Tolerability of the Combination of Lapatinib and Trastuzumab in Adults Age 60 or Older With HER2 Positive Locally Advanced or Metastatic Breast Cancer

Study Overview
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Brief Summary
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This phase II trial studies the side effects and how well lapatinib ditosylate and trastuzumab work in treating older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced) or to other parts of the body (metastatic). Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor to grow and spread. Others find tumor cells and help kill them or tumor cancer-killing substances to them. Giving lapatinib ditosylate together with trastuzumab may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the safety and tolerability of the combination of trastuzumab and lapatinib (lapatinib ditosylate) in adults age 60 or older with locally advanced or metastatic breast cancer. SECONDARY OBJECTIVES: I. To describe the full toxicity profile including all grades; to estimate the rate of all grades of cardiac toxicity; to estimate the rate of all grades of diarrhea, nausea, and vomiting. II. To describe the pharmacokinetic parameters of lapatinib in older adults. III. To estimate objective response rate and clinical benefit rate as defined by modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria. IV. To estimate median progression-free and overall survival. V. To explore factors other than chronological age that can affect toxicity rates as identified using a cancer-specific geriatric assessment. VI. To estimate rates of adherence to lapatinib in older adults. OUTLINE: Patients receive lapatinib ditosylate orally (PO) once daily (QD) and trastuzumab intravenously (IV) over 30-90 minutes once weekly OR once every 3 weeks. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days and then periodically thereafter.

Official Title
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Tolerability of the Combination of Lapatinib and Trastuzumab in Adults Age 60 or Older With HER2 Positive Locally Advanced or Metastatic Breast Cancer

Conditions
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Breast Neoplasms, HER2/Neu Positive, Geriatric Health Services

Intervention / Treatment
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* Drug: Lapatinib
* Drug: Trastuzumab
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Locally advanced or metastatic Her2/Neu positive breast cancer (defined as immunohistochemistry [IHC] 3+ or a fluorescence in situ hybridization [FISH] ratio of >= 2.0); this may be on either a primary tumor or a metastatic site, and there is no time limit from the time the specimen was obtained; locally advanced breast cancer (LABC) includes breast cancers with advanced primary tumors, i.e., large diameter (at least 5 cm) or those with skin and/or chest wall involvement, and advanced regional lymph node involvement; it also includes a rare subgroup, inflammatory breast cancer; in the 2010 American Joint Committee on Cancer and the International Union for Cancer Control (AJCC-UICC) TNM breast cancer staging system, locally advanced breast cancer (LABC) includes patients with stage III disease; this comprises: Advanced primary tumors (tumors > 5 cm in greatest dimension [T3]; direct extension to the chest wall and/or to the skin [T4]: ulceration, skin nodules, and/or edema (including peau d'orange) confined to the same breast, inflammatory breast cancer [IBC, T4d]) Advanced regional lymph nodes (ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted or clinically detected internal mammary lymph nodes in the absence of axillary lymph node metastases [N2], ipsilateral infraclavicular [level III axillary] lymph nodes, ipsilateral internal mammary lymph node[s] with axillary lymph nodes, or ipsilateral supraclavicular lymph nodes [N3]) Both measurable and non-measurable disease are allowed Life expectancy of greater than 12 weeks Women of child-bearing potential and sexually active men must agree to use adequate contraception prior to study entry for six months following duration of study participation Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky performance status >= 60%) Hemoglobin >= 10 g/dL (after transfusion if necessary) Absolute neutrophil count >= 1,500/mcL Platelets >= 100,000/mcL Total bilirubin within normal institutional limits Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/aspartate aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal Creatinine clearance >= 30 mL/min as measured using either the Cockcroft-Gault method or 24-hour creatinine clearance The above tests must be obtained within 14 days of study treatment Cardiac ejection fraction >= 50% as measured by echocardiogram or multiple gated acquisition scan (MUGA) scan The ability to swallow and retain oral medication Prior treatment with lapatinib or trastuzumab are allowed, provided that the agents have never been given in combination Any number of prior cancer treatments, including investigational agents, chemotherapy, hormone therapy, or targeted therapy are allowed All patients must have the ability to understand and the willingness to sign a written informed consent Exclusion Criteria: Concurrent investigational treatment, chemotherapy, or targeted therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) Unstable or symptomatic brain metastases (however, patients with stable or treated brain metastases who do not require steroids at doses above those permitted for control of symptoms may be enrolled) History of allergic reactions attributed to compounds of similar chemical or biological composition to lapatinib or trastuzumab; however, patients with a history of infusion reaction to trastuzumab which was controlled with premedication on subsequent infusions without a recurring infusion reaction are eligible Concomitant medications listed are prohibited; inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) not listed can be used with caution Ongoing or active infection (including human immunodeficiency virus [HIV]) or psychiatric illness/social situations that would limit compliance with study requirements Inability to take oral medication Malabsorption syndrome, (prior surgical procedures affecting absorption), or inflammatory gastrointestinal (GI) disease (e.g., Crohn's, ulcerative colitis) which in the opinion of the study coordinator is likely to limit normal absorption of the drug Current active 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) Active cardiac disease, defined as (but not limited to): History of documented congestive heart failure (CHF) or systolic dysfunction (left ventricular ejection fraction [LVEF] < 50%) High-risk uncontrolled arrhythmias (ventricular tachycardia, high-grade atrio-ventricular [AV]-block, supraventricular tachycardias which are not adequately rate-controlled) Angina pectoris requiring antianginal medications Evidence of transmural infarction on electrocardiogram (ECG) Clinically significant valvular heart disease Poorly controlled hypertension (e.g. systolic > 180 mm HG or diastolic > 100 mm Hg) Any other cardiac condition, which in the opinion of the treating physician would make this protocol unreasonably hazardous for the patient Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study are not eligible

Ages Eligible for Study
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Minimum Age: 60 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lapatinib and trastuzumab<br>Patients receive lapatinib ditosylate PO QD and trastuzumab IV once weekly OR once every 3 weeks. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Lapatinib<br>* 250 mg tablets<br>* Other names: GW2016;Drug: Trastuzumab<br>* Intravenous injection<br>* Other names: Herceptin;Other: laboratory biomarker analysis<br> <br> * Other names: Correlative studies;Other: pharmacological study<br> <br> * Other names: Correlative studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With Grade 3 or Higher Non-hematological Toxicities and Symptomatic Congestive Heart Failure | Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for grade 3 or higher toxicities attributed to lapatinib or trastuzumab. | Until 30 days after last dose of treatment, an average of 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With a Dose Modifications | Rates and associated 95% exact Clopper and Pearson binomial confidence intervals will be estimated. A dose modification was defined as a hold (participant started the dose later than scheduled), reduction (subject was given a lower dose than originally scheduled), or discontinuation (subject stopped treatment) of lapatinib. | While on treatment, up to 4.5 years | 
| Number of Participants With Tumor Response Using Response Evaluation Criteria in Solid Tumors (RECIST) | RECIST: Complete Response (CR): Disappearance of all target lesions. Lymph node CR is when the lymph node has decreased to less than 10mm in the short axis. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started (including the baseline scan if that is the smallest), and at least a 5mm increase or the appearance of new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | While on treatment, up to 4.5 years | 
| Median Progression-free Survival (PFS) | Median PFS and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated across all ages per protocol plan. Progression is defined using RECIST v1.0, as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started (including the baseline scan if that is the smallest), and at least a 5mm increase or the appearance of new lesions. | From the date treatment begins until the first date on which recurrence, progression or death due to any cause, with an average follow up of 1 year. | 
| Median Overall Survival (OS) | OS will be estimated using the product limit method of Kaplan and Meier across all ages per protocol plan. | Time from start of treatment to death due to any cause, with average follow up of 4.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Neoplasms, HER2 protein, human, Geriatric Health Services, Antineoplastic Agents, Combined, Geriatric Assessment, Pharmacokinetics, Toxicity, Patient Adherence