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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
N/A
Open (Enrolling)
Female
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


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. 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).

Inclusion Criteria


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

Type of Study:

Interventional

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:

No

Principal Investigator

Karen A. Gelmon, MD

Investigator Role:

Study Chair

Investigator Affiliation:

British Columbia Cancer Agency

Authority:

United States: Food and Drug Administration

Study ID:

MA31

NCT ID:

NCT00667251

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

Name

Location

Advocate Christ Medical CenterOak Lawn, Illinois  60453
Bozeman Deaconess HospitalBozeman, Montana  59715
Denver Health Medical CenterDenver, Colorado  80204-4507
Penrose Cancer CenterColorado Springs, Colorado  80933
Cancer Care CenterNew Albany, Indiana  47150
Arizona Clinical Research CenterTucson, Arizona  85712
University of WashingtonSeattle, Washington  98195
Genesis Cancer CenterHot Springs, Arkansas  71913
South Carolina Oncology AssociatesColumbia, South Carolina  29201
Greenwich Hospital - Bendheim Cancer CenterGreenwich, Connecticut  06830
Saint Joseph Medical Center, Cancer Care ProgramTowson, Maryland  21204
Cascade Cancer CenterKirkland, Washington  98034-3013
Osceola Cancer CenterKissimmee, Florida  34741
Creticos Cancer CenterChicago, Illinois  60657
Florida Cancer InstituteNew Port Richey, Florida  34652
Kaiser PermanentePortland, Oregon  97227
The West ClinicMemphis, Tennessee  38120
Suburban Hematology-OncologySnellville, Georgia  30078-6782
Multicare Health SystemTacoma, Washington  98415
Clinical Trials and Research Associates, Inc.Montebello, California  60460
Hematology Oncology P.C.Stamford, Connecticut  06902-3628
Medical Oncology and HematologyWaterbury, Connecticut  06708
Augusta Oncology Associates, PCAugusta, Georgia  30901
Kootenai Cancer CenterPost Falls, Idaho  83854
Skagit Valley HospitalMt. Vernon, Washington  98273
Summit Cancer CareSavannah, Georgia  31405
Cancer Specialists of Tidewater, Ltd.Chesapeake, Virginia  23320
Cancer Center of Central ConnecticutSouthington, Connecticut  
St. Francis Medical CenterGrand Island, Nebraska  68803
Katmai Oncology AssociatesAnchorage, Alaska  99508
Alta Bates Comprehensive Cancer CentreBerkeley, California  94704
Oncology Association of Bridgeport-Bridgeport-USTrumbull, Connecticut  06611
Oncology and Hematology Associates of Palm BeachLake Worth, Florida  33461
St. Francis Hospital and Health CentresBeech Grove, Indiana  46107
Deaconess Clinic, Inc.Evansville, Indiana  47713
IU Health Goshen Center for Cancer CareGoshen, Indiana  46526
Community Hospital - MunsterMunster, Indiana  46321
Holy Cross Hospital Cancer ResearchSilver Spring, Maryland  20902
Heartland Hematology and OncologyKearney, Nebraska  68845
Platte Valley Medical GroupKearney, Nebraska  68847
Saint Clares Hospital Oncology and HematologyDenville, New Jersey  7834
Saint Clares Health System at Parsippany CommonsParsippany, New Jersey  07054
NY Medical CollegeValhalla, New York  10595
Moses Cone Health System - Regional Cancer CenterGreensboro, North Carolina  27403
Tri-County Hematology and Oncology SpecialistsCanton, Ohio  44718
Lawrence M. Stallings, MD, Ltd.Wooster, Ohio  44691
Blue Ridge Cancer CentreSalem, Virginia  24153
Overlake Internal Medicine AssociatesBellevue, Washington  98004
Olympic Medical Cancer Center Olympic Medical ParkSequim, Washington  98382