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A Phase 2 Study of GW572016 for Brain Metastases in Patients With HER2-Positive Breast Cancer

Phase 2
18 Years
Not Enrolling
Central Nervous System Metastases, HER2-positive Breast Cancer, Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer, Tumors Metastatic to Brain

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Trial Information

A Phase 2 Study of GW572016 for Brain Metastases in Patients With HER2-Positive Breast Cancer


I. To evaluate the objective response rate in the central nervous system (CNS) (complete
plus partial responses), as assessed by standard MRI, to oral GW572016 among patients with
progressive brain metastases from HER2-positive breast cancer.


I. To evaluate the site of first failure (CNS, extra-CNS, both, or death) and overall
survival of patients treated with GW572016 for brain metastases.

II. To evaluate the overall objective response rate (complete plus partial response) and
time to first progression at any site.

III. To assess quality of life (QOL), neurologic QOL, and cause of death in patients treated
with GW572016 for brain metastases.

IV. To determine the qualitative and quantitative toxicities associated with oral GW572016,
given at a dose of 750 mg orally, twice daily.

V. To evaluate the sensitivity of PET with dedicated brain sequences to detect brain
metastases from breast cancer.

VI. To explore the relationship between decline in PET uptake at 1 week and decline in PET
uptake at 8 weeks.

VII. To characterize the vessel patterns seen on MRI at baseline, 8 weeks, and 16 weeks of
treatment with GW572016.

VIII. To describe changes in serum HER2 ECD over time. IX. To describe the baseline EGFR,
HER2, IGF-IR, and degree of HER2 gene amplification in primary tumor blocks.

OUTLINE: This is an open-label, multicenter study.

Patients receive oral lapatinib twice daily on days 1-28. Courses repeat every 28 days in
the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline and at 8 weeks.

Patients are followed every 2 months.

PROJECTED ACCRUAL: A total of 12-37 patients will be accrued for this study within 0.5-1.5

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed invasive breast cancer,
with stage IV disease

- HER2 overexpressing breast cancer, defined as 3+ staining by immunohistochemistry
(IHC), or 2+ staining by IHC in conjunction with HER2 gene amplification by
fluorescent in situ hybridization (FISH), or HER2 gene amplification by FISH alone
(in patients whose tumor blocks were not assessed by IHC); patients with tumors that
are 2+ by IHC but negative by FISH assay are ineligible

- At least one measurable lesion in the CNS, defined as any lesion >= 10 mm in longest
dimension on T1-weighted, gadolinium-enhanced MRI

- One of the following:

- Cohort 1: Prior treatment of CNS metastases with whole brain radiotherapy (WBRT)
and/or stereotactic radiosurgery (SRS), OR;

- Cohort 2: Asymptomatic CNS metastases discovered on a screening radiological
study without prior WBRT or SRS

- Disease progression in the CNS, as assessed by at least one of the following:

- New neurological signs or symptoms

- New lesions in the CNS on an imaging study

- Progressive lesions on an imaging study

- Note: patients with progressive lesions are not required to meet Response
Evaluation Criteria in Solid Tumors (RECIST) criteria for progression in order
to be eligible for this study

- Prior treatment with trastuzumab, either alone or in combination with chemotherapy is
required; trastuzumab will be discontinued at least 2 weeks prior to enrollment on
study; note: patients who have documented CNS-only metastases are not required to
have had prior treatment with trastuzumab; in this situation, the absence of
extra-CNS disease must be documented with a physical examination, CT scan of the
chest, abdomen, and pelvis, and bone scan

- At least 2 weeks since prior radiotherapy, last chemotherapy, immunotherapy, biologic
therapy, or hormonal therapy for cancer, and sufficiently recovered or stabilized
from side effects associated with prior therapy; concurrent treatment with
bisphosphonates is permitted

- At least 3 weeks since major surgical procedures

- At least 2 weeks since last dose of trastuzumab

- Life expectancy >= 12 weeks

- ECOG performance status 0-2 (Karnofsky >= 60%)

- Hemoglobin >= 9 g/dL (after transfusion if needed)

- Platelets >= 50 x 10^9/L

- Albumin >= 2.5 g/dL

- Serum bilirubin =< 1.5 x ULN unless due to Gilbert's syndrome

- AST and ALT =< 5 x ULN

- Serum creatinine =< 1.5 mg/dL or calculated creatinine clearance >= 25 mL/min
(calculated by the Cockcroft and Gault method)

- Cardiac ejection fraction within institutional normal limits, as assessed by
echocardiogram or MUGA scan

- Women of childbearing potential are eligible for this study provided they agree to
one of the following:

- Complete abstinence from intercourse from 2 weeks prior to administration of the
first dose of GW572016 until 28 days after the final dose of GW572016; or

- Consistent and correct use of one of the following acceptable methods of birth

- Male partner who is sterile prior to the female subject's entry into the study
and is the sole sexual partner for that female subject; or

- Implants of levonorgestrel

- Injectable progestogen

- Any intrauterine device (IUD) with a documented failure rate of less than 1% per
year; or

- Oral contraceptives (either combined or progestogen only)

- Barrier methods including diaphragm or condom with a spermicide Should a woman
become pregnant or suspect she is pregnant while participating in this study,
she should inform her treating physician immediately

- Able to swallow and retain oral medications

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L

- Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering
the study or who have unresolved or unstable, serious toxicity from prior
administration of another investigational drug and/or of prior cancer treatment

- Patients may not be receiving any other investigational agents

- Patients may not be receiving concurrent chemotherapy, radiation therapy,
immunotherapy, biologic therapy (including an ErbB1 and/or ErbB2 inhibitor), or
hormonal therapy for treatment of their cancer; concurrent treatment with
bisphosphonates is allowed

- Patients with leptomeningeal carcinomatosis as the only site of CNS involvement will
be excluded from this clinical trial, because disease is not measurable, and standard
treatment options may differ

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to GW572016

- Concurrent treatment with medications that are either inducers or inhibitors of
CYP3A4 is prohibited; some common examples are phenytoin, carbamazepine, and
phenobarbital; if a patient requires an anticonvulsant, valproic acid or
levetiracetam (Keppra) may be substituted, under the direction of his/her treating
physician and/or neurologist

- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel; subjects with active ulcerative colitis are
also excluded

- History of immediate or delayed hypersensitivity reaction to gadolinium contrast
agents, or other contraindication to gadolinium contrast

- Other known contraindication to MRI, such as a cardiac pacemaker, implanted cardiac
defibrillator, brain aneurysm clips, cochlear implant, ocular foreign body, or

- Concurrent disease or condition that would make the subject inappropriate for study
participation, or any serious medical or psychiatric disorder that would interfere
with the subject's safety

- Dementia, altered mental status, or any psychiatric condition that would prohibit the
understanding or rendering of informed consent

- Pre-existing severe cerebral vascular disease, such as stroke involving a major
vessel, CNS vasculitis, or malignant hypertension

- Active cardiac disease, defined as:

- History of uncontrolled or symptomatic angina

- History of arrhythmias requiring medications, or clinically significant, with
the exception of asymptomatic atrial fibrillation requiring anticoagulation

- Myocardial infarction < 6 months from study entry

- Uncontrolled or symptomatic congestive heart failure

- Ejection fraction below the institutional normal limit

- Any other cardiac condition, which in the opinion of the treating physician,
would make this protocol unreasonably hazardous for the patient

- Active or uncontrolled infection

- History of other malignancy, except for curatively treated basal cell carcinoma or
squamous cell carcinoma of the skin, or carcinoma in situ of the cervix; subjects
with other malignancies who have been disease-free for at least 5 years are eligible

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with GW572016

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Objective response rate defined as the percentage of patients with a complete response (CR) or partial response (PR) in the CNS

Outcome Description:

A 95% confidence interval (CI) for percent of patients with CNS response will be calculated if the study does not terminate accrual early. The method of Atkinson and Brown will be used to calculate the CI conditional on the sequential design.

Outcome Time Frame:

Up to 5 years

Safety Issue:


Principal Investigator

Eric Winer

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

October 2004

Completion Date:

Related Keywords:

  • Central Nervous System Metastases
  • HER2-positive Breast Cancer
  • Male Breast Cancer
  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Tumors Metastatic to Brain
  • Breast Neoplasms
  • Neoplasm Metastasis
  • Neoplasms, Second Primary
  • Brain Neoplasms
  • Breast Neoplasms, Male



Dana-Farber Cancer Institute Boston, Massachusetts  02115