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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01622868
First received: June 15, 2012
Last updated: July 28, 2014
Last verified: June 2014
  Purpose

This randomized phase II trial studies how well whole-brain radiation therapy (WBRT) with or without lapatinib ditosylate works in treating patients with brain metastasis from human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Radiation therapy uses high energy x rays to kill tumor cells. 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 radiation therapy together with lapatinib ditosylate is an effective treatment for brain metastasis from breast cancer.


Condition Intervention Phase
HER2-positive Breast Cancer
Male Breast Cancer
Recurrent Breast Cancer
Stage IV Breast Cancer
Tumors Metastatic to Brain
Drug: lapatinib ditosylate
Radiation: whole-brain radiation therapy
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Randomized Study of Whole Brain Radiotherapy in Combination With Concurrent Lapatinib in Patients With Brain Metastasis From HER2-Positive Breast Cancer: A Collaborative Study of RTOG and KROG

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • CR rate in the brain measured by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 based on MRI scan of the brain [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Response in the brain also will be measured using bidimensional measurements (World Health Organization [WHO]/modified McDonald's criteria).


Secondary Outcome Measures:
  • CR rate in the brain measured using revise 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).

  • Objective response rate (ORR) (CR + PR) 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) measured using RECIST version 1.1 based on MRI scan of the brain [ Time Frame: At 12 weeks ] [ Designated as safety issue: No ]
  • Lesion-specific ORR (CR + PR) [ Time Frame: At 4 weeks ] [ Designated as safety issue: No ]
  • Lesion-specific ORR (CR + PR) [ Time Frame: At 12 weeks ] [ Designated as safety issue: No ]
  • Overall response (CR, PR, or stable disease [SD]) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  • Treatment-related toxicity as measured by Common Terminology Criterial for Adverse Events version 4 [ Time Frame: Up to 12 weeks post WBRT ] [ Designated as safety issue: Yes ]
  • CNS PFS [ Time Frame: From the time of randomization to the date of first failure (CNS progression or death due to any cause), assessed up to 2 years ] [ Designated as safety issue: No ]
    Estimated by the Kaplan-Meier method. Compared between arms using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with PFS.

  • PFS [ Time Frame: From the date of randomization to the date of first failure or last follow-up, assessed up to 2 years ] [ Designated as safety issue: No ]
    Estimated by the Kaplan-Meier method. Compared between arms using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with PFS.

  • OS [ Time Frame: From the date of randomization to the date of first failure, assessed up to 2 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.


Estimated Enrollment: 143
Study Start Date: July 2012
Estimated Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (WBRT)
Patients undergo WBRT QD 5 days a week for 3 weeks.
Radiation: whole-brain radiation therapy
Undergo WBRT
Other Names:
  • WBRT
  • whole-brain radiotherapy
Experimental: Arm II (lapatinib ditosylate, WBRT)
Patients receive lapatinib ditosylate PO QD on days 1-42 and undergo WBRT as in arm I.
Drug: lapatinib ditosylate
Given PO
Other Names:
  • GSK572016
  • GW-572016
  • GW2016
  • Lapatinib
  • Tykerb
Radiation: whole-brain radiation therapy
Undergo WBRT
Other Names:
  • WBRT
  • whole-brain radiotherapy

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine if there is a signal for an increase in complete response (CR) rate in the brain at 12 weeks post whole-brain radiotherapy (WBRT) as determined by magnetic-resonance imaging (MRI) scan of the brain, with the addition of lapatinib (lapatinib ditosylate) to WBRT compared to WBRT alone.

SECONDARY OBJECTIVES:

I. To evaluate CR rate in the brain at 4 weeks post WBRT as determined by MRI scan of the brain, with the addition of lapatinib to WBRT compared to WBRT alone.

II. To evaluate objective response rate in the brain at 4 and 12 weeks post WBRT as determined by MRI scan of the brain, with the addition of lapatinib to WBRT compared to WBRT alone.

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

IV. To evaluate overall response with addition of lapatinib to WBRT compared to WBRT alone.

V. To evaluate the central nervous system (CNS) progression-free survival (PFS) rate and overall survival (OS) rate, with the addition of lapatinib to WBRT compared to WBRT alone.

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

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

ARM I: Patients undergo WBRT once daily (QD) 5 days a week for 3 weeks.

ARM II: Patients receive lapatinib ditosylate orally (PO) QD on days 1-42 and undergo WBRT as in arm I.

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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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] >= 2.2)
  • At least 1 measurable, unirradiated parenchymal brain lesion (>= 10 mm on T1-weighted gadolinium-enhanced MRI) within 21 days prior to study entry; patients may also have the following:

    • Progressive parenchymal brain metastases following stereotactic radiosurgery for 1-3 brain metastases, with at least 1 new measurable lesion
    • Progressive parenchymal brain metastases following surgical resection of 1-3 brain metastases, as long as at least 1 brain metastasis is measurable
  • 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
  • At least 14 days between FINAL dose of prior chemotherapy and study entry, with recovery of toxicities to grade 0 or 1
  • 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
  • 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

Exclusion Criteria:

  • Prior WBRT
  • Prior lapatinib therapy
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01622868

  Show 205 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: In Ah Kim Radiation Therapy Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01622868     History of Changes
Other Study ID Numbers: NCI-2012-01977, NCI-2012-01977, CDR0000735353, RTOG 1119, RTOG-1119, U10CA021661
Study First Received: June 15, 2012
Last Updated: July 28, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasm Metastasis
Breast Neoplasms, Male
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Neoplastic Processes
Pathologic Processes
Lapatinib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 28, 2014