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

• Symptomatic congestive heart failure [ Time Frame: Until 30 days after last dose of treatment ] [ Designated as safety issue: Yes ]
• Dose reductions, dose interruptions, dose discontinuations [ Time Frame: While on treatment ] [ Designated as safety issue: Yes ]
• Tumor response (using RECIST criteria) [ Time Frame: While receiving treatment ] [ Designated as safety issue: No ]
• Progression-free survival [ Time Frame: From enrollment until documented disease progression or death ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: From enrollment until death from any cause ] [ Designated as safety issue: No ]
• Trough level of lapatinib [ Time Frame: During week 3, week 4, and week 5 of therapy ] [ Designated as safety issue: No ]
• Percentage of doses of lapatinib received [ Time Frame: While on active therapy ] [ Designated as safety issue: No ]

The purpose of this study is to determine how well adults age 60 and older tolerate the combination of trastuzumab and lapatinib when being treated for locally advanced or metastatic breast cancer overexpressing the human epidermal growth factor receptor 2 (HER2) marker. This combination has been shown to be safe and effective in a cohort of predominantly younger adults. The safety of the combination in older adults has not yet been systematically studied.

Limited evidence exists to guide the risks and benefits of cancer therapy in the older adult. Adults age 70 and older make up only 20% of subjects enrolled in FDA registration trials but 46% of all patients with cancer. Dose-finding studies specifically for older adults are not routinely performed. This is despite changes in drug metabolism, absorption, and distribution with increasing age. Trastuzumab is a monoclonal humanized antibody directed to the extracellular domain of the HER2 receptor. It is FDA-approved in combination with chemotherapy and as a single agent in MBC. Lapatinib is a tyrosine kinase inhibitor that binds to the intracellular domain of both the HER2 receptor and the EGFR receptor, thus inactivating downstream signaling essential to tumor proliferation. A recently reported phase III study demonstrated a survival benefit for the combination of lapatinib with trastuzumab in patients who had received multiple prior therapies. Anti-HER2 agents have not been well studied in older adults due to poor enrollment of older adults in the relevant clinical trials. In the pivotal trial of lapatinib, for example, only 17% of adults were 65 years or older and only 1% were 75 or older. This a multi-center study to evaluate the toxicity and efficacy of lapatinib and trastuzumab in patients age 60 and older. A detailed evaluation of toxicity will be performed with a specific focus on cardiac toxicity, as measured by clinical and imaging criteria.

• Breast Neoplasms
• HER2 Protein, Human
• Geriatric Health Services

• Drug: Lapatinib
  250 mg tablets
  Other Names:

  • Tykerb
  • Tyverb
• Drug: Trastuzumab
  Intravenous injection
  Other Name: Herceptin

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• Hurria A, Lichtman SM. Pharmacokinetics of chemotherapy in the older patient. Cancer Control. 2007 Jan;14(1):32-43. Review.
• Kimmick GG, Fleming R, Muss HB, Balducci L. Cancer chemotherapy in older adults. A tolerability perspective. Drugs Aging. 1997 Jan;10(1):34-49. Review.
• Talarico L, Chen G, Pazdur R. Enrollment of elderly patients in clinical trials for cancer drug registration: a 7-year experience by the US Food and Drug Administration. J Clin Oncol. 2004 Nov 15;22(22):4626-31.
• Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010 Mar 1;28(7):1124-30. Epub 2010 Feb 1.

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
• 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 glutamic pyruvic transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
• Creatinine clearance >= 30 mL/min as measured using either the Cockroft-Gault method or 24-hour creatinine clearance
• The above tests must be obtained within 14 days of study enrollment
• Cardiac ejection fraction >= 50% as measured by echocardiogram of 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
• Concomitant medications listed are prohibited; inhibitors or inducers of 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 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)
• 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 > 180mm HG or diastolic > 100mm 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

• GlaxoSmithKline
• Genentech