Clinical trial NCT00320385: Lapatinib In Combination With Trastuzumab Versus Lapatinib Monotherapy In Subjects With HER2-positive Metastatic Breast Cancer
Official title: A Randomized, Multicenter, Open-Label, Phase III Study of Lapatinib in Combination With Trastuzumab Versus Lapatinib Monotherapy in Subjects With HER2-positive Metastatic Breast Cancer Whose Disease Has Progressed on Trastuzumab-Containing Regimens
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neoplasms, Breast
Keywords: lapatinib
GW572016
ErbB2
EGFR
ErbB1
MBC
FISH amplification
Metastatic Breast Cancer
dual tyrosine kinase inhibitor
Her-2/neu
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2006-05-03
Enrollment: 296
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will evaluate and compare the safety and efficacy of lapatinib in combination with trastuzumab versus lapatinib monotherapy in subjects with HER2-positive metastatic breast cancer.


Eligibility criteria: Inclusion Criteria:

* Signed informed consent.
* Female ≥18 years. Women of childbearing potential must have a negative serum pregnancy test at screening and must use an approved contraceptive method, if appropriate (for example, intrauterine device \[IUD\], birth control pills, or barrier device) beginning 2 weeks before the first dose of investigational product and for 28 days after the final dose of investigational product.
* Metastatic breast cancer, histologically/cytologically confirmed. If the disease is restricted to a solitary lesion, its neoplastic nature must be confirmed by cytology or histology.
* Subjects must have stage IV breast cancer whereby their disease has progressed in either the adjuvant or metastatic setting. Prior therapies must include, but are not limited to:
* Taxane-containing regimen for at least 4 cycles, or 2 cycles provided disease progression occurred while on taxane.
* Anthracycline-containing regimen for at least 4 cycles, or 2 cycles provided disease progression occurred while on anthracycline.
* Subjects must have documented progression following at least ONE trastuzumab plus cytotoxic chemotherapy or anti-hormonal regimen in the metastatic setting.
* Note: The most recent treatment must have contained trastuzumab, either alone or in combination with other therapy in the metastatic setting, and subjects must have progressed while on this regimen. Progression is defined as either new lesions or a ≥20% increase in the sum of longest diameter (LD) on the progression radiologic scan.
* Subjects must have archived tumor tissue available for testing.
* Documented amplification of the ErbB2 gene by fluorescence in situ hybridization (FISH) or documented overexpression of the ErbB2 protein by IHC in primary or metastatic tumor tissue. The IHC or FISH amplification may be documented by a local or central laboratory for randomization into the study. Subjects may be randomized on the basis of ErbB2 positivity by IHC 3+ overexpression or FISH amplification.
* Lesion eligibility is as follows:
* at least one measurable lesion(s) according to Response Evaluation Criteria in Solid Tumors \[RECIST; Therasse, 2000\], or
* bone-only disease.
* Note: Tumor lesions which are situated in a previously irradiated field, and have well-defined margins which are located in soft tissue will be defined as measurable disease.
* Subjects with stable CNS metastases defined as asymptomatic and off systemic steroids and anticonvulsants for at least 1 month. Treatment with prophylactic anticonvulsants is permitted, unless listed within the Prohibited Medications (Section 8.2).
* Radiotherapy if received within 2 weeks prior to initiation of investigational product to a limited area (e.g., palliative treatment for painful disease) other than the sole site of measurable disease is allowed; however, subject must have completed treatment and recovered from all treatment-related toxicities prior to administration of the first dose of investigational product.
* With the single exception of prior trastuzumab treatment, all prior chemotherapy, immunotherapy, biologic therapy, or surgery (except for minor surgical procedures) must be discontinued at least 3 weeks prior to the first dose of investigational product. Subjects must have recovered or stabilized sufficiently from treatment-related toxicities prior to administration of the first dose of investigational product.
* Bisphosphonate therapy for bone metastases is allowed; however, treatment must be initiated prior to the first dose of investigational product. Prophylactic use of bisphosphonates is permitted only for the treatment of osteoporosis.
* ECOG Performance Status of 0 to 2.
* Able to swallow and retain oral medication.
* Cardiac ejection fraction within institutional range of normal as measured by echocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive. Same modality used at baseline must be used for repeat assessments throughout study.
* Subject must have adequate organ function as defined in Table 1 :
* Table 1 (Definitions for Adequate Hematologic and Hepatic Function)
* SYSTEM (LABORATORY VALUES)
* Hematologic:
* ANC (absolute neutrophil count) (≥ 1x10\^9/ L)
* Hemoglobin (≥ 9 g / dL)
* Platelets (≥75x10\^9/ L)
* Hepatic
* Albumin (≥ 2.5 g / dL)
* Serum bilirubin (≤ 2 mg / dL)
* AST and ALT (≤ 3 x ULN without liver metastases) (≤ 5 xULN if documented liver metastases)
* Renal
* Serum Creatinine (≤1.5 mg / dL)
* OR -
* Calculated Creatinine Clearance1 (≥40 mL / min)
* Calculated by the Cockcroft and Gault Method.
* Subjects may continue anti-estrogen therapy only if treatment was initiated at least 1 month prior to the first dose of investigational product (IP). After randomization, no anti-hormonal therapy may be initiated.

Exclusion Criteria:

* Pregnant or lactating females.
* Prior therapy with an ErbB1 and/or ErbB2 inhibitor other than trastuzumab.
* Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded.
* History of other malignancy. However, subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
* Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety.
* Unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment.
* Active or uncontrolled infection.
* Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.
* Known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure.
* Known history or clinical evidence of leptomeningeal carcinomatosis.
* Concurrent cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy).
* Concurrent treatment with an investigational agent or participation in another clinical trial.
* Used an investigational drug within 3 weeks or 5 half-lives, whichever is longer, preceding the first dose of investigational product.
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trastuzumab or lapatinib or their excipients.
* Have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).

Primary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: Baseline to disease progression or death due to any cause or 30 days after last dose (up to 216 weeks)
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Baseline to death or 30 days after last dose for the last participant (up to 216 weeks)
measure: Overall Tumor Response (OR)
timeFrame: Baseline to disease progression or death or discontinuation from study or 30 days after last dose (up to 216 weeks)
measure: Clinical Benefit Response (CBR)
timeFrame: Baseline to disease progression or death or discontinuation from study or 30 days after last dose (up to 216 weeks)
measure: Time to Response (TTR)
timeFrame: Baseline until first documented evidence of CR or PR or 30 days after last dose (up to 216 weeks)
measure: Duration of Response (DR)
timeFrame: Time from first documented evidence of CR or PR until the first documented sign of disease progression or death or 30 days after last dose (up to 216 weeks)
measure: Time to Progression (TTP)
timeFrame: Baseline to disease progression or death or 30 days after last dose (up to 216 weeks)
measure: Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Scores at Week 4, Week 12, Week 16, Week 24, and Conclusion or Withdrawal From Study
timeFrame: Baseline, Week 4, Week 12, Week 16, Week 24, and conclusion or withdrawal from study (up to Week 108)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: GSK Investigational Site
state: Arizona
city: Sedona
country: United States
facility: GSK Investigational Site
state: Arizona
city: Highland
country: United States
facility: GSK Investigational Site
state: California
city: Sacramento
country: United States
facility: GSK Investigational Site
state: California
city: San Diego
country: United States
facility: GSK Investigational Site
state: California
city: San Francisco
country: United States
facility: GSK Investigational Site
state: California
city: Santa Rosa
country: United States
facility: GSK Investigational Site
state: California
city: Vallejo
country: United States
facility: GSK Investigational Site
state: California
city: Newark
country: United States
facility: GSK Investigational Site
state: Delaware
city: Boca Raton
country: United States
facility: GSK Investigational Site
state: Florida
city: Fort Myers
country: United States
facility: GSK Investigational Site
state: Florida
city: Gainesville
country: United States
facility: GSK Investigational Site
state: Florida
city: Hollywood
country: United States
facility: GSK Investigational Site
state: Florida
city: Jacksonville
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Ocala
country: United States
facility: GSK Investigational Site
state: Florida
city: Ocoee
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: West Palm Beach
country: United States
facility: GSK Investigational Site
state: Florida
city: Lawrenceville
country: United States
facility: GSK Investigational Site
state: Georgia
city: Niles
country: United States
facility: GSK Investigational Site
state: Illinois
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: Terre Haute
country: United States
facility: GSK Investigational Site
state: Indiana
city: Cedar Rapids
country: United States
facility: GSK Investigational Site
state: Iowa
city: Kansas City
country: United States
facility: GSK Investigational Site
state: Kansas
city: Overland Park
country: United States
facility: GSK Investigational Site
state: Kansas
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Minneapolis
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Robbinsdale
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Columbia
country: United States
facility: GSK Investigational Site
state: Missouri
city: St. Joseph
country: United States
facility: GSK Investigational Site
state: Missouri
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Montclair
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Morristown
country: United States
facility: GSK Investigational Site
state: New Jersey
city: New Brunswick
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Summit
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Voorhees
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Albany
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Cary
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Charlotte
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Hickory
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Canton
country: United States
facility: GSK Investigational Site
state: Ohio
city: Kettering
country: United States
facility: GSK Investigational Site
state: Ohio
city: Oklahoma City
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Tulsa
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Bryn Mawr
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Hershey
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Kingston
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: West Reading
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Greenville
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Nashville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Arlington
country: United States
facility: GSK Investigational Site
state: Texas
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Beaumont
country: United States
facility: GSK Investigational Site
state: Texas
city: Bedford
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Denton
country: United States
facility: GSK Investigational Site
state: Texas
city: El Paso
country: United States
facility: GSK Investigational Site
state: Texas
city: Fort Worth
country: United States
facility: GSK Investigational Site
state: Texas
city: Fredericksburg
country: United States
facility: GSK Investigational Site
state: Texas
city: Lewisville
country: United States
facility: GSK Investigational Site
state: Texas
city: Longview
country: United States
facility: GSK Investigational Site
state: Texas
city: McAllen
country: United States
facility: GSK Investigational Site
state: Texas
city: Mesquite
country: United States
facility: GSK Investigational Site
state: Texas
city: Midland
country: United States
facility: GSK Investigational Site
state: Texas
city: Odessa
country: United States
facility: GSK Investigational Site
state: Texas
city: Paris
country: United States
facility: GSK Investigational Site
state: Texas
city: Tyler
country: United States
facility: GSK Investigational Site
state: Texas
city: Waco
country: United States
facility: GSK Investigational Site
state: Texas
city: Norfolk
country: United States
facility: GSK Investigational Site
state: Virginia
city: Richmond
country: United States
facility: GSK Investigational Site
state: Virginia
city: Salem
country: United States
facility: GSK Investigational Site
state: Virginia
city: Edmunds
country: United States
facility: GSK Investigational Site
state: Washington
city: Seattle
country: United States
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state: Washington
city: Spokane
country: United States
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state: Washington
city: Vancouver
country: United States
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state: Washington
city: Yakima
country: United States
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state: Washington
city: Green Bay
country: United States
facility: GSK Investigational Site
state: Wisconsin
city: Salzburg
country: Austria
facility: GSK Investigational Site
city: Vienna
country: Austria
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city: Plovdiv
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Laval
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Split
country: Croatia
facility: GSK Investigational Site
city: Zagreb
country: Croatia
facility: GSK Investigational Site
city: Brno
country: Czech Republic
facility: GSK Investigational Site
city: Praha 5
country: Czech Republic
facility: GSK Investigational Site
city: Praha 8
country: Czech Republic
facility: GSK Investigational Site
city: Tampere
country: Finland
facility: GSK Investigational Site
city: Heidelberg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Stuttgart
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Stuttgart
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Augsburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Coburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Fuerstenwalde
country: Germany
facility: GSK Investigational Site
state: Brandenburg
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Leer
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Herne
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Troisdorf
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Velbert
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Saarbruecken
country: Germany
facility: GSK Investigational Site
state: Saarland
city: Halle
country: Germany
facility: GSK Investigational Site
state: Sachsen-Anhalt
city: Magdeburg
country: Germany
facility: GSK Investigational Site
state: Sachsen-Anhalt
city: Kiel
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Neo Faliro
country: Greece
facility: GSK Investigational Site
city: Ravenna
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Rozzano (MI)
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Bari
country: Italy
facility: GSK Investigational Site
state: Puglia
city: Lecce
country: Italy
facility: GSK Investigational Site
state: Puglia
city: Perugia
country: Italy
facility: GSK Investigational Site
state: Umbria
city: Bialystok
country: Poland
facility: GSK Investigational Site
city: Olsztyn
country: Poland
facility: GSK Investigational Site
city: Olsztyn
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Wroclaw
country: Poland
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Hospitalet de Llobregat (Barcelona)
country: Spain
facility: GSK Investigational Site
city: Lerida
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Santa Cruz de Tenerife
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Huddersfield
country: United Kingdom
facility: GSK Investigational Site
city: Ipswich
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Wu Y, Amonkar MM, Sherrill BH, O'Shaughnessy J, Ellis C, Baselga J, Blackwell KL, Burstein HJ. Impact of lapatinib plus trastuzumab versus single-agent lapatinib on quality of life of patients with trastuzumab-refractory HER2+ metastatic breast cancer. Ann Oncol. 2011 Dec;22(12):2582-2590. doi: 10.1093/annonc/mdr014. Epub 2011 Mar 15.
citation: Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, Ellis C, Florance A, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012 Jul 20;30(21):2585-92. doi: 10.1200/JCO.2011.35.6725. Epub 2012 Jun 11.