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Capecitabine and Lapatinib Ditosylate With or Without Cixutumumab in Treating Patients With Previously Treated HER2-Positive Stage IIIB-IV Breast Cancer

This study is ongoing, but not recruiting participants.
Southwest Oncology Group
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: May 22, 2008
Last updated: January 11, 2017
Last verified: January 2017
This randomized 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 human epidermal growth factor receptor 2 (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. Monoclonal antibodies, such as cixutumumab, can block 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.

Condition Intervention Phase
HER2/Neu Positive
Recurrent Breast Carcinoma
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer
Drug: Capecitabine
Biological: Cixutumumab
Other: Laboratory Biomarker Analysis
Drug: Lapatinib Ditosylate
Other: Quality-of-Life Assessment
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase II Trial of Capecitabine and Lapatinib With or Without IMC-A12 in Patients With HER2 Positive Breast Cancer Previously Treated With Trastuzumab and an Anthracycline and/or a Taxane

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Progression-free Survival (PFS) [ Time Frame: From randomization to the earliest date of documentation of disease progression, up to 5 years ]
    Analysis of the primary endpoint, PFS, will be performed using Cox regression with treatment group as a single covariate.

Secondary Outcome Measures:
  • Overall Survival [ Time Frame: From randomization to death due to any cause, up to 5 years ]
    Median Survival time (months)

  • Time to Treatment Failure [ Time Frame: From the date of randomization to the date at which the patient is removed from treatment due to progression, adverse events, or refusal, up to 5 years ]
    Distribution estimated by the Kaplan-Meier (1958) method for each treatment arm.

  • Confirmed Tumor Response, Defined as Either a Complete Response (CR) or Partial Response (PR) Noted as the Objective Status on 2 Consecutive Evaluations at Least 6 Weeks Apart, Assessed by Response Evaluation Criteria for Solid Tumors (RECIST) [ Time Frame: Up to 5 years ]
  • Duration of Response [ Time Frame: Up to 5 years ]
    Distribution estimated by the Kaplan-Meier (1958) method for each treatment arm.

  • Adverse Event Profile as Assessed by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Up to 5 years ]

Enrollment: 64
Study Start Date: July 2008
Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm I (lapatinib ditosylate, capecitabine)
Patients receive capecitabine PO BID on days 1-14 and lapatinib ditosylate PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Capecitabine
Given PO
Other Names:
  • Ro 09-1978/000
  • Xeloda
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Lapatinib Ditosylate
Given PO
Other Name: Tykerb
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Experimental: Arm II (cixutumumab, lapatinib ditosylate, capecitabine)
Patients receive capecitabine and lapatinib ditosylate as in Arm I. Patients also receive cixutumumab IV over 1 hour on days 1, 8, and 15. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Capecitabine
Given PO
Other Names:
  • Ro 09-1978/000
  • Xeloda
Biological: Cixutumumab
Given IV
Other Names:
  • Anti-IGF-1R Recombinant Monoclonal Antibody IMC-A12
  • IMC-A12
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Lapatinib Ditosylate
Given PO
Other Name: Tykerb
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

  Show Detailed Description


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
  • White blood cells (WBC) >= 3,000/mL
  • Absolute neutrophil count (ANC) >= 1500/mL
  • Platelet count >= 75,000/mL
  • Total bilirubin =< 1.5 x upper limit of normal (ULN)
  • 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
  • Serum creatinine =< 1.5 x ULN
  • Creatinine clearance >= 30 mL/min (calculated according to Cockroft and Gault)

    • 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

    • 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
  • 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:

    • 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 (epidermal growth factor receptor [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 - cytochrome P450, family 3, subfamily A, polypeptide 4 (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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00684983

  Show 358 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Southwest Oncology Group
Principal Investigator: Tufia Haddad Alliance for Clinical Trials in Oncology
  More Information

Responsible Party: National Cancer Institute (NCI) Identifier: NCT00684983     History of Changes
Other Study ID Numbers: NCI-2009-00665
NCI-2009-00665 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
N0733 ( Other Identifier: Alliance for Clinical Trials in Oncology )
N0733 ( Other Identifier: CTEP )
U10CA180821 ( US NIH Grant/Contract Award Number )
U10CA025224 ( US NIH Grant/Contract Award Number )
Study First Received: May 22, 2008
Results First Received: October 1, 2014
Last Updated: January 11, 2017

Keywords provided by National Cancer Institute (NCI):

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors processed this record on May 23, 2017