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

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVE: I. To compare progression-free survival of HER2+ breast cancer patients randomized to receive lapatinib ditosylate (lapatinib) and capecitabine +/- cixutumumab (IMC-A12). SECONDARY OBJECTIVES: I. To assess the safety and tolerability of lapatinib and capecitabine +/- IMC-A12 in HER2+ breast cancer patients. II. To compare the overall survival time, time to treatment failure, confirmed tumor response rate, and duration of response of lapatinib and capecitabine +/- IMC-A12 in HER2+ breast cancer patients. III. To assess patient compliance per treatment arm and to compare overall quality of life and treatment side effects via patient-reported outcomes between treatment arms. TRANSLATIONAL RESEARCH OBJECTIVES: I. To determine the role of the following in predicting response to lapatinib and capecitabine +/- IMC-A12: Ia. Expression patterns and/or activation IGF- and ErbB family of receptors and signaling molecules in formalin-fixed, paraffin-embedded breast tumor tissue. Ib. Expression patterns and/or activation IGF- and ErbB receptors and signaling molecules in circulating tumor cells from breast cancer patients. Ic. Changes in expression patterns and/or activation IGF- and ErbB receptors and signaling molecules following treatment with lapatinib and capecitabine +/- IMC-A12 in circulating tumor cells from breast cancer patients. Id. Expression patterns of IGF-1, IGF-II, insulin, growth hormone, and the IGF binding proteins in the serum of breast cancer patients. Ie. Changes in expression patterns of IGF-1, IGF-II, insulin, growth hormone, and the IGF binding proteins in the serum of breast cancer patients. II. Banking of paraffin-embedded tissue blocks/slides and blood products (i.e., serum, plasma, and buffy coat) for future studies. III. To assess the proportion of patients whose pathologic specimens were correctly diagnosed as HER2 positive (according to 2007 American Society of Clinical Oncology [ASCO] College of American Pathologist [CAP] guidelines) metastatic breast cancer. OUTLINE: The first 10 patients enrolled on this study are assigned to cohort I (safety analysis). All other patients are assigned to cohort II (randomized treatment). COHORT I (SAFETY ANALYSIS, closed to accrual): Patients receive cixutumumab intravenously (IV) over 1 hour on days 1, 8, and 15. Patients also receive capecitabine orally (PO) twice daily (BID) on days 1-14 and lapatinib ditosylate PO once daily (QD) on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. COHORT II (RANDOMIZED TREATMENT): Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive capecitabine PO BID on days 1-14 and lapatinib ditosylate PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive capecitabine and lapatinib ditosylate as in Arm A. Patients also receive cixutumumab IV over 1 hour on days 1, 8, and 15. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months until disease progression and then every 6 months for up to 5 years.

Official Title
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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

Conditions
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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

Intervention / Treatment
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* Drug: Capecitabine
* Biological: Cixutumumab
* Drug: Lapatinib Ditosylate
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (lapatinib ditosylate, capecitabine)<br>Patients receive capecitabine PO BID on days 1-14 and lapatinib ditosylate PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Capecitabine<br>* Given PO<br>* Other names: Xeloda;Drug: Lapatinib Ditosylate<br>* Given PO<br>* Other names: Tykerb;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm B (cixutumumab, lapatinib ditosylate, capecitabine)<br>Patients receive capecitabine and lapatinib ditosylate as in Arm A. Patients also receive cixutumumab IV over 1 hour on days 1, 8, and 15. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Capecitabine<br>* Given PO<br>* Other names: Xeloda;Biological: Cixutumumab<br>* Given IV<br>* Other names: IMC-A12;Drug: Lapatinib Ditosylate<br>* Given PO<br>* Other names: Tykerb;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Median Survival time (months) | From randomization to death due to any cause, up to 5 years | 
| Time to Treatment Failure | Distribution estimated by the Kaplan-Meier (1958) method for each treatment arm. | 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 | 
| 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) |  | Up to 5 years | 
| Duration of Response | Distribution estimated by the Kaplan-Meier (1958) method for each treatment arm. | Up to 5 years | 
| Adverse Event Profile of Capecitabine and Lapatinib With and Without IMC-A12 (Using NCI CTCAE v3.0) | All eligible patients that have initiated treatment will be considered evaluable for assessing adverse event rate(s) according to CTCAE v3.0 within each treatment arm. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. 4/19 (21.05%) 14/45 (31.11%) | Baseline to 30 days past end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IGF-1R, IMC-A12