Whole-Brain Radiation Therapy or Stereotactic Radiosurgery With or Without Lapatinib Ditosylate in Treating Patients With Brain Metastasis From HER2-Positive Breast Cancer

• CNS progressive disease outside the targeted measurable disease [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: No ]
• CR rate of measurable brain metastases measured using revised RECIST version 1.1 based on MRI scan of the brain [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
  Response in the brain also will be measured using bidimensional measurements (WHO/modified McDonald's criteria).
• Incidence of treatment-related toxicity as measured by Common Terminology Criteria for Adverse Events version 4 [ Time Frame: Up to 12 weeks post WBRT ] [ Designated as safety issue: Yes ]
• Objective response rate (ORR) (CR + PR) of measurable brain metastases measured using RECIST version 1.1 based on MRI scan of the brain [ Time Frame: At 4 weeks ] [ Designated as safety issue: No ]
• ORR (CR + PR) of measurable brain metastases measured using RECIST version 1.1 based on MRI scan of the brain [ Time Frame: At 12 weeks ] [ Designated as safety issue: No ]
• OS [ Time Frame: From the date of randomization to the date of first failure, assessed up to 6 years ] [ Designated as safety issue: No ]
  Estimated by the Kaplan-Meier method. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with OS.
• Overall CNS complete response [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Overall CNS progressive disease [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: No ]
• Targeted lesion-specific progression [ Time Frame: At 4 weeks ] [ Designated as safety issue: No ]
• Targeted lesion-specific progression [ Time Frame: At 12 weeks ] [ Designated as safety issue: No ]

• CR rate in the brain at 4-weeks post WBRT [ Designated as safety issue: No ]
• Objective response rate (ORR) (CR + PR) at 4 weeks post-WBRT [ Designated as safety issue: No ]
• ORR at 12 weeks post-WBRT [ Designated as safety issue: No ]
• Lesion-specific ORR at 4 weeks post-WBRT [ Designated as safety issue: No ]
• Lesion-specific ORR at 12 weeks post-WBRT [ Designated as safety issue: No ]
• Overall response (CR, PR, or stable disease [SD]), assessed up to 12 weeks post-WBRT and then every 12 weeks thereafter [ Designated as safety issue: No ]
• Treatment-related toxicity as measured by Common Terminology Criterial for Adverse Events (CTCAE) version 4, assessed up to 12 weeks post-WBRT and then every 12 weeks thereafter [ Designated as safety issue: Yes ]
• CNS PFS from the time of randomization to the date of first failure (CNS progression or death due to any cause) [ Designated as safety issue: No ]
• OS from the date of randomization to the date of first failure [ Designated as safety issue: No ]

PRIMARY OBJECTIVES:

I. To determine if there is a signal for an increase in complete response (CR) rate in the measurable brain metastases at 12 weeks post radiation therapy (RT) (whole brain or stereotactic radiosurgery [SRS]) as determined by magnetic-resonance imaging (MRI) scan of the brain, with the addition of lapatinib (lapatinib ditosylate) to WBRT/SRS compared to WBRT/SRS alone.

SECONDARY OBJECTIVES:

I. To evaluate CR rate of the measurable brain metastases at 4 weeks post RT (WBRT/SRS) as determined by MRI scan of the brain, with the addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone.

II. To evaluate objective response rate of measurable brain metastases at 4 and 12 weeks post RT (WBRT/SRS) as determined by MRI scan of the brain, with the addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone.

III. To evaluate targeted lesion-specific objective response rate (CR + partial response [PR]) at 4 and 12 weeks post WBRT/SRS.

IV. To evaluate central nervous system (CNS) progressive disease outside the targeted measurable disease with addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone.

V. To evaluate targeted lesion-specific progression at 4 and 12 weeks post WBRT/SRS.

VI. To evaluate treatment related adverse events when adding lapatinib to WBRT/SRS compared to WBRT/SRS alone.

VII. To evaluate overall CNS complete response: disappearance of all CNS target lesions sustained for at least 4 weeks; with no new lesions, no use of corticosteroids, and patient is stable or improved clinically, when adding lapatinib to WBRT/SRS compared to WBRT/SRS alone.

VIII. To evaluate overall CNS progressive disease (within or outside targeted measurable disease) with addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone.

IX. To evaluate overall survival when adding lapatinib to WBRT/SRS compared to WBRT/SRS alone.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients undergo WBRT 5 days a week for 3 weeks for a total of 15 treatments or SRS for 1 treatment.

ARM B: Patients undergo WBRT or SRS as in Arm A. Patients also receive lapatinib ditosylate orally (PO) once daily (QD) for 6 weeks.

After completion of study treatment, patients are followed up at 4 and 12 weeks and then every 12 weeks thereafter.

• HER2 Positive Breast Carcinoma
• Invasive Breast Carcinoma
• Metastatic Malignant Neoplasm in the Brain
• Recurrent Breast Carcinoma
• Stage IV Breast Cancer

• Other: Laboratory Biomarker Analysis
  Correlative studies
• Drug: Lapatinib Ditosylate
  Given PO
  Other Name: Tykerb
• Radiation: Stereotactic Radiosurgery
  Undergo SRS
  Other Names:

  • Stereotactic External Beam Irradiation
  • stereotactic external-beam radiation therapy
  • Stereotactic Radiation Therapy
  • Stereotactic Radiotherapy
  • stereotaxic radiation therapy
  • stereotaxic radiosurgery
• Radiation: Whole-Brain Radiotherapy
  Undergo WBRT
  Other Names:

  • WBRT
  • whole-brain radiation therapy

• Experimental: Arm A (WBRT or SRS)
  Patients undergo WBRT 5 days a week for 3 weeks for a total of 15 treatments, or SRS for 1 treatment.
  Interventions:

  • Other: Laboratory Biomarker Analysis
  • Radiation: Stereotactic Radiosurgery
  • Radiation: Whole-Brain Radiotherapy
• Experimental: Arm B (lapatinib ditosylate, WBRT or SRS)
  Patients undergo WBRT or SRS as in Arm A. Patients also receive lapatinib ditosylate PO QD for 6 weeks.
  Interventions:

  • Other: Laboratory Biomarker Analysis
  • Drug: Lapatinib Ditosylate
  • Radiation: Stereotactic Radiosurgery
  • Radiation: Whole-Brain Radiotherapy

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of invasive breast cancer
• HER2-overexpressing breast cancer (3+ staining by immunohistochemistry or HER2 gene amplification by fluorescent in situ hybridization [FISH] or silver in situ hybridization [SISH] >= 2.0)

• At least 1 measurable and no more than 10 unirradiated parenchymal brain metastasis within 21 days prior to study entry; the minimum size as measured on T1-weighted gadolinium-enhanced MRI must be as follows according to the number of brain metastases:

  • For a single solitary lesion the size must be >= 10 mm
  • For 2 or more lesions, the size of at least 2 of the lesions must be >= 5 mm

  • Patients may also have the following provided the size requirements above are met:

    • Progressive parenchymal brain metastasis following stereotactic radiosurgery for 1-3 brain metastases, with at least 1 new measurable brain lesion
    • Progressive parenchymal brain metastasis following surgical resection of 1-3 brain metastases, with at least 1 measurable brain lesion
• History/physical examination within 21 days prior to study entry
• Karnofsky performance status >= 60% within 21 days prior to study entry
• Able to swallow and retain oral medication (note: for patients unable to swallow tablets, an oral suspension preparation is acceptable)
• Absolute neutrophil count (ANC) >= 1,200 cells/mm^3
• Platelets >= 70,000 cells/mm^3
• Hemoglobin >= 8.0 g/dL (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dL is acceptable)
• Creatinine < 1.5 times institutional upper limit of normal
• Bilirubin < 1.5 times institutional upper limit of normal
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 times institutional upper limit of normal with or without liver metastasis
• Patient must provide study specific informed consent prior to study entry
• Women of childbearing potential must have a negative serum pregnancy test within 21 days prior to study entry
• Sexually active women of childbearing potential and sexually active men must practice adequate contraception during therapy and for 12 months after protocol treatment completion
• Prior lapatinib is allowed as long as the last dose received was > 21 days prior to study entry and provided the patient has not received it at any time after the diagnosis of brain metastasis

Exclusion Criteria:

• Prior WBRT
• Prior radiation therapy (RT) (any site) with concurrent lapatinib defined as 1 or more days on which the patient received both radiation therapy and lapatinib on the same day
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Prior invasive malignancy (except non-melanomatous skin cancer, curatively resected thyroid papillary carcinoma, and invasive and non-invasive cancers related to the breast cancer) unless disease free for a minimum of 3 years
• Leptomeningeal disease
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields except patients who have progressed following stereotactic radiosurgery for 1-3 brain metastases, with at least one new lesion

• Severe, active co-morbidity, defined as follows:

  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
  • Transmural myocardial infarction within the last 6 months
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study entry
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of study entry
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; hepatic or biliary disease that is acute or currently active or that requires antiviral therapy (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment)
  • History of left ventricular ejection fraction (LVEF) below institutional normal unless repeated and within institutional normal range within 90 days of study entry
• Grade 2 or greater rash of any cause at time of study entry
• Grade 2 or greater diarrhea of any cause at time of study entry