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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


Phase 2
18 Years
N/A
Open (Enrolling)
Both
HER2-positive Breast Cancer, Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer, Tumors Metastatic to Brain

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Trial Information

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


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 ditosylate (lapatinib) 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: This is a multicenter study. Patients are stratified according to graded prognostic
assessment for breast cancer (II vs III vs IV), use of concurrent trastuzumab (yes vs no),
use of non-CNS-penetrating HER2 blockade at time of study entry (none vs trastuzumab ±
pertuzumab), and history of stereotactic radiosurgery (SRS) for limited brain metastasis (no
vs yes). Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients undergo whole-brain radiation therapy (WBRT) once daily (QD) 5 days a week
for 3 weeks in the absence of disease progression or unacceptable toxicity.

Arm II: Patients receive lapatinib ditosylate orally (PO) QD on days 1-42 and undergo WBRT
as in arm I in the absence of disease progression or unacceptable toxicity.

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


Inclusion Criteria:



- Pathologically (histologically or cytologically) proven diagnosis of invasive breast
cancer

- Human epidermal growth factor receptor 2 (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)

- Brain metastases that fulfill 1 of 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

- At least 1 measurable, unirradiated parenchymal brain lesion (≥ 10 mm on T1-weighted
gadolinium-enhanced MRI) within 21 days prior to study entry

- No leptomeningeal disease

- Karnofsky performance status ≥ 60%

- 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/mm³

- Platelets ≥ 70,000 cells/mm³

- Hemoglobin [Hgb] ≥ 8.0 g/dL (Note: The use of transfusion or other intervention to
achieve Hgb ≥ 8.0 g/dL is acceptable)

- Creatinine < 1.5 times institutional upper limit of normal (ULN)

- Bilirubin < 1.5 times institutional ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 times
institutional ULN with or without liver metastasis

- 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

- Women should not breastfeed while on this study

- No 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

- No prior invasive malignancy (except non-melanomatous skin cancer) unless disease
free for a minimum of 3 years

- No 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 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

- No grade 2 or greater rash of any cause at time of study entry

- No grade 2 or greater diarrhea of any cause at time of study entry

- At least 14 days between FINAL dose of prior chemotherapy and study entry, with
recovery of toxicities to grade 0 or 1

- No prior whole-brain radiation therapy (WBRT)

- No prior lapatinib therapy

- No 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

- No concurrent intensity-modulated radiation therapy

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

CR rate in the brain measured by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 based on MRI scan of the brain

Outcome Time Frame:

12 weeks

Safety Issue:

No

Principal Investigator

In Ah Kim

Investigator Role:

Principal Investigator

Investigator Affiliation:

Radiation Therapy Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-01977

NCT ID:

NCT01622868

Start Date:

September 2012

Completion Date:

Related Keywords:

  • HER2-positive Breast Cancer
  • Male Breast Cancer
  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Tumors Metastatic to Brain
  • Breast Neoplasms
  • Neoplasm Metastasis
  • Breast Neoplasms, Male

Name

Location

Washington University School of MedicineSaint Louis, Missouri  63110
Abington Memorial HospitalAbington, Pennsylvania  19001
Bronson Methodist HospitalKalamazoo, Michigan  49007
West Michigan Cancer CenterKalamazoo, Michigan  49007-3731
Borgess Medical CenterKalamazooaa, Michigan  49001
Fairview Ridges HospitalBurnsville, Minnesota  55337
United HospitalSt. Paul, Minnesota  55102
Ridgeview Medical CenterWaconia, Minnesota  55387
Akron General Medical CenterAkron, Ohio  44302
Reading Hospital and Medical CenterReading, Pennsylvania  19612-6052
Boston Medical CenterBoston, Massachusetts  02118
University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
Mercy Medical CenterSpringfield, Ohio  45504
Mercy HospitalCoon Rapids, Minnesota  55433
Fairview-Southdale HospitalEdina, Minnesota  55435
Abbott-Northwestern HospitalMinneapolis, Minnesota  55407
Regions HospitalSaint Paul, Minnesota  55101
Rice Memorial HospitalWillmar, Minnesota  56201
Northeast Georgia Medical CenterGainesville, Georgia  30501
Cancer Treatment CenterWooster, Ohio  44691
Menorah Medical CenterOverland Park, Kansas  66209
Research Medical CenterKansas City, Missouri  64132
Heartland Regional Medical CenterSaint Joseph, Missouri  64506
Singing River HospitalPascagoula, Mississippi  39581
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
Hennepin County Medical CenterMinneapolis, Minnesota  
Cancer Care Center, IncorporatedSalem, Ohio  44460
University of RochesterRochester, New York  14642
Ohio State University Medical CenterColumbus, Ohio  43210
Metro-Minnesota CCOPSt. Louis Park, Minnesota  
Radiation Oncology CenterAlliance, Ohio  44601
Thomas Jefferson University HospitalPhiladelphia, Pennsylvania  19131
John H Stroger Jr Hospital of Cook CountyChicago, Illinois  60612-3785
Grand Rapids Clinical Oncology ProgramGrand Rapids, Michigan  49503
Saint Mary's Health CareGrand Rapids, Michigan  49503
Spectrum Health at Butterworth CampusGrand Rapids, Michigan  49503
Mercy Health Partners-Mercy CampusMuskegon, Michigan  49443
Unity HospitalFridley, Minnesota  55432
Minnesota Oncology Hematology PA-MaplewoodMaplewood, Minnesota  55109
North Memorial Medical Health CenterRobbinsdale, Minnesota  55422
Saint Luke's Hospital of Kansas CityKansas City, Missouri  64111
Saint Louis-Cape Girardeau CCOPSaint Louis, Missouri  63141
Saint John's Mercy Medical CenterSaint Louis, Missouri  63141
Ozark Health Ventures LLC dba Cancer Research for The Ozarks SpringfieldSpringfield, Missouri  65802
Saint John's HospitalSpringfield, Missouri  65804
Cox Medical CenterSpringfield, Missouri  65807
Elliot HospitalManchester, New Hampshire  03103
Saint Barnabas Medical CenterLivingston, New Jersey  07039
Highland HospitalRochester, New York  14620
Summa Barberton HospitalBarberton, Ohio  44203
Natalie W Bryant Cancer CenterTulsa, Oklahoma  74136
Saint Vincent HospitalGreen Bay, Wisconsin  54301
Saint Mary's HospitalGreen Bay, Wisconsin  54303
Green Bay Oncology at Saint Vincent HospitalGreen Bay, Wisconsin  54301-3526
Bay Area Medical CenterMarinette, Wisconsin  54143
Holy Family Memorial HospitalManitowoc, Wisconsin  54221
Kansas City CCOPPrairie Village, Kansas  66208
The Kirklin Clinic at Acton RoadBirmingham, Alabama  35243
Hematology Oncology Associates of Central New York PCEast Syracuse, New York  13057
Summa Akron City HospitalAkron, Ohio  44304
Barnes West County HospitalSaint Louis, Missouri  63141
Siteman Cancer Center - Saint PetersSaint Peters, Missouri  63376
Door County Cancer CenterSturgeon Bay, Wisconsin  54235-1495
Christiana Care Health System-Christiana HospitalNewark, Delaware  19718
Bronson Battle CreekBattle Creek, Michigan  49017