Breast Cancer Clinical Trial
Chemotherapy and Lapatinib or Trastuzumab in Treating Women With HER2/Neu-Positive Metastatic Breast Cancer
Summary
RATIONALE: HER2/neu is a receptor (protein) which is found in unusually high amounts in approximately 1 in 5 cancer patients. Scientific evidence suggests that having high amounts of the HER2/neu receptor is important for breast cancer to grow and spread. Women with previously untreated metastatic breast cancer (breast cancer that has spread to other organs) and with high levels of the HER2/neu receptor receive as their usual treatment chemotherapy with one of the approved chemotherapy drugs paclitaxel or docetaxel (called "taxanes") together with another approved drug called "trastuzumab". Chemotherapy drugs, such as paclitaxel and docetaxel, work either by killing tumour cells or by stopping them from dividing. Trastuzumab is an antibody that is given through a vein in the arm and it works by specifically "targeting" the HER2/neu i.e. it attaches to it and "turns it off". Although some of the patients who receive this taxane plus trastuzumab treatment feel better for some months, the cancer usually starts to grow again. Lapatinib is a new drug. Like trastuzumab, it also works by specifically "targeting" the HER2/neu receptor, but it does so in a different way. Lapatinib is not an antibody. It is a pill that is taken daily by mouth. Because lapatinib works in a different way than trastuzumab, it may be worse, as good as or better than trastuzumab in keeping metastatic HER/neu positive cancer from growing. However, this is not known.
Purpose: This randomized Phase III trial is comparing chemotherapy (a taxane) given together with lapatinib with chemotherapy (a taxane) given together with trastuzumab in women with HER2/neu positive breast cancer.
Full Description
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).
Eligibility 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
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There are 254 Locations for this study
Anchorage Alaska, 99508, United States
Tucson Arizona, 85715, United States
Hot Springs Arkansas, 71913, United States
Berkeley California, 94704, United States
Highland California, 92346, United States
Montebello California, 90640, United States
Colorado Springs Colorado, 80907, United States
Denver Colorado, 80204, United States
Greenwich Connecticut, 06830, United States
Southington Connecticut, 06489, United States
Stamford Connecticut, 06902, United States
Trumbull Connecticut, 06611, United States
Waterbury Connecticut, 06708, United States
Kissimmee Florida, 34741, United States
Loxahatchee Groves Florida, 33470, United States
New Port Richey Florida, 34655, United States
Augusta Georgia, 30901, United States
Lawrenceville Georgia, 30046, United States
Savannah Georgia, 31405, United States
Post Falls Idaho, 83854, United States
Chicago Illinois, 60657, United States
Oak Lawn Illinois, 60453, United States
Evansville Indiana, 47713, United States
Goshen Indiana, 46526, United States
Indianapolis Indiana, 46237, United States
Munster Indiana, 46321, United States
New Albany Indiana, 47150, United States
Towson Maryland, 21204, United States
Wheaton Maryland, 20902, United States
Bozeman Montana, 59715, United States
Grand Island Nebraska, 68803, United States
Kearney Nebraska, 68845, United States
Kearney Nebraska, 68847, United States
Denville New Jersey, 07834, United States
Parsippany New Jersey, 07054, United States
Cooperstown New York, 13326, United States
Greensboro North Carolina, 27403, United States
Canton Ohio, 44718, United States
Wooster Ohio, 44691, United States
Portland Oregon, 97227, United States
Pittsburgh Pennsylvania, 15212, United States
Columbia South Carolina, 29210, United States
Memphis Tennessee, 38120, United States
Chesapeake Virginia, 23320, United States
Salem Virginia, 24153, United States
Bellevue Washington, 98004, United States
Kirkland Washington, 98034, United States
Mount Vernon Washington, 98273, United States
Seattle Washington, 98109, United States
Sequim Washington, 98382, United States
Tacoma Washington, 98405, United States
Wenatchee Washington, 98801, United States
Milwaukee Wisconsin, 53226, United States
Capital Federal Buenos Aires, C1405, Argentina
Capital Federal Buenos Aires, C1426, Argentina
Ciudad Autonoma de Buenos Aires Buenos Aires, C1280, Argentina
La Plata Buenos Aires, B1920, Argentina
Cipolletti RÃo Negro, R8324, Argentina
Viedma RÃo Negro, R8500, Argentina
Rosario Santa Fe, S2000, Argentina
Santa Fe , 3000, Argentina
Tucuman , 4000, Argentina
Garran Australian Capital Territory, 2606, Australia
Liverpool New South Wales, 2170, Australia
North Sydney New South Wales, 2060, Australia
Tweed Heads New South Wales, 2485, Australia
Woolloongabba Queensland, 4102, Australia
Adelaide South Australia, 5000, Australia
Bedford Park South Australia, 5042, Australia
Kurralta Park South Australia, 5037, Australia
Hobart Tasmania, 7000, Australia
Box Hill Victoria, 3128, Australia
Fitzroy Victoria, 3065, Australia
Wodonga Victoria, 3690, Australia
Subiaco Western Australia, 6008, Australia
Gent , 9000, Belgium
Jette , 1090, Belgium
Liege , 4000, Belgium
Namur , 5000, Belgium
Edmonton Alberta, T6G 1, Canada
Kelowna British Columbia, V1Y 5, Canada
Surrey British Columbia, V3V 1, Canada
Vancouver British Columbia, V5Z 4, Canada
Victoria British Columbia, V8R 6, Canada
Winnipeg Manitoba, R3E 0, Canada
Moncton New Brunswick, E1C 6, Canada
Saint John New Brunswick, E2L 4, Canada
Barrie Ontario, L4M 6, Canada
Hamilton Ontario, L8V 5, Canada
Kingston Ontario, K7L 5, Canada
London Ontario, N6A 4, Canada
Newmarket Ontario, L3Y 2, Canada
Ottawa Ontario, K1H 8, Canada
Sault Ste. Marie Ontario, P6B 0, Canada
St Catharines Ontario, L2R 7, Canada
Sudbury Ontario, P3E 5, Canada
Thunder Bay Ontario, P7B 6, Canada
Charlottetown Prince Edward Island, C1A 8, Canada
Montreal Quebec, H1T 2, Canada
Montreal Quebec, H2L 4, Canada
Montreal Quebec, H2W 1, Canada
Regina Saskatchewan, S4T 7, Canada
Saskatoon Saskatchewan, S7N 4, Canada
Quebec , G1S 4, Canada
Angers , 49033, France
Bordeaux , 33075, France
Bordeaux , 33077, France
Caen Cedex 05 , 14076, France
Marseille cedex 9 , 13273, France
Metz-Tessy , 74370, France
Nantes cedex , 44202, France
Paris , 75014, France
Strasbourg , 67085, France
Heidelberg Baden-Wuerttemberg, 69115, Germany
Stuttgart Baden-Wuerttemberg, 70190, Germany
Coburg Bayern, 96450, Germany
Eggenfelden Bayern, 84307, Germany
Fuerth Bayern, 90766, Germany
Regensburg Bayern, 93049, Germany
Rosenheim Bayern, 83022, Germany
Weiden Bayern, 92637, Germany
Fuerstenwalde Brandenburg, 15517, Germany
Frankfurt Hessen, 60596, Germany
Fulda Hessen, 36043, Germany
Lich Hessen, 35423, Germany
Goslar Niedersachsen, 38642, Germany
Hannover Niedersachsen, 30559, Germany
Leer Niedersachsen, 26789, Germany
Bielefeld Nordrhein-Westfalen, 33611, Germany
Bonn Nordrhein-Westfalen, 53113, Germany
Coesfeld Nordrhein-Westfalen, 48653, Germany
Essen Nordrhein-Westfalen, 45122, Germany
Koeln Nordrhein-Westfalen, 51067, Germany
Porta Westfalica Nordrhein-Westfalen, 32457, Germany
Troisdorf Nordrhein-Westfalen, 53840, Germany
Velbert Nordrhein-Westfalen, 42551, Germany
Witten Nordrhein-Westfalen, 58452, Germany
Koblenz Rheinland-Pfalz, 56068, Germany
Saarbruecken Saarland, 66113, Germany
Halle Sachsen-Anhalt, 06120, Germany
Dresden Sachsen, 01127, Germany
Luebeck Schleswig-Holstein, 23538, Germany
Berlin , 10117, Germany
Berlin , 10367, Germany
Brandenburg , 14770, Germany
Hamburg , 20095, Germany
Hamburg , 22081, Germany
Hamburg , 22767, Germany
Bangalore , 56003, India
Nagpur , 44001, India
Pune , 41100, India
Beer-Sheva , 84101, Israel
Holon , 58100, Israel
Petah-Tikva , 49100, Israel
Poriya , 15208, Israel
Ramat Gan , 52621, Israel
Aviano (pn) Friuli-Venezia-Giulia, 33081, Italy
Roma Lazio, 00189, Italy
Sora (FR) Lazio, 03039, Italy
Genova Liguria, 16132, Italy
Lecce Puglia, 73100, Italy
Sassari Sardegna, 07100, Italy
Prato (PO) Toscana, 59100, Italy
Chieti , 66100, Italy
Aichi , 464-8, Japan
Chiba , 277-8, Japan
Ehime , 791-0, Japan
Kagoshima , 892-0, Japan
Kanagawa , 241-8, Japan
Osaka , 540-0, Japan
Osaka , 565-0, Japan
Saitama , 350-1, Japan
Saitama , 362-0, Japan
Shizuoka , 411-8, Japan
Tokyo , 104-8, Japan
Tokyo , 113-8, Japan
Gyeonggi-do , 10408, Korea, Republic of
Gyeonggi-do , 410-7, Korea, Republic of
Seoul , 03722, Korea, Republic of
Seoul , 110-7, Korea, Republic of
Seoul , 120-7, Korea, Republic of
Songpa-gu, Seoul , 138-7, Korea, Republic of
Cuernavaca Morelos, 62450, Mexico
Ciudad Obregon Sonora, 85000, Mexico
Mexico City , CP 14, Mexico
Amsterdam , 1091 , Netherlands
Delft , 2625 , Netherlands
Dordrecht , 3318 , Netherlands
Maastricht , 6229 , Netherlands
Gdansk , 80-21, Poland
Lodz , 93-50, Poland
Olsztyn , 10-22, Poland
Olsztyn , 10-51, Poland
Plock , 09-40, Poland
Rzeszow , 35-02, Poland
Warszawa , 02-78, Poland
Warszawa , 04-12, Poland
Arkhangelsk , 16304, Russian Federation
Ivanovo , 15301, Russian Federation
Kazan , 42002, Russian Federation
Kirov , 61002, Russian Federation
Lipetsk , 39800, Russian Federation
Moscow , 115 4, Russian Federation
Ryazan , 39001, Russian Federation
St. Petersburg , 19702, Russian Federation
St. Petersburg , 19775, Russian Federation
Stavropol , 35504, Russian Federation
Ufa, , 45005, Russian Federation
Ufa , 45005, Russian Federation
Alcorcon , 28922, Spain
Alicante , 03010, Spain
Badalona , 08916, Spain
Barcelona , 08036, Spain
Elche , 03202, Spain
Girona , 17007, Spain
Jaen , 23007, Spain
La Coruna , 15009, Spain
Lugo , 27003, Spain
Madrid , 28007, Spain
Madrid , 28034, Spain
Madrid , 28040, Spain
Majadahonda (Madrid) , 28222, Spain
Pozuelo De Alarcon (Madrid) , 28223, Spain
Sevilla , 41013, Spain
Valencia , 46009, Spain
Changhua , 500, Taiwan
Taichung , 404, Taiwan
Tainan County , 736, Taiwan
Taipei , 100, Taiwan
Taipei , 112, Taiwan
Bangkok , 10700, Thailand
Chiangmai , 50200, Thailand
Dnepropetrovsk , 49102, Ukraine
Dnipropetrovsk , 49100, Ukraine
Lviv , 79031, Ukraine
Sumy , 40005, Ukraine
Bournemouth , BH7 7, United Kingdom
Brighton , BN2 5, United Kingdom
Chelmsford , CM1 7, United Kingdom
Cheltenham , GL53 , United Kingdom
Colchester , CO3 3, United Kingdom
Cottingham, Hull , HU16 , United Kingdom
Derby , DE22 , United Kingdom
Edmonton , N18 1, United Kingdom
Guildford , GU2 7, United Kingdom
Harrogate , HG2 7, United Kingdom
Huddersfield , HD3 3, United Kingdom
London , SW3 6, United Kingdom
Newcastle upon Tyne , NE7 7, United Kingdom
Norwich , NR4 7, United Kingdom
Nottingham , NG5 1, United Kingdom
Oxford , OX3 7, United Kingdom
Poole, Dorset , BH15 , United Kingdom
Sheffield , S10 2, United Kingdom
Shrewsbury , SY3 8, United Kingdom
Sutton , SM2 5, United Kingdom
Whitchurch, Cardiff , CF14 , United Kingdom
York , YO31 , United Kingdom
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