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Lapatinib in Combination With Radiation Therapy in Patients With Brain Metastases From HER2-Positive Breast Cancer

Primary Purpose

Breast Cancer, Brain Metastases

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Lapatinib
Whole Brain Radiation
Herceptin
Sponsored by
Nancy Lin, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring Herceptin, breast cancer, radiation therapy, stereotactic radiosurgery, SRS, whole brain radiation, WBRT

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Histologically or cytologically-confirmed invasive breast cancer
  • HER2 overexpressing breast cancer defined as 3+ staining by immunohistochemistry, or HER2 gene amplification by FISH
  • At least one parenchymal brain metastasis
  • Disease progression in the CNS as assessed by at least one of the following; new neurological signs or symptoms; new lesion(s) in the CNS on an imaging study; progressive lesions on an imaging study
  • At least two weeks since prior radiotherapy, last chemotherapy, immunotherapy, biologic therapy, or major surgery for cancer
  • 18 years of age or older
  • Life expectancy of greater than 12 weeks
  • ECOG performance status 0-2
  • Normal organ and marrow function as described in the protocol
  • Left ventricular ejection fraction > 50%
  • Able to swallow and retain oral medications

Exclusion Criteria:

  • Prior WBRT
  • Receiving any other investigational agents
  • Concurrent chemotherapy, immunotherapy, biologic therapy or hormonal therapy for treatment of their cancer
  • History of grade 3 or 4 allergic reactions attributed to compounds of similar chemical or biologic composition to herceptin or lapatinib
  • Leptomeningeal carcinomatosis as the only site of CNS involvement
  • Concurrent treatment with medications that are either inducers of inhibitors of CYP3A4
  • Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or active ulcerative colitis
  • History of immediate or delayed hypersensitivity reaction to gadolinium contrast agents
  • Other known contraindication to MRI
  • Uncontrolled intercurrent illness
  • History of other active malignancy except curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix
  • Pregnant or breastfeeding women

Sites / Locations

  • Indiana University Melvin and Bren Simon Cancer Center
  • Brigham and Women's Hospital
  • Dana-Farber Cancer Institute

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Lapatinib,Whole Brain Radiation,Herceptin

Arm Description

Lapatinib before and during Whole Brain Radiation Therapy (WBRT), then Herceptin 4mg/kg IV weekly

Outcomes

Primary Outcome Measures

The Maximum Tolerated Dose of Lapatinib When Combined With Cranial Radiation in Patients With CNS Metastases From HER2-positive Breast Cancer.
The maximum tolerated dose is defined as :The highest dose of a drug or treatment that does not cause unacceptable side effects.

Secondary Outcome Measures

Progression Free Survival
Progression Free Survival is the time from date of start of treatment to the date of the first documented progression or death due to any cause. If a patient has not progressed or died, progression free survival is censored at the time of last tumor assessment. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0), as a 20 % increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Objective Response Rate in Central Nervous System Sites
Objective Response Rate was defined using volumetric response as the following: Complete Response (CR) is the disappearance of all target lesions, stable/responsive non-target lesions, and no new lesions. Partial response (PR) is at least a 50% reduction in the sum of the target lesions, stable/responsive non-target lesions, and no new lesions. Stable Disease (SD) is neither CR PR or Progressive Disease (PD). And Progressive Disease (PD) is at least 40% increase in sum of target lesionsor the appearance of any new lesion >=6mm in the longest dimension. If a patient progressed in a non-central nervous system(CNS) site first, died, or withdrew from the study for any reason after the first dose of drug was administered, and before a CR or PR in the central nervous system was determined, she was considered a CNS non-responder.
Percentage of Participants Having Central Nervous System as the Site of the First Progression
Percentage of Participants Having Non-Central Nervous System Sites as the Site of First Progression
Overall Survival
Overall average length of participant survival after protocol initiation

Full Information

First Posted
May 7, 2007
Last Updated
April 28, 2014
Sponsor
Nancy Lin, MD
Collaborators
Brigham and Women's Hospital, Breast Cancer Research Foundation, GlaxoSmithKline
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1. Study Identification

Unique Protocol Identification Number
NCT00470847
Brief Title
Lapatinib in Combination With Radiation Therapy in Patients With Brain Metastases From HER2-Positive Breast Cancer
Official Title
A Phase I Study of Lapatinib in Combination With Radiation Therapy in Patients With Brain Metastases From HER2-Positive Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
April 2014
Overall Recruitment Status
Completed
Study Start Date
April 2007 (undefined)
Primary Completion Date
December 2009 (Actual)
Study Completion Date
June 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Nancy Lin, MD
Collaborators
Brigham and Women's Hospital, Breast Cancer Research Foundation, GlaxoSmithKline

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this research study is to determine the safety of combining lapatinib plus radiation in patients with breast cancer that has spread to the brain. Depending upon the participants cancer, they may also have stereotactic radiosurgery (SRS). Lapatinib s a compound that may stop cancer cells from growing abnormally. It is thought that lapatinib might also make cancer cells more sensitive to radiation. This drug has been used in other research studies in women with breast cancer, and information from those other research studies suggests that lapatinib may help to shrink or stabilize breast tumors both inside the brain and outside the brain.
Detailed Description
Participant's will be given a study medication-dosing calendar for each treatment cycle. Each treatment cycle lasts four weeks. On the first day of the treatment cycle, participants will take 1 lapatinib orally twice per day, 12 hours apart. After the first day, lapatinib will be taken once a day in the morning. Whole brain radiation treatments will begin approximately 1-8 days after the first dose of lapatinib. The radiation treatments will follow standard guidelines and will be supervised by a radiation oncologist. Radiation will be given in 15 treatments over a period of three weeks. Some participants will also undergo stereotactic radiosurgery (SRS). SRS is a highly focused and intense form of radiation treatment generally done as an outpatient procedure in a single treatment. After whole brain radiation treatments are completed, lapatinib will be continued at the same dose for one more week. After that, the lapatinib dose may change. In addition at the same time, Herceptin will be started. Participants will continue with both lapatinib and herceptin together as long as there is evidence that they are benefitting from it. During all treatment cycles participants will have a physical exam and be asked general questions about their health. Photographs will be taken of the tumor, if visible, to assess the response of the tumor to the treatment. An assessment of the tumor by CT scan of the body, and MRI imaging of the brain will be performed every two months. An assessment of heart function by MUGA scan or echocardiogram will be performed every 8 weeks. The participant will also be asked to complete a brief questionnaire measuring quality of life and asking about symptoms related to the cancer at baseline, 6 months, and one year. Blood tests will be performed every 4 weeks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer, Brain Metastases
Keywords
Herceptin, breast cancer, radiation therapy, stereotactic radiosurgery, SRS, whole brain radiation, WBRT

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
35 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Lapatinib,Whole Brain Radiation,Herceptin
Arm Type
Other
Arm Description
Lapatinib before and during Whole Brain Radiation Therapy (WBRT), then Herceptin 4mg/kg IV weekly
Intervention Type
Drug
Intervention Name(s)
Lapatinib
Other Intervention Name(s)
Tykerb
Intervention Description
Orally twice daily
Intervention Type
Procedure
Intervention Name(s)
Whole Brain Radiation
Intervention Description
15 treatments over a period of 3 weeks
Intervention Type
Drug
Intervention Name(s)
Herceptin
Other Intervention Name(s)
Trastuzumab
Intervention Description
Herceptin 4mg/kg loading dose then 2 mg/kg IV once weekly, then once every three weeks after cycle 3.
Primary Outcome Measure Information:
Title
The Maximum Tolerated Dose of Lapatinib When Combined With Cranial Radiation in Patients With CNS Metastases From HER2-positive Breast Cancer.
Description
The maximum tolerated dose is defined as :The highest dose of a drug or treatment that does not cause unacceptable side effects.
Time Frame
5 Years
Secondary Outcome Measure Information:
Title
Progression Free Survival
Description
Progression Free Survival is the time from date of start of treatment to the date of the first documented progression or death due to any cause. If a patient has not progressed or died, progression free survival is censored at the time of last tumor assessment. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0), as a 20 % increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame
5 years
Title
Objective Response Rate in Central Nervous System Sites
Description
Objective Response Rate was defined using volumetric response as the following: Complete Response (CR) is the disappearance of all target lesions, stable/responsive non-target lesions, and no new lesions. Partial response (PR) is at least a 50% reduction in the sum of the target lesions, stable/responsive non-target lesions, and no new lesions. Stable Disease (SD) is neither CR PR or Progressive Disease (PD). And Progressive Disease (PD) is at least 40% increase in sum of target lesionsor the appearance of any new lesion >=6mm in the longest dimension. If a patient progressed in a non-central nervous system(CNS) site first, died, or withdrew from the study for any reason after the first dose of drug was administered, and before a CR or PR in the central nervous system was determined, she was considered a CNS non-responder.
Time Frame
5 years
Title
Percentage of Participants Having Central Nervous System as the Site of the First Progression
Time Frame
5 years
Title
Percentage of Participants Having Non-Central Nervous System Sites as the Site of First Progression
Time Frame
5 years
Title
Overall Survival
Description
Overall average length of participant survival after protocol initiation
Time Frame
Participants were followed for an average of 3.8 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histologically or cytologically-confirmed invasive breast cancer HER2 overexpressing breast cancer defined as 3+ staining by immunohistochemistry, or HER2 gene amplification by FISH At least one parenchymal brain metastasis Disease progression in the CNS as assessed by at least one of the following; new neurological signs or symptoms; new lesion(s) in the CNS on an imaging study; progressive lesions on an imaging study At least two weeks since prior radiotherapy, last chemotherapy, immunotherapy, biologic therapy, or major surgery for cancer 18 years of age or older Life expectancy of greater than 12 weeks ECOG performance status 0-2 Normal organ and marrow function as described in the protocol Left ventricular ejection fraction > 50% Able to swallow and retain oral medications Exclusion Criteria: Prior WBRT Receiving any other investigational agents Concurrent chemotherapy, immunotherapy, biologic therapy or hormonal therapy for treatment of their cancer History of grade 3 or 4 allergic reactions attributed to compounds of similar chemical or biologic composition to herceptin or lapatinib Leptomeningeal carcinomatosis as the only site of CNS involvement Concurrent treatment with medications that are either inducers of inhibitors of CYP3A4 Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or active ulcerative colitis History of immediate or delayed hypersensitivity reaction to gadolinium contrast agents Other known contraindication to MRI Uncontrolled intercurrent illness History of other active malignancy except curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix Pregnant or breastfeeding women
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nancy Lin, MD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Indiana University Melvin and Bren Simon Cancer Center
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States

12. IPD Sharing Statement

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Lapatinib in Combination With Radiation Therapy in Patients With Brain Metastases From HER2-Positive Breast Cancer

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