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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

Phase 2
60 Years
Open (Enrolling)
Breast Neoplasms, HER2 Protein, Human, Geriatric Health Services

Thank you

Trial Information

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

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.

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

- 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

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Grade 3 or higher toxicities (as defined by NCI CTCAE v.4.0)

Outcome Time Frame:

Until 30 days after last dose of treatment

Safety Issue:


Principal Investigator

Arti Hurria, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

City of Hope Medical Center


United States: Institutional Review Board

Study ID:




Start Date:

April 2011

Completion Date:

Related Keywords:

  • Breast Neoplasms
  • HER2 Protein, Human
  • Geriatric Health Services
  • Breast Neoplasms
  • HER@ protein, human
  • Geriatric Health Services
  • Antineoplastic Agents, Combined
  • Geriatric Assessment
  • Pharmacokinetics
  • Toxicity
  • Patient Adherence
  • Breast Neoplasms
  • Neoplasms



City of Hope Medical CenterDuarte, California  91010
Case Western Reserve UniversityCleveland, Ohio  44106
Thomas Jefferson UniversityPhiladelphia, Pennsylvania  19107-6541
South Pasadena Cancer CenterSouth Pasadena, California  91030
Lineberger Comprehensive Cancer Center, University of North CarolinaChapel Hill, North Carolina  27599