Chemotherapy and Lapatinib or Trastuzumab in Treating Women With HER2/Neu-Positive Metastatic Breast Cancer

OBJECTIVES:

Primary

- To compare the progression-free survival of women with HER2/neu-positive metastatic
breast cancer treated with taxane-based chemotherapy in combination with lapatinib
ditosylate or trastuzumab (Herceptin®).

Secondary

- To compare the overall survival.

- To compare the time to CNS metastases at the time of first progression.

- To compare the incidence rates of CNS metastases at the time of progression.

- To compare the overall objective response rate (complete or partial response), time to
response, and duration of response in patients with measurable disease at baseline.

- To compare the clinical benefit response rate.

- To compare the adverse event profile.

- To compare the quality of life.

- To compare clinical outcomes using biomarker changes in biological samples.

- To compare health economics, including healthcare utilization and health utilities.

OUTLINE: This is a multicenter study. Patients are stratified according to prior
neoadjuvant/adjuvant anti-HER2/neu-targeted therapy (yes vs no), prior neoadjuvant/adjuvant
taxane chemotherapy (yes vs no), planned taxane therapy (paclitaxel vs docetaxel), and liver
metastasis (yes vs no). Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive either paclitaxel IV on days 1, 8, and 15; treatment with
paclitaxel repeats every 4 weeks for 6 courses in the absence of disease progression or
unacceptable toxicity. Alternatively, patients may receive docetaxel IV on day 1;
treatment with docetaxel repeats every 3 weeks for 8 courses in the absence of disease
progression or unacceptable toxicity. Patients on docetaxel also receive filgrastim
(G-CSF) according to institutional standard. All patients receive oral lapatinib
ditosylate once daily during taxane treatment and continue after completion of taxane
treatment, in the absence of disease progression or unacceptable toxicity.

- Arm II: Patients receive paclitaxel IV on days 1, 8, and 15 and trastuzumab (Herceptin®)
IV on days 1, 8, 15, and 22. Treatment repeats every 4 weeks for 6 courses in the
absence of disease progression or unacceptable toxicity. Alternatively, patients may
receive docetaxel IV and trastuzumab IV on day 1. Treatment repeats every 3 weeks for 8
courses in the absence of disease progression or unacceptable toxicity. After completion
of taxane chemotherapy and trastuzumab, all patients receive trastuzumab alone IV once
every 3 weeks in the absence of disease progression or unacceptable toxicity.

Formalin-fixed paraffin-embedded tissue samples are analyzed for ER, PgR, EGFR, CK5/6, Ki67,
and other molecular biomarkers by tissue microarray and immunohistochemistry.

Patients complete quality of life questionnaires (EORTC QLQ-C30 and a Trial Specific
Checklist) at baseline, every 12 weeks for 96 weeks, and then every 24 weeks until disease
progression.

After completion of study treatment, patients are followed at 4 weeks post treatment, and
then every 12 weeks thereafter (counting from the beginning of study therapy).

DISEASE CHARACTERISTICS:

- Histologically confirmed adenocarcinoma of the breast

- Metastatic (stage IV) disease at primary diagnosis or at relapse after curative intent
therapy

- Local or central laboratory confirmedHER2/neu* overexpressing and/or amplified disease
in the invasive component of the primary or metastatic lesion as defined by the
following:

- 3+ overexpression (in > 30% of invasive tumor cells) by immunohistochemistry
(IHC)

- 2+ or 3+ overexpression (in ≤ 30% of invasive tumor cells) by IHC AND
demonstrates HER2/neu gene amplification by fluorescence in situ hybridization
(FISH) or chromogenic in situ hybridization (CISH)

- HER2/neu gene amplification by FISH/CISH (> 6 HER2/neu gene copies per nucleus,
or a FISH/CISH ratio [HER2 gene copies to chromosome 17 signals] of ≥ 2.2) NOTE:
*Patients with a negative or equivocal overall result (FISH/CISH ratio of < 2.2,
≤ 6.0 HER2/neu gene copies per nucleus, or staining scores of 0, 1+, 2+, or 3+
[in ≤ 30% of neoplastic cells] by IHC) are not eligible

- Formalin-fixed paraffin-embedded tumor specimen available

- No CNS metastases (including leptomeningeal involvement)

- Hormone receptor status not specified

PATIENT CHARACTERISTICS:

- Menopausal status not specified

- ECOG performance status 0-2

- Life expectancy > 6 months

- Absolute granulocyte count > 1,500/mm³

- Platelet count > 75,000/mm³

- Hemoglobin > 10 g/dL

- Serum creatinine ≤ 2.0 times upper limit of normal (ULN)

- Total bilirubin ≤ 1.5 times ULN (< 3 times ULN for patients with Gilbert's disease)

- AST and/or ALT ≤ 2.5 times ULN (< 5 times ULN for patients planning to receive
paclitaxel-based therapy)

- LVEF ≥ 50% by MUGA or ECHO

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Must be accessible for study treatment and follow-up

- No history of other malignancies, except adequately treated ductal carcinoma in situ
or lobular carcinoma in situ, adequately treated nonmelanoma skin cancer, curatively
treated carcinoma in situ of the cervix, or other curatively treated solid tumor
(non-breast) with no evidence of disease for ≥ 5 years

- No serious cardiac illness or condition including, but not limited to, any of the
following:

- History of documented congestive heart failure

- Systolic dysfunction (LVEF < 50%)

- High-risk uncontrolled arrhythmias (i.e., ventricular tachycardia, high-grade
atrioventricular block, or supraventricular arrhythmias that are not adequately
rate-controlled)

- Unstable angina pectoris requiring anti-anginal medication

- Clinically significant valvular heart disease

- Evidence of transmural infarction on ECG

- Inadequately controlled hypertension (i.e., systolic blood pressure [BP] > 180 mm
Hg or diastolic BP > 100 mm Hg)

- New York Heart Association class III-IV functional status

- No serious illness or medical condition that would not allow the patient to be managed
according to the protocol including, but not limited to, any of the following:

- History of significant neurologic or psychiatric disorder that would impair the
ability to obtain informed consent or limit compliance with study requirements

- Active uncontrolled infection

- Serious or nonhealing wound, ulcer, or bone fracture

- No peripheral neuropathy ≥ grade 2

- No gastrointestinal (GI) tract disease resulting in an inability to take oral
medication including, but not limited to, any of the following:

- Malabsorption syndrome

- Requirement for IV alimentation

- Uncontrolled inflammatory GI disease (e.g., Crohn's disease or ulcerative
colitis)

- No history of allergic or hypersensitivity reactions to any study drug or their
excipients or to compounds with similar chemical composition to any of the study drugs

- Prior allergic reactions to taxanes are allowed provided they were adequately
treated and, according to the treating physician, would not prohibit further
treatment with taxanes

PRIOR CONCURRENT THERAPY:

- Recovered from all prior therapy

- No prior chemotherapy, immunotherapy, biological therapy, or anti-HER2/neu-targeted
therapy for recurrent or metastatic breast cancer

- At least 12 months since prior chemotherapeutic agents, including taxanes, in the
neoadjuvant or adjuvant setting

- At least 12 months since prior anti-HER2/neu-targeted therapy in the neoadjuvant or
adjuvant setting

- Prior treatment with endocrine therapy in the neoadjuvant, adjuvant, or metastatic
setting allowed

- At least 2 weeks since prior radiotherapy in the adjuvant or metastatic setting

- Prior radiotherapy to a solitary metastatic lesion allowed provided there is
documented disease progression after completion of radiotherapy

- More than 30 days (or 5 half-lives) since prior investigational drugs

- At least 7 days since prior and no concurrent CYP3A4 inhibitors (6 months for
amiodarone)

- At least 14 days since prior and no concurrent CYP3A4 inducers

- No prior surgical procedures affecting absorption (e.g., resection of stomach or small
bowel)

- No concurrent palliative radiotherapy

- No other concurrent anticancer treatment

- No other concurrent investigational drugs for breast cancer