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1B-12-10 Phase II Trial of Metronomic Capecitabine and Cyclophosphamide with Lapatinib and Trastuzumab in Patients with HER2 Positive Metastatic Breast Cancer Who Have Progressed on a Previous Trastuzumab-Based Regimen


Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in women. About 20% of patients will initially be diagnosed with breast cancer that has spread (metastatic), and 20-80% of patients initially diagnosed with localized disease will ultimately develop metastatic disease. Despite recent advances in therapy, metastatic breast cancer (MBC) remains an incurable disease and further improvements in systemic therapy are needed. Chemotherapy is usually given at the highest possible dose that does not cause life-threatening side effects. This dose does not target tumor cells specifically, but damages normal cells and results in toxic side effects that require time between each dose for recovery. Metronomic chemotherapy is an emerging new model in cancer therapy, in which low doses of chemotherapy drugs are given at frequent intervals. The major advantage of metronomic chemotherapy is the low toxicity, which significantly improves patients quality of life, allows for longer administration of chemotherapy drugs without dose reductions or delays, and provides opportunities to combine different classes of drugs that would otherwise be difficult with full dose regimens. Metronomic chemotherapy has been found to have moderate activity with low toxicity in several phase II clinical trials in patients with MBC and improved activity was seen in studies when it was combined with targeted therapies. Human epidermal growth factor receptor 2 (HER2) is overexpressed in about 20-30% of all breast cancers and is associated with earlier recurrence and shorter overall survival. Trastuzumab, a targeted therapy against HER2, improves survival in HER2 positive patients and when combined with chemotherapy has response rates that are 60-70%. However, patients eventually progress after initial response, but trastuzumab is usually continued in these patients even after their disease progresses. Lapatinib is an orally active small molecule that inhibits the tyrosine kinases of HER2 and epidermal growth factor receptor type 1 (EGFR). A phase III, randomized, open-label study showed that lapatinib in combination with capecitabine is also active in women with HER2-positive MBC who had previously received trastuzumab and is now the standard treatment in patients whose disease has progressed after treatment with trastuzumab. Other studies combining trastuzumab with lapatinib suggest that inhibiting HER2 with both drugs is better than using either drug alone in the treatment of HER2-positive breast cancer.This study proposes a phase II clinical trial using metronomic chemotherapy (capecitabine and cyclophosphamide), in combination with dual HER2 inhibition (lapatinib and trastuzumab), in HER2 positive MBC patients previously treated with trastuzumab. The primary objective of this study is to estimate the progression free survival (PFS) in patients with MBC that is HER2 positive and who have had previous treatment with trastuzumab.Patients who will be enrolled for this study will have laboratory confirmed HER2-positive breast cancer whose disease has spread and have had prior treatment with trastuzumab. Once participants sign the informed consent and are deemed eligible for the study, participants will receive either cyclophosphamide, cytoxan, lapatinib, and trastuzumab. They will take cyclophosphamide, cytoxan, lapatinib once a day and receive an injection of trastuzumab every 21 days. Every 21 days is called a cycle. During the study, participants will have the following procedures done during each cycle: a physical exam, blood tests, performance status, assessment of side effects, and review of medications. They will have tumor assessments every 2 cycles with radiographic scans and MUGA or Echo to assess heart function every 3 cycles. Participants will stop taking study drug(s) if their disease worsens, they have another illness which prevents them from taking the study drug(s), they cannot tolerate the side effects, they withdraw from the study, or their study doctor thinks that being on the study is no longer in their best interest. Participants will be followed every 3 months for one year after stopping the study drugs.The primary endpoint for participants is PFS. One-sided one-sample logrank test will be used to evaluate the improvement in PFS compared to the reported historical PFS rate. One futility analysis will be performed during the trial, at the end of the 1st year after enrollment starts using the Hazard Ratio for progression.



Inclusion and Exclusion Criteria

  • Histologically confirmed HER2-positive metastatic breast cancer
  • HER2 overexpression of tumor by either immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH); tumors tested by IHC must be 3+ positive; tumors tested by FISH must have a ratio of HER2:CEP17 > 2.0; when both tests are performed, the FISH result must be positive
  • Prior trastuzumab use in the adjuvant or metastatic setting
  • No more than two prior cytotoxic chemotherapeutic regimens for metastatic breast cancer. In addition, prior Trastuzumab emtansine (TDM-1, Kadcyla) is allowed.
  • Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Platelets >= 100,000/mm^3
  • Hemoglobin >= 9 g/dL
  • Bilirubin =< 1.5 x upper limit of normal (ULN)
  • Serum creatinine =< 1.5 x ULN or calculated creatinine clearance >= 60 ml/min
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
  • Fully recovered from toxicity due to prior therapy
  • Capable of understanding the informed consent and complying with the protocol and signed the informed consent document prior to any study-specific screening procedures or evaluations being performed
  • Must be able to swallow pills
  • May have either measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
  • Sexually active participants must agree to use a medically accepted barrier method of contraception (i.e. male condom or female condom) during the course of the study and for 3 months following discontinuation of study treatments; for participants of childbearing potential, a barrier method and a second method of contraception must be used
  • Participants of childbearing potential must have a negative pregnancy test at screening and enrollment; participants of childbearing potential are defined as premenopausal females capable of becoming pregnant, i.e. females who have had any evidence of menses in the past 12 months with the exception of those who had prior hysterectomy (oophorectomy or surgical sterilization); however, women who have been amenorrheic for >= 12 months are still considered to be of childbearing potential if the amenorrhea is possibly due to any other cause including prior chemotherapy, antiestrogens, or ovarian suppression

  • Prior treatment with capecitabine or lapatinib
  • Radiation therapy within 2 weeks before the first dose of study treatment
  • Hormonal therapy within 2 weeks before the first dose of study treatment
  • Cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) within 3 weeks before the first dose of study treatment
  • Biologic therapy (including antibodies [other than trastuzumab], immune modulators, cytokines) within 4 weeks before the first dose of study treatment; Note: there is no washout period required for trastuzumab
  • Any other type of investigational agent within 4 weeks before the first dose of study treatment
  • Major surgery, or not recovered from major surgery within 4 weeks before the first dose of study treatment
  • Untreated, symptomatic, or progressive brain metastases; participants must have no radiographic or other signs of progression in the brain for >= 1 month after completion of local therapy; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 4 weeks prior to first study treatment
  • Uncontrolled significant intercurrent illness that would preclude the patient from study participation per investigator assessment
  • Left ventricular ejection fraction (LVEF) =< 50% as documented by multi gated acquisition scan (MUGA) or echocardiogram performed within 28 days prior to the first study treatment
  • Currently receiving anticoagulation with therapeutic doses of warfarin (low-molecular weight heparin is permitted)
  • Pregnant or breastfeeding
  • Known to be positive for the human immunodeficiency virus (HIV) (a test for HIV at screening is not required)
  • Have acute or currently active/requiring anti-viral therapy hepatic or biliary disease (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
  • Previously identified allergy or hypersensitivity or intolerance to components of the study treatment formulation (cyclophosphamide, capecitabine, lapatinib [lapatinib ditosylate], trastuzumab)
  • Any other diagnosis of malignancy or evidence of malignancy (except non-melanoma skin cancer, in-situ carcinoma of the cervix) within 2 years prior to screening for this study
  • Unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee


  • California

    • USC Norris Comprehensive Cancer Center, Los Angeles, California, 90033
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