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

Tracking Information
First Submitted Date ICMJE	June 15, 2012
First Posted Date ICMJE	June 19, 2012
Last Update Posted Date	April 23, 2018
Actual Study Start Date ICMJE	July 26, 2012
Estimated Primary Completion Date	March 1, 2019 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: February 28, 2018)	Complete response (CR) rate in the measurable brain metastases measured by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 based on magnetic resonance imaging (MRI) scan of the brain [ Time Frame: 12 weeks ]; Response in the brain also will be measured using bidimensional measurements (World Health Organization [WHO]/modified McDonald's criteria).
Original Primary Outcome Measures ICMJE; (submitted: June 15, 2012)	CR rate in the brain at 12-weeks post-WBRT measured by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 based on MRI scan of the brain
Change History	Complete list of historical versions of study NCT01622868 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: March 2, 2018)	CR rate of measurable brain metastases measured using revised RECIST version 1.1 based on MRI scan of the brain [ Time Frame: 4 weeks ]Response in the brain also will be measured using bidimensional measurements (WHO/modified McDonald's criteria).; Objective response rate (ORR) (CR + partial response [PR]) of measurable brain metastases measured using RECIST version 1.1 based on MRI scan of the brain [ Time Frame: At 4 weeks ]; 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 ]; Central nervous system (CNS) progressive disease outside the targeted measurable disease [ Time Frame: Up to 4 weeks ]; Targeted lesion-specific progression [ Time Frame: At 4 weeks ]; Targeted lesion-specific progression [ Time Frame: At 12 weeks ]; Incidence of treatment-related toxicity as measured by Common Terminology Criteria for Adverse Events version 4 [ Time Frame: Up to 12 weeks post whole-brain radiation therapy ]; Overall CNS complete response [ Time Frame: Up to 2 years ]; Overall CNS progressive disease [ Time Frame: Up to 4 weeks ]; Overall survival (OS) [ Time Frame: From the date of randomization to the date of first failure, assessed up to 6 years ]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.
Original Secondary Outcome Measures ICMJE; (submitted: June 15, 2012)	CR rate in the brain at 4-weeks post WBRT; Objective response rate (ORR) (CR + PR) at 4 weeks post-WBRT; ORR at 12 weeks post-WBRT; Lesion-specific ORR at 4 weeks post-WBRT; Lesion-specific ORR at 12 weeks post-WBRT; Overall response (CR, PR, or stable disease [SD]), assessed up to 12 weeks post-WBRT and then every 12 weeks thereafter; 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; CNS PFS from the time of randomization to the date of first failure (CNS progression or death due to any cause); OS from the date of randomization to the date of first failure
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Whole-Brain Radiation Therapy or Stereotactic Radiosurgery With or Without Lapatinib Ditosylate in Treating Patients With Brain Metastasis From HER2-Positive Breast Cancer
Official Title ICMJE	Phase II Randomized Study of Whole Brain Radiotherapy/Stereotactic Radiosurgery in Combination With Concurrent Lapatinib in Patients With Brain Metastasis From HER2-Positive Breast Cancer: A Collaborative Study of NRG Oncology and KROG
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.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	ERBB2 Gene Amplification; HER2 Positive Breast Carcinoma; Invasive Breast Carcinoma; Metastatic Malignant Neoplasm in the Brain; Recurrent Breast Carcinoma; Stage IV Breast Cancer AJCC v6 and v7
Intervention ICMJE	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
Study Arms	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
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Recruiting
Estimated Enrollment ICMJE; (submitted: June 15, 2012)	143
Original Estimated Enrollment ICMJE	Same as current
Study Completion Date	Not Provided
Estimated Primary Completion Date	March 1, 2019 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE
Listed Location Countries ICMJE	Canada, Korea, Republic of, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01622868
Other Study ID Numbers ICMJE	NCI-2012-01977; NCI-2012-01977 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); RTOG-1119; CDR0000735353; RTOG-1119 ( Other Identifier: NRG Oncology ); RTOG-1119 ( Other Identifier: CTEP ); U10CA180868 ( U.S. NIH Grant/Contract ); U10CA021661 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	National Cancer Institute (NCI)
Study Sponsor ICMJE	National Cancer Institute (NCI)
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: In Kim NRG Oncology
PRS Account	National Cancer Institute (NCI)
Verification Date	March 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP