Study EGF107671 - a Phase II Study of Lapatinib Plus Topotecan or Lapatinib Plus Capecitabine in the Treatment of Recurrent Brain Metastases From ErbB2-Positive Breast Cancer Following Cranial Radiotherapy

Inclusion Criteria

Inclusion criteria:

Subjects eligible for enrollment in the study must meet all of the following criteria:

- Signed written informed consent;

- Females or males age ≥ 18 years old;

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1;

- Life expectancy of at least 12 weeks;

- Subjects must have histologically or cytologically confirmed invasive breast cancer,
with Stage IV disease;

- ErbB2 overexpressing breast cancer, defined as 3+ staining by immunohistochemistry
(IHC), or 2+ staining by IHC in conjunction with ErbB 2 gene amplification by FISH,
or ErbB 2 gene amplification by FISH alone (in subjects whose tumor blocks were not
assessed by IHC). Subjects with tumors that are 2+ by IHC but negative or borderline
by FISH assay are ineligible. For subjects with a history of more than one primary
breast cancer, each breast cancer must be ErbB2 overexpressing to be eligible;

- ErbB2 overexpressing breast cancer, defined as 3+ staining by immunohistochemistry
(IHC), or 2+ staining by IHC in conjunction with ErbB2 gene amplification by FISH, or
ErbB2 gene amplification by FISH alone (in subjects whose tumor blocks were not
assessed by IHC). ErbB2 gene amplification is defined by: > 6 ErbB2 gene
copies/nucleus for test systems without an internal control probe or an ErbB2/CEP 17
ratio of more than 2.2. Subjects with tumors that are 2+ by IHC but negative or
borderline by FISH assay are ineligible. For subjects with a history of more than
one primary breast cancer, each breast cancer must be ErbB2 overexpressing to be
eligible;

- Prior treatment of brain metastases with WBRT and/or SRS;

- Unequivocal evidence of new and / or progressive lesions in the brain on an imaging
study; Note: Subjects with progressive brain lesions are not required to meet RECIST
criteria for CNS 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;

- Cardiac ejection fraction within institutional range of normal as measured by
echocardiogram. Subjects who require cardiac medications (e.g. positive inotropic
agents or afterload reducers) for normal ejection fraction are ineligible. MUGA scans
will be accepted in cases where an echocardiogram cannot be performed or is
inconclusive;

- 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;

- Able to swallow and retain oral medications;

- Women of childbearing potential must have a negative serum pregnancy test at
screening and must use an approved contraceptive method, if appropriate (for example,
intrauterine device [IUD], birth control pills, or barrier device) beginning 2 weeks
before the first dose of investigational product and for 28 days after the final dose
of investigational product. Males able to father a child must practice adequate
methods of birth control or practice complete abstinence from intercourse from the
first dose of investigational treatment until one week after the final dose of
investigational treatment.

- Subjects must complete all screening assessments as outlined in the protocol;

- Normal organ and marrow function as defined by these LABORATORY VALUES : ANC
(absolute neutrophil count) ≥ 1.5 x 10^9/L; Hemoglobin ≥ 10 g/dL (after transfusion
if needed); Platelets ≥ 100 x 10^9/L; Albumin ≥ 2.5 g/dL; Serum bilirubin ≤ 1.5x ULN
unless due to Gilbert's syndrome; AST and ALT ≤ 5x ULN if documented liver metastases
≤ 3x ULN without liver metastases; Serum Creatinine ≤ 1.2 mg/dL or Calculated
Creatinine Clearance1 ≥ 50 mL/min

Exclusion Criteria:

Subjects meeting any of the following criteria must not be enrolled in the study:

- Subjects 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;

- Concurrent treatment with an investigational agent or participation in another
treatment clinical trial;

- Prior therapy with a topoisomerase 1 inhibitor;

- Prior lapatinib therapy;

- Prior therapy with capecitabine;

- Known dihydropyrimidine dehydrogenase (DPD) deficiency;

- ECOG Performance Status 2 or greater;

- Subjects receiving concurrent chemotherapy, radiation therapy, immunotherapy,
biologic therapy (including an ErbB1 and/or ErbB2 inhibitor), or hormonal therapy for
treatment of their cancer. Hormone therapy for ovarian suppression which has been
used for > 6 months, during which time there has been disease progression in the
brain, is allowed. Concurrent treatment with bisphosphonates is allowed;

- Subjects with evidence of leptomeningeal carcinomatosis at screening;

- History of allergic reactions attributed to compounds of similar chemical composition
(quinazolines) to lapatinib;

- History of allergic reactions attributed to compounds chemically related to
capecitabine, fluorouracil or any excipients;

- Concurrent treatment with medications listed as Prohibited Medications;

- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel. Subjects with active, uncontrolled
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
shrapnel;

- 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;

- Anticoagulant therapy (other than coumadin or aspirin as catheter prophylaxis) at
study entry;

- Dementia, altered mental status, or any psychiatric condition that would prohibit the
understanding or rendering of informed consent, unless a legally acceptable
representative could provide informed consent (if in accord with the policies of the
local Ethics Committee);

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

- Active cardiac disease, defined as one or more of the following:

- History of uncontrolled or symptomatic angina

- History of arrhythmias requiring medications, or clinically significant

- 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;

- Uncontrolled infection;

- Pregnant or lactating females;

- 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.

- Have current active hepatic or biliary disease (with exception of subjects with
Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver
disease per investigator assessment).