Lapatinib + Vinorelbine in ErbB2 Overexpressing, First or Second Line Metastatic Breast Cancer Subjects
Condition: Neoplasms, Breast
MeSH terms: Breast Neoplasms
Intervention: Lapatinib, Vinorelbine
Intervention description: Vinorelbine intravenously once weekly for 3 weeks, followed by a rest week in a 4-week cycle) plus lapatinib daily
Intervention MeSH terms: Vinorelbine; Lapatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 44.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Erbb2; MBC; First or Second line therapy; Metastatic Breast Cancer; Vinorelbine; Tykerb

Summary:

      This is an open-label, single-arm, multi-center, Phase II study to determine the activity of
      vinorelbine plus lapatinib in either first- or second-line setting in women with ErbB2
      overexpressing metastatic breast cancer (MBC). Sixty subjects will be enrolled in the study.
      Subjects will receive vinorelbine intravenously once weekly for 3 weeks, followed by a rest
      week in a 4-week cycle) plus lapatinib daily. Subjects will receive treatment until disease
      progression or withdrawal from the study. The primary objective of this study is to evaluate
      overall tumor response rate of lapatinib in combination with vinorelbine. Secondary
      objectives include progression-free survival, overall survival, duration of response, time to
      response and time to progression and safety. Safety and efficacy assessments will be
      performed at 4, 8 and 12 week intervals, and at the end of treatment.

      Subject: Metastatic Breast Cancer, ErbB2, First-line or Second-line therapy, Lapatinib,
      Vinorelbine
    

Eligibility criteria:

        Inclusion Criteria:

        A subject will be eligible for inclusion in this study only if all of the following
        criteria apply:

          1. Signed informed consent prior to registration.

          2. Considered by the Investigator to have a life expectancy of ≥12 weeks.

          3. Subjects must have histologically confirmed invasive breast cancer with Stage IV
             disease at primary diagnosis or at relapse after curative-intent surgery.

             • Where the disease is restricted to a solitary lesion, the neoplastic nature of the
             lesion should be confirmed by cytology or histology.

          4. Documented amplification of ErbB2 3+ by immunohistochemistry or a positive score
             (>2.2) by fluorescence in situ hybridization (FISH) using a local laboratory result
             (which will be considered sufficient in this study with no further verification by a
             central laboratory). NOTE: If both IHC and FISH results available, FISH results must
             be used for eligibility.

          5. Subjects must not have received more than 1 prior chemotherapeutic regimen in the
             metastatic setting.

          6. All prior chemotherapy, immunotherapy, biologic therapy, or surgery (except for minor
             surgical procedures) must be discontinued at least 4 weeks prior to first dose of
             investigational product. Hormonal therapy must be discontinued at least 1 week prior
             to first dose.

          7. Prior diagnosis of cancer is allowed as long as the subject is free of disease and has
             been off treatment for prior malignancies for 5 years. Subjects with completely
             resected basal or squamous cell skin cancer or successfully treated cervical carcinoma
             in situ will be allowed if it has been 1 year or longer since definitive surgery.

          8. Subjects must have measurable disease, according to Response Evaluation Criteria in
             Solid Tumors (RECIST) guidelines.

          9. Females aged ≥18 years with any menopausal status:

               -  Non-child-bearing potential (i.e., women with functioning ovaries who have a
                  current documented tubal ligation or hysterectomy, or women who are
                  postmenopausal)

               -  Child-bearing potential (i.e., women with functioning ovaries and no documented
                  impairment of oviductal or uterine function that would cause sterility): This
                  category includes women with oligomenorrhea (severe), women who are
                  perimenopausal, and young women who have begun to menstruate. These subjects must
                  have a negative serum pregnancy test at screening and agree to one of the
                  following:

               -  Complete abstinence from intercourse from 2 weeks prior to administration of the
                  first dose of study medication until 28 days after the final dose of study
                  medication; or

               -  Consistent and correct use of one of the following acceptable methods of birth
                  control: male partner who is sterile prior to the female subject's entry into the
                  study and is the sole sexual partner for that female subject; any intrauterine
                  device with a documented failure rate of less than 1% per year; oral
                  contraceptives (either combined or progestogen only) where not contraindicated
                  for this subject population or per local practice.; or barrier methods, including
                  diaphragm or condom with a spermicide.

         10. ECOG performance status (PS) of 0 to 2 [Oken, 1982] (Appendix 1).

         11. Subjects must have normal organ and marrow function as defined in Table 1. Table 1
             Baseline Laboratory Values for Adequate Organ Function System Laboratory Value
             Hematologic Absolute neutrophil count ≥1.5 × 10^9/L Hemoglobin ≥9 g/dL Platelets ≥100
             × 10^9/L Hepatic Serum bilirubin ≤1.25 × upper limit of normal (ULN) Aspartate
             aminotransferase and alanine aminotransferase

               -  3 × ULN without liver metastases

               -  5 × ULN if documented liver metastases Renal Serum creatinine ≤1.5 mg/dL

                    -  OR - Calculated creatinine clearance ≥40 mL/min

         12. Subjects must have a cardiac ejection fraction of at least 50% (as measured by
             echocardiogram [ECHO] or multigated acquisition scan [MUGA]) and within the
             institutional range of normal. Subjects who require cardiac medications (e.g. positive
             inotropic agents or afterload reducers) for abnormal ejection fraction are ineligible.
             MUGA scans will be accepted in cases where an ECHO cannot be performed or is
             inconclusive. The same modality to assess cardiac ejection fraction must be used
             consistently throughout the study.

         13. Radiotherapy prior to initiation of study medication is allowed to a limited area
             (e.g., palliative therapy), if it is not the sole site of disease. Subjects must have
             completed radiation treatment and recovered from all acute radiation treatment-related
             toxicities (e.g., bone marrow suppression) prior to commencement of combination
             treatment.

         14. Subjects with stable central nervous system (CNS) metastases. Subjects with stable CNS
             metastases are defined as follows: subject is asymptomatic with CNS metastases that
             have been stable for at least 3 months as confirmed by computed tomography
             (CT)/magnetic resonance imaging (MRI). Subjects with evidence of
             leptomeningeal/parenchymal involvement are eligible only if they are not taking
             steroids or enzyme-inducing anticonvulsants within 4 weeks of commencement of the
             study. Treatment with prophylactic anticonvulsants is permitted, unless listed as a
             prohibited medication.

         15. Subject must be free of gastrointestinal diseases that impede swallowing and retaining
             of oral medications.

         16. Able to swallow and retain oral medication (intact pill).

         17. Bisphosphonate therapy for bone metastases is allowed; however, treatment must be
             initiated prior to the first dose of study medication. Prophylactic use of
             bisphosphonates in subjects without bone disease, except for the treatment of
             osteoporosis, is not permitted.

         18. Subjects whose disease is estrogen receptor + and/or progesterone receptor + or
             unknown status will only be included in the study if they meet the following criteria:

               -  They have symptomatic visceral disease that requires chemotherapy.

               -  The disease is considered by the Investigator to be progressing rapidly or is
                  life threatening.

               -  Subjects who have received endocrine therapy and who are no longer benefiting
                  from this therapy.

        Exclusion Criteria:

        A subject will not be eligible for inclusion in this study if any of the following criteria
        apply:

          1. Subjects taking treatment with medications provided in the list of restricted
             medications and substances in the drug information section for lapatinib are not
             eligible for the study. This includes human immunodeficiency virus-positive subjects
             receiving combination anti-retroviral therapy because of possible pharmacokinetic
             interactions with lapatinib.

          2. Prior therapy with lapatinib.

          3. Prior therapy with vinorelbine for treatment of breast cancer.

          4. More than 1 line of therapy for treatment of MBC.

          5. Concurrent anticancer or concomitant radiotherapy treatment.

          6. History of uncontrolled or symptomatic angina; history of arrhythmias requiring
             medications; clinically significant myocardial infarction <6 months from study entry;
             uncontrolled or symptomatic congestive heart failure; ejection fraction below the
             institutional normal limit; or any other cardiac condition, which in the opinion of
             the treating physician, would make this protocol unreasonably hazardous for the
             patient.

          7. Have current active hepatic or biliary disease (with exception of patients with
             Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver
             disease per investigator assessment)

          8. Use of an investigational drug within 30 days or 5 half-lives, whichever is longer,
             preceding the first dose of investigational treatment, or, concurrent treatment with
             an investigational agent or participation in another clinical trial involving
             investigational agents.

          9. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to any of the agents used in this study or their excipients.

         10. Known history of uncontrolled inter-current illness including, but not limited to,
             ongoing or active infection, symptomatic congestive heart failure, unstable angina
             pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social
             situations that would limit compliance with study requirements.

         11. Concurrent disease or condition that would make the woman inappropriate for study
             participation, or any serious medical disorder that would interfere with the woman's
             safety.

         12. Pregnant or lactating females at any time during the study (due to the potential
             teratogenic or abortifacient effects of lapatinib and breastfeeding).

         13. Subjects with diseases affecting gastrointestinal function resulting in an inability
             to take oral medication, including; malabsorption syndrome, disease significantly
             affecting gastrointestinal function, or resection of the stomach or small bowel.

             Women with ulcerative colitis are also excluded.

         14. Peripheral neuropathy of Grade 2 or greater.

         15. Unresolved or unstable, serious toxicity from prior administration of another
             investigational drug and/or of prior cancer treatment.

         16. Dementia, altered mental status, or any psychiatric condition that would prohibit the
             understanding or rendering of informed consent.