Capecitabine and Lapatinib Ditosylate With or Without Cixutumumab in Treating Patients With Previously Treated HER2-Positive Stage IIIB-IV Breast Cancer
Condition: HER2 Positive Breast Carcinoma; Recurrent Breast Carcinoma; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7; Stage IV Breast Cancer AJCC v6 and v7
MeSH terms: Carcinoma; Breast Neoplasms
Intervention: Capecitabine; Cixutumumab; Lapatinib Ditosylate; Quality-of-Life Assessment
Intervention description: Given PO; Given IV; Given PO; Ancillary studies
Intervention MeSH terms: Capecitabine; Lapatinib; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 64.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: IGF-1R; IMC-A12

Summary:

      This phase II trial studies capecitabine and lapatinib ditosylate to see how well they work
      compared with capecitabine, lapatinib ditosylate, and cixutumumab in treating patients with
      previously treated HER2-positive stage IIIB-IV breast cancer. Drugs used in chemotherapy,
      such as capecitabine, work in different ways to stop the growth of tumor cells, either by
      killing the cells, by stopping them from dividing, or by stopping them from spreading.
      Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes
      needed for cell growth. Immunotherapy with cixutumumab, may induce changes in body's immune
      system and may interfere with the ability of tumor cells to grow and spread. It is not yet
      known whether capecitabine and lapatinib ditosylate are more effective when given with or
      without cixutumumab in treating breast cancer that has spread nearby or to other areas of the
      body.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed, locally advanced: (a T4 primary tumor and stage IIIB or IIIC
             disease) or metastatic breast cancer that has progressed after treatment with regimens
             that included trastuzumab and either an anthracycline or a taxane or both

               -  NOTE: Agents need not have been given concurrently, nor in the same regimen

               -  NOTE: Prior treatment with trastuzumab is required unless there is a
                  contraindication for trastuzumab treatment

          -  Pre-treatment requirements:

               -  Prior treatment with trastuzumab in the neo-adjuvant, adjuvant or metastatic
                  setting is required

                    -  NOTE: Prior treatment with trastuzumab is required unless there is a
                       contraindication for trastuzumab treatment

                    -  NOTE: Concomitant use of trastuzumab is not allowed in this study

               -  Prior chemotherapy allowed in the neo-adjuvant, adjuvant, or metastatic setting;
                  unlimited prior chemotherapy is allowed

               -  Prior hormonal therapy allowed in the neo-adjuvant, adjuvant, or metastatic
                  setting; unlimited prior hormonal therapy is allowed

               -  HER2 positive, defined as:

                    -  Validated immunohistochemistry (IHC) assay score of 3+ (defined as uniform,
                       intense staining of > 30% of invasive tumor cells)

                    -  -OR- Average HER2 gene copy number of > 6

                    -  -OR- Gene amplified (HER2:D17Z1 ratio > 2.20)

          -  Must have measurable disease according to Response Evaluation Criteria in Solid Tumors
             (RECIST) criteria

          -  Negative pregnancy test done =< 7 days prior to registration, for women of
             childbearing potential only

          -  Hemoglobin > 9.0 g/dL (obtained =< 7 days prior to registration)

          -  White blood cells (WBC) >= 3,000/mL (obtained =< 7 days prior to registration)

          -  Absolute neutrophil count (ANC) >= 1500/mL (obtained =< 7 days prior to registration)

          -  Platelet count >= 75,000/mL (obtained =< 7 days prior to registration)

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 7 days prior to
             registration)

          -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
             serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x
             ULN or SGOT (AST) and SGPT (ALT) =< 5 x ULN if elevations are due to liver metastases
             (obtained =< 7 days prior to registration)

          -  Serum creatinine =< 1.5 x ULN (obtained =< 7 days prior to registration)

          -  Creatinine clearance >= 30 mL/min (calculated according to Cockcroft and Gault)
             (obtained =< 7 days prior to registration)

               -  NOTE: In patients with moderate renal impairment (calculated creatinine clearance
                  30-50 mL/min) at baseline, a dose reduction of the capecitabine starting dose is
                  required

          -  Fasting glucose < 120 mg/dL (obtained =< 7 days prior to registration)

               -  NOTE: Patients with diabetes are allowed to participate, provided that their
                  blood glucose is within the guidelines above upon enrollment

          -  International normalization ratio (INR) =< 1.5 x ULN (obtained =< 7 days prior to
             registration)

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2

          -  Adequate cardiac function defined as an ejection fraction >= 50% as determined by
             multi gated acquisition scan (MUGA) or echocardiogram

          -  Life expectancy > 3 months

          -  Has written informed consent been obtained?

          -  Willingness to return to a North Central Cancer Treatment Group (NCCTG) or other
             participating cooperative group institution for treatment and follow-up

          -  Patient willing to provide tissue and blood samples for research purposes

          -  Availability of diagnostic material (i.e., diagnostic slides confirming locally
             advanced/metastatic disease and HER2 stained slides) and operative and pathology
             reports from diagnosis of locally advanced or metastatic breast cancer

               -  NOTE: Biopsy of recurrent disease and submission of these materials is not
                  required if materials available from initial diagnosis of locally
                  advanced/metastatic disease

          -  Ability to complete questionnaire(s) by themselves or with assistance

        Exclusion Criteria:

          -  Any of the following because this study involves an investigational agent whose
             genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
             unknown:

               -  Pregnant women

               -  Nursing women

               -  Men or women of childbearing potential who are unwilling to employ adequate
                  contraception (as determined by the treating physician)

          -  Stage III or IV invasive cancer, other than breast cancer, in =< 5 years prior to
             registration

          -  Actively being treated for other malignancy, excepting non-melanotic skin cancer or
             carcinoma-in-situ of the cervix; if there is a history of prior malignancy, patient
             must not be receiving other specific treatment for their cancer

          -  New York Heart Association class III or IV cardiovascular disease

          -  Current, active hepatic or biliary disease except Gilbert's syndrome or asymptomatic
             gallstones

          -  Evidence of active brain metastasis including leptomeningeal involvement; central
             nervous system (CNS) metastasis controlled by prior surgery and/or radiotherapy is
             allowed

               -  NOTE: To be considered controlled, there must be at least 2 months of no symptoms
                  or evidence of progression prior to study entry and corticosteroid therapy must
                  have been discontinued

          -  Major surgery, chemotherapy, or immunologic therapy =< 4 weeks prior to registration

          -  Radiotherapy =< 4 weeks prior to registration, except if to a non-target lesion only;
             prior radiation to a target lesion is permitted only if there has been clear
             progression of the lesion since radiation was completed; if patient receives single
             dose radiation for palliation or radiation to non-target lesion, they may immediately
             proceed to registration without waiting; acute adverse events from radiation must have
             resolved to =< Common Terminology Criteria for Adverse Events (CTCAE) version (v) 3.0
             grade 1

          -  Prior treatment with any therapy targeting IGF-I, IGF-II or its receptors (either
             monoclonal antibody or tyrosine kinase inhibitor), including but not limited to any of
             the following (which would have been received on a previous clinical trial):

               -  IMC-A12 (cixutumumab)

               -  CP-751,871 (figitumumab)

               -  AMG-479

               -  INSM-18

               -  MK0646 (h7C10)

               -  SCH717454 (19D12, robatumumab)

               -  R1507

               -  OSI-906

               -  BMS-754807

               -  PPP

               -  NVP-AEW541

               -  AVE-1642

               -  MEDI-573

          -  Prior therapy with any therapy targeting HER1 (EGFR) and/or HER2 (either monoclonal
             antibody or tyrosine kinase) other than trastuzumab, including but not limited to any
             of the following:

               -  Lapatinib (Tykerb)

               -  Gefitinib (Iressa)

               -  Erlotinib (Tarceva)

               -  Cetuximab (Erbitux)

               -  Panitumumab (Vectibix)

          -  Currently receiving treatment with any agents that are contraindicated by study
             therapies:

               -  IMC-A12 - none identified to date

               -  Lapatinib - CYP3A4 inhibitors and inducers, including grapefruit and grapefruit
                  juice

               -  Capecitabine - warfarin (Coumadin), cimetidine (Tagamet), allopurinol (Lopurin),
                  sorivudine (Usevir) or brivudine (Brivex), ketoconazole (Nizoral), itraconazole
                  (Sporanox), ritonavir (Norvir), amprenavir (Agenerase) or indinavir (Crixivan)

          -  Uncontrolled intercurrent illness including, but not limited to:

               -  Poorly controlled diabetes

               -  Ongoing or active infection

               -  Symptomatic congestive heart failure

               -  Unstable angina pectoris

               -  Cardiac arrhythmia

               -  Psychiatric illness/social situations that would limit compliance with study
                  requirements

          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
             of the investigator, would make the patient inappropriate for entry into this study or
             interfere significantly with the proper assessment of the safety of the prescribed
             regimens

          -  Currently receiving treatment in a different clinical study in which investigational
             procedures are performed or investigational therapies are administered

          -  Immunocompromised patients (other than that related to the use of corticosteroids)
             including patients known to be human immunodeficiency virus (HIV) positive with an
             acquired immune deficiency syndrome (AIDS)-defining illness; HIV positive patients
             with cluster of differentiation (CD) 4 count within institutional normal range and no
             history of an AIDS-defining illness are eligible; however, some
             antiviral/antiretroviral medications which have CYP3A4 interactions are prohibited on
             this study