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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01622868
Recruitment Status : Active, not recruiting
First Posted : June 19, 2012
Last Update Posted : September 16, 2020
Sponsor:
Collaborator:
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE June 15, 2012
First Posted Date  ICMJE June 19, 2012
Last Update Posted Date September 16, 2020
Actual Study Start Date  ICMJE July 26, 2012
Actual Primary Completion Date December 30, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 22, 2019)
Complete response (CR) rate in the measurable brain metastases [ Time Frame: 12 weeks ]
Measured by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 based on magnetic resonance imaging (MRI) scan of the brain. 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
Current Secondary Outcome Measures  ICMJE
 (submitted: April 22, 2019)
  • CR rate of measurable brain metastases [ Time Frame: 4 weeks ]
    Measured using revised RECIST version 1.1 based on MRI scan of the brain. 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 [ Time Frame: At 4 weeks ]
    Measured using RECIST version 1.1 based on MRI scan of the brain.
  • ORR (CR + PR) of measurable brain metastases [ Time Frame: At 12 weeks ]
    Measured using RECIST version 1.1 based on MRI scan of the brain.
  • 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 [ Time Frame: Up to 12 weeks post whole-brain radiation therapy ]
    Measured by Common Terminology Criteria for Adverse Events (CTCAE) version 4. Beginning April 1, 2018, CTCAE version 5.0 will be utilized for all adverse events reporting, Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS), and case report forms.
  • 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 Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures 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  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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  ICMJE
  • 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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: June 15, 2012)
143
Original Estimated Enrollment  ICMJE Same as current
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date December 30, 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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
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  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE NRG Oncology
Investigators  ICMJE
Principal Investigator: In A Kim NRG Oncology
PRS Account National Cancer Institute (NCI)
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP