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

Phase 2

Completed

Conditions: Metastatic Malignant Neoplasm in the Brain
Recurrent Breast Carcinoma
HER2-Positive Breast Carcinoma
Invasive Breast Carcinoma
Stage IV Breast Cancer AJCC v6 and v7

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

Registration Number: NCT01622868

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This randomized phase II trial studies how well whole-brain radiation therapy or stereotactic radiosurgery with or without lapatinib ditosylate works in treating patients with breast cancer that has too many of a protein called human epidermal growth factor receptor 2 (HER2) on its cells and has spread to the brain. Radiation therapy uses high energy x rays to kill tumor cells and shrink tumors. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may kill more tumor cells and cause less damage to normal tissue. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether whole-brain radiation therapy or stereotactic radiosurgery together with lapatinib ditosylate is an effective treatment for brain metastasis from breast cancer.

Detailed Description: 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 whole-brain radiation therapy (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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 143

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 unirradiated parenchymal brain metastasis within 21 days prior to study entry; patients who are to undergo SRS must have no more than 10 brain metastases; there is no limit on number of brain metastases for WBRT; 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 (within 21 days prior to study entry)
Platelets >= 70,000 cells/mm^3 (within 21 days prior to study entry)
Hemoglobin >= 8.0 g/dL (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dL is acceptable) (within 21 days prior to study entry)
Creatinine < 1.5 times institutional upper limit of normal (within 21 days prior to study entry)
Bilirubin < 1.5 times institutional upper limit of normal (within 21 days prior to study entry)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 times institutional upper limit of normal with or without liver metastasis (within 21 days prior to study entry)
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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A (WBRT or SRS)	Laboratory Biomarker Analysis	Patients undergo WBRT 5 days a week for 3 weeks for a total of 15 treatments, or SRS for 1 treatment.
Arm A (WBRT or SRS)	Stereotactic Radiosurgery	Patients undergo WBRT 5 days a week for 3 weeks for a total of 15 treatments, or SRS for 1 treatment.
Arm A (WBRT or SRS)	Whole-Brain Radiotherapy	Patients undergo WBRT 5 days a week for 3 weeks for a total of 15 treatments, or SRS for 1 treatment.
Arm B (lapatinib ditosylate, WBRT or SRS)	Laboratory Biomarker Analysis	Patients undergo WBRT or SRS as in Arm A. Patients also receive lapatinib ditosylate PO QD for 6 weeks.
Arm B (lapatinib ditosylate, WBRT or SRS)	Lapatinib Ditosylate	Patients undergo WBRT or SRS as in Arm A. Patients also receive lapatinib ditosylate PO QD for 6 weeks.
Arm B (lapatinib ditosylate, WBRT or SRS)	Stereotactic Radiosurgery	Patients undergo WBRT or SRS as in Arm A. Patients also receive lapatinib ditosylate PO QD for 6 weeks.
Arm B (lapatinib ditosylate, WBRT or SRS)	Whole-Brain Radiotherapy	Patients undergo WBRT or SRS as in Arm A. Patients also receive lapatinib ditosylate PO QD for 6 weeks.

Primary Outcome Measures

Name	Time	Method
Complete Response (CR) Rate in the Brain at 12 Weeks Post-radiation Therapy (RT) Using the RECIST 1.1 Criteria Based on Brain Magnetic Resonance Imaging (MRI)	Baseline and 12 weeks post RT (approximately 12 weeks from start of treatment if SRS and 15 if WBRT)	The Response Evaluation Criteria in Solid Tumors (RECIST) criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Complete response is defined as the complete disappearance of all enhancing disease and off all steroids. Rate is calculated by dividing the number of patients with complete response by the number of analyzable patients.

Secondary Outcome Measures

Name	Time	Method
Complete Response Rate in the Brain at 4 Weeks Post-RT Using the RECIST 1.1 Criteria Based on Brain MRI	Baseline and 4 weeks post RT (approximately 4 weeks from start of treatment if SRS and 7 if WBRT)	The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Complete response is defined as the complete disappearance of all enhancing disease and off all steroids. Rate is calculated by dividing the number of patients with complete response by the number of analyzable patients.
Targeted Lesion-specific Objective Response Rate Using the RECIST 1.1 Measurement Criteria Based on Brain MRI	Baseline, 4 and 12 weeks post RT (approximately 4 and 12 weeks from start of treatment if SRS, 7 and 15 if WBRT)	The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Objective response is defined as a complete or partial response. Complete response is defined as the complete disappearance of all enhancing disease and partial response is defined as ≥ 30% reduction in the diameter of the target lesion. Lesions were evaluated individually. Rate is calculated by dividing the number of lesions with objective response by the number of analyzable lesions.
Targeted Lesion-specific Progression Rate Using the RECIST 1.1 Measurement Criteria Based on Brain MRI	Baseline, 4 and 12 weeks post RT (approximately 4 and 12 weeks from start of treatment if SRS, 7 and 15 if WBRT)	The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Progression is defined as ≥ 20% increase in the diameter of the target lesion relative to nadir. Lesions were evaluated individually. Rate is calculated by dividing the number of lesions with progression by the number of analyzable lesions.
Complete Response Rate in the Brain Using the World Health Organization (WHO)/Modified McDonald Criteria Based on Brain MRI	Baseline, 4 and 12 weeks post RT (approximately 4 and 12 weeks from start of treatment if SRS, 7 and 15 if WBRT)	The WHO/modified McDonald Criteria evaluates changes in bidimensional tumor measurements. Complete response is defined as the complete disappearance of all enhancing disease and off all steroids. Rate is calculated by dividing the number of patients with complete response by the number of analyzable patients.
Percentage of Participants With Progression in the Brain Outside the Targeted Measurable Disease Using the RECIST 1.1 Criteria Based on Brain MRI	From randomization to last follow-up. MRIs occurred at baseline, 4 and 12 weeks post RT, then every 12 weeks thereafter until progression. Maximum follow-up at time of analysis was 71.6 months.	The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. CNS progressive disease outside the targeted measureable disease was determined by a retrospective central review of MRI scans by the study neuroradiology co-chair and is defined as the first occurrence since baseline of new lesions or progression of non-target lesions. Time to CNS progressive disease is defined as time from randomization to the date of progressive disease, last known follow-up (censored), or death (competing risk). Progression rates are estimated using the cumulative incidence method. One-year rates are provided.
Overall Complete Response Rate in the Brain Using the RECIST 1.1 Criteria Based on Brain MRI	From randomization to last follow-up. MRIs occurred at baseline, 4 and 12 weeks post RT, then every 12 weeks thereafter until progression. Maximum follow-up at time of analysis was 71.6 months.	The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Overall complete response is defined as the complete 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. All site-reported MRI data and all site-reporting of clinical progressive disease indicators were used in this analysis. Rate is calculated by dividing the number of participants with overall complete response by the number of analyzable participants.
Objective Response Rate in the Brain Using the RECIST 1.1 Criteria Based on Brain MRI	Baseline, 4 and 12 weeks post RT (approximately 4 and 12 weeks from start of treatment if SRS, 7 and 15 if WBRT)	The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Objective response is defined as a complete or partial response. Complete response is defined as the complete disappearance of all enhancing disease and off all steroids. Partial response is defined as ≥ 30% reduction in the sum of diameters of up to 2 of the largest target lesions. Rate is calculated by dividing the number of patients with objective response by the number of analyzable patients.
Overall Progression Rate in the Brain Using the RECIST 1.1 Criteria Based on Brain MRI	From randomization to last follow-up. MRIs occurred at baseline, 4 and 12 weeks post RT, then every 12 weeks thereafter until progression. Maximum follow-up at time of analysis was 71.6 months.	The RECIST criteria evaluates changes in the largest diameter (unidimensional measurement) of the tumor lesions. Overall progression is defined as unequivocal progression, new or worsening tumor-related neurological symptoms, tumor-related increase in steroid dose, new primary in brain, or progression in target lesions. All site-reported MRI data and all site-reporting of clinical progressive disease indicators were used in this analysis. Rate is calculated by dividing the number of participants with progression by the number of analyzable participants.
Frequency of Highest Treatment-related Adverse Event Per Participant	From randomization to last follow-up. Maximum follow-up at time of analysis was 71.6 months.	Adverse events reported as definitely, probably, or possibly related to protocol treatment. Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data provided in this outcome measure. See Adverse Events Module for specific Adverse Event data.
Overall Survival (OS)	From randomization to last follow-up. Maximum follow-up at time of analysis was 71.6 months.	An event for overall survival is death due to any cause. Survival time is defined as time from randomization to the date of death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. Analysis occurred after 101 deaths were reported.

Trial Locations

Locations (302): University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
The Kirklin Clinic at Acton Road
🇺🇸
Birmingham, Alabama, United States
University of South Alabama Mitchell Cancer Institute
🇺🇸
Mobile, Alabama, United States
Saint Joseph's Hospital and Medical Center
🇺🇸
Phoenix, Arizona, United States
Banner University Medical Center - Tucson
🇺🇸
Tucson, Arizona, United States
Sutter Auburn Faith Hospital
🇺🇸
Auburn, California, United States
Sutter Cancer Centers Radiation Oncology Services-Auburn
🇺🇸
Auburn, California, United States
Alta Bates Summit Medical Center-Herrick Campus
🇺🇸
Berkeley, California, United States
Mills-Peninsula Medical Center
🇺🇸
Burlingame, California, United States
Sutter Cancer Centers Radiation Oncology Services-Cameron Park
🇺🇸
Cameron Park, California, United States
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University of Alabama at Birmingham Cancer Center
🇺🇸Birmingham, Alabama, United States