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A Randomized, Open-Label, Phase III Study of Taxane Based Chemotherapy With Lapatinib or Trastuzumab as First-Line Therapy for Women With HER2/Neu Positive Metastatic Breast Cancer

Phase 3
18 Years
Open (Enrolling)
Breast Cancer

Thank you

Trial Information

A Randomized, Open-Label, Phase III Study of Taxane Based Chemotherapy With Lapatinib or Trastuzumab as First-Line Therapy for Women With HER2/Neu Positive Metastatic Breast Cancer



- 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®).


- 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. 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

- 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

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

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).

Inclusion Criteria


- 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

- 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


- 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

- 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

- 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

- 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

- 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

- 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


- 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

- 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

Type of Study:


Study Design:

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

Outcome Measure:

Progression-free survival

Outcome Time Frame:

4 years

Safety Issue:


Principal Investigator

Karen A. Gelmon, MD

Investigator Role:

Study Chair

Investigator Affiliation:

British Columbia Cancer Agency


United States: Food and Drug Administration

Study ID:




Start Date:

July 2008

Completion Date:

January 2014

Related Keywords:

  • Breast Cancer
  • stage IV breast cancer
  • recurrent breast cancer
  • HER2-positive breast cancer
  • Breast Neoplasms



Advocate Christ Medical Center Oak Lawn, Illinois  60453
Bozeman Deaconess Hospital Bozeman, Montana  59715
Denver Health Medical Center Denver, Colorado  80204-4507
Penrose Cancer Center Colorado Springs, Colorado  80933
Cancer Care Center New Albany, Indiana  47150
Arizona Clinical Research Center Tucson, Arizona  85712
University of Washington Seattle, Washington  98195
Genesis Cancer Center Hot Springs, Arkansas  71913
South Carolina Oncology Associates Columbia, South Carolina  29201
Greenwich Hospital - Bendheim Cancer Center Greenwich, Connecticut  06830
Saint Joseph Medical Center, Cancer Care Program Towson, Maryland  21204
Cascade Cancer Center Kirkland, Washington  98034-3013
Osceola Cancer Center Kissimmee, Florida  34741
Creticos Cancer Center Chicago, Illinois  60657
Florida Cancer Institute New Port Richey, Florida  34652
Kaiser Permanente Portland, Oregon  97227
The West Clinic Memphis, Tennessee  38120
Suburban Hematology-Oncology Snellville, Georgia  30078-6782
Multicare Health System Tacoma, Washington  98415
Clinical Trials and Research Associates, Inc. Montebello, California  60460
Hematology Oncology P.C. Stamford, Connecticut  06902-3628
Medical Oncology and Hematology Waterbury, Connecticut  06708
Augusta Oncology Associates, PC Augusta, Georgia  30901
Kootenai Cancer Center Post Falls, Idaho  83854
Skagit Valley Hospital Mt. Vernon, Washington  98273
Summit Cancer Care Savannah, Georgia  31405
Cancer Specialists of Tidewater, Ltd. Chesapeake, Virginia  23320
Cancer Center of Central Connecticut Southington, Connecticut  
St. Francis Medical Center Grand Island, Nebraska  68803
Katmai Oncology Associates Anchorage, Alaska  99508
Alta Bates Comprehensive Cancer Centre Berkeley, California  94704
Oncology Association of Bridgeport-Bridgeport-US Trumbull, Connecticut  06611
Oncology and Hematology Associates of Palm Beach Lake Worth, Florida  33461
St. Francis Hospital and Health Centres Beech Grove, Indiana  46107
Deaconess Clinic, Inc. Evansville, Indiana  47713
IU Health Goshen Center for Cancer Care Goshen, Indiana  46526
Community Hospital - Munster Munster, Indiana  46321
Holy Cross Hospital Cancer Research Silver Spring, Maryland  20902
Heartland Hematology and Oncology Kearney, Nebraska  68845
Platte Valley Medical Group Kearney, Nebraska  68847
Saint Clares Hospital Oncology and Hematology Denville, New Jersey  7834
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NY Medical College Valhalla, New York  10595
Moses Cone Health System - Regional Cancer Center Greensboro, North Carolina  27403
Tri-County Hematology and Oncology Specialists Canton, Ohio  44718
Lawrence M. Stallings, MD, Ltd. Wooster, Ohio  44691
Blue Ridge Cancer Centre Salem, Virginia  24153
Overlake Internal Medicine Associates Bellevue, Washington  98004
Olympic Medical Cancer Center Olympic Medical Park Sequim, Washington  98382