Gemcitabine/ Trastuzumab and Gemcitabine/ Cisplatin/ Trastuzumab in Patients With Metastatic Breast Cancer

Rationale: Previous studies have demonstrated the anti-tumor efficacy of gemcitabine and
trastuzumab against metastatic breast cancer when given alone and in combination. Yet,
research indicates that the two drugs given together work more effectively than either alone.
Laboratory studies testing the combination of trastuzumab and cisplatin have shown
synergistic anti-tumor activity with the two drugs. In addition, clinical studies suggest a
high level of anti-tumor activity with the combination of gemcitabine and cisplatin.
Researchers are testing the triple drug combination of gemcitabine, trastuzumab, and
cisplatin in the current study to evaluate the potential for enhanced responsiveness in
patients with Her-2/neu overexpressing breast cancer as well as comparing it to the double
drug combination of gemcitabine and trastuzumab.

Purpose: This study will measure patient responses and compare the efficacy of a double drug
combination (gemcitabine and trastuzumab) with a triple drug combination (gemcitabine,
trastuzumab, and cisplatin) in patients with metastatic breast cancer. Side effects will be
carefully assessed in patients.

Treatment: Patients in this study will receive one of two treatment combinations. A computer
will randomly assign patients to a treatment group. Group one will be given gemcitabine and
trastuzumab. Gemcitabine will be given to patients on days 1 and 8, and trastuzumab on days
1, 8, and 15. Group two will receive gemcitabine, trastuzumab, and cisplatin. Gemcitabine and
cisplatin will both be administered on days 1 and 8, and trastuzumab on days 1, 8, and 15.
Each treatment cycle (for both groups) will last a total of 21 days. All study drugs will be
administered through intravenous infusions. Several tests and exams will be given throughout
the study to closely monitor patients. Thorough patient exams will be given at the beginning
of each treatment cycle. Imaging tests will be done every two cycles for the first eight
cycles and then every three cycles until study completion. Study treatment will be
discontinued due to disease growth or unacceptable side effects.

Eligibility Criteria:

- Must have invasive metastatic breast cancer

- Tumor must be Her 2/neu 3+ by IHC (must be confirmed by Ohio State University
pathology)or positive FISH

- Histological confirmation of invasive breast cancer either from the original diagnosis
and/or diagnosis of metastatic disease.

- Tumor must be detectable clinically or radiographically (a positive bone scan is
allowed as the only site of disease). Unidimensional measurements must be obtained
whenever possible). Bone marrow only disease is not eligible for enrollment on this
study.

- No evidence of congestive heart failure, symptoms of coronary artery disease, serious
cardiac arrhythmias, or evidence of prior myocardial infarction on EKG or ECHO.
Patients must have normal LV function and LVEF(left ventricular ejection fraction)>
50% as demonstrated by either echo or muga within the proceeding 4 weeks.

- Must have adequate renal and hepatic function documented by a serum creatinine < 1.5 x
the institutional upper limit of normal (ULN), serum bilirubin <1.5 x ULN and liver
enzymes (AST, ALT, or alkaline phosphatase) < 2 x ULN (< 5 x ULN if hepatic
metastasis) within 21 days prior to registration.

- Patients must have an ANC (absolute neutrophil count) > 1.5, platelets > 100,000,
Hemoglobin >9.0 within 21 days of registration.

- If patients are on bisphosphonates at the time of registration, with a stable
creatinine over the preceding 2 months, then they may continue bisphosphonates during
the study.

- No more than one prior Trastuzumab/chemotherapy or Trastuzumab/biotherapy combination
for metastatic disease. Additional Trastuzumab therapy may have been given in the
adjuvant setting. Prior hormonal therapy is allowed for either adjuvant or metastatic
disease.

- Must be >3 weeks since administration of last chemotherapy prior to initiation of
treatment on this trial. Prior trastuzumab may have been administered within one week
of initiation of treatment on this trial if the last dose was 2 mg/kg. Any prior
trastuzumab dosing greater than 2 mg/kg requires a 3 week washout period.

- Patients may have received prior cisplatin or carboplatin for metastatic disease.

- No CNS(central nervous system)metastasis disease.

- No active infection at time of registration.

- Pregnant or nursing women may not participate in trial.

- Patients must be informed of the investigational nature of this study and sign and
give written informed consent in accordance with institutional and federal guidelines.

- ECOG (Eastern Cooperative Oncology Group)performance status < 2 at the time of
registration.

- Patients may participate in a non-treatment related protocol while participating in
this study.

- No other active malignancy is allowed. Adequately treated basal cell, squamous cell
skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from
which the patient is currently in complete remission, or any other cancer from which
the patient has been disease-free for 5 years is allowed.