who agree to participate in the pharmacokinetics (PK) portion of the study
             must be able to swallow lapatinib tablets for the duration of the PK studies.

        EXCLUSION CRITERIA:

          -  Patients may not be currently receiving any other investigational agents.

          -  Patients may not have received prior treatment with tyrosine kinase inhibitors (e.g.,
             lapatinib erlotinib, or gefitinib).

          -  Patients currently receiving any medication known to induce/inhibit cytochrome P450
             3A4 (CYP3A4) as listed in Appendix D, which in the opinion of the principal
             investigator, would make the administration of study drug hazardous. Note: patients
             receiving any strong or moderate CYP3A4 inhibitors will be excluded.

          -  Patients with active hepatic or biliary disease (with exception of patients with
             Gilberts syndrome, asymptomatic gallstones, liver metastases or stable chronic liver
             disease per investigator assessment)

          -  Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
             or active infection, symptomatic congestive heart failure, unstable angina pectoris,
             cardiac arrhythmia, or psychiatric illness/social situations that would limit
             compliance with study requirements.

          -  Human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy are
             excluded because most antiretrovirals are strong or moderate CYP3A4 inhibitors.

          -  Any underlying medical condition which, in the opinion of the principal investigator,
             will make the administration of study drug hazardous or obscure the interpretation of
             adverse events

          -  Patients with any other concurrent malignancy, except for the following:

               -  adequately treated basal or squamous cell skin cancer, superficial bladder
                  cancer, carcinoma in situ of the cervix, or any other cancer from which the
                  patient has been disease-free for five (5) years or more.

        INCLUSION OF WOMEN AND MINORITIES:

        Both men and women and members of all races and ethnic groups are eligible for this trial.