Lapatinib In Combination With Trastuzumab Versus Lapatinib Monotherapy In Subjects With HER2-positive Metastatic Breast Cancer

Neoplasms, Breast Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00320385
• Other study ID #: EGF104900
• Status: Completed
• Phase: Phase 3
• First received: May 1, 2006
• Last updated: January 28, 2016
• Start date: November 2005
• Est. completion date: October 2010

Study information

• Verified date: April 2015
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 296
• Est. completion date: October 2010
• Est. primary completion date: June 2007
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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).

Study Design

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

Related Conditions & MeSH terms

• Breast Neoplasms
• Neoplasms, Breast

Intervention

Drug:
• Lapatinib
oral lapatinib once daily

Biological:
• Trastuzumab
IV trastuzumab 2mg/kg weekly after 4mg/kg loading dose

Locations

Country	Name	City	State
Austria	GSK Investigational Site	Salzburg
Austria	GSK Investigational Site	Vienna
Bulgaria	GSK Investigational Site	Plovdiv
Bulgaria	GSK Investigational Site	Sofia
Canada	GSK Investigational Site	Laval	Quebec
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Montreal	Quebec
Croatia	GSK Investigational Site	Split
Croatia	GSK Investigational Site	Zagreb
Czech Republic	GSK Investigational Site	Brno
Czech Republic	GSK Investigational Site	Praha 5
Czech Republic	GSK Investigational Site	Praha 8
Finland	GSK Investigational Site	Tampere
Germany	GSK Investigational Site	Augsburg	Bayern
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Coburg	Bayern
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Fuerstenwalde	Brandenburg
Germany	GSK Investigational Site	Halle	Sachsen-Anhalt
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Heidelberg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Herne	Nordrhein-Westfalen
Germany	GSK Investigational Site	Kiel	Schleswig-Holstein
Germany	GSK Investigational Site	Leer	Niedersachsen
Germany	GSK Investigational Site	Magdeburg	Sachsen-Anhalt
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Saarbruecken	Saarland
Germany	GSK Investigational Site	Stuttgart	Baden-Wuerttemberg
Germany	GSK Investigational Site	Stuttgart	Baden-Wuerttemberg
Germany	GSK Investigational Site	Troisdorf	Nordrhein-Westfalen
Germany	GSK Investigational Site	Velbert	Nordrhein-Westfalen
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Neo Faliro
Italy	GSK Investigational Site	Bari	Puglia
Italy	GSK Investigational Site	Lecce	Puglia
Italy	GSK Investigational Site	Perugia	Umbria
Italy	GSK Investigational Site	Ravenna	Emilia-Romagna
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Rozzano (MI)	Lombardia
Poland	GSK Investigational Site	Bialystok
Poland	GSK Investigational Site	Olsztyn
Poland	GSK Investigational Site	Olsztyn
Poland	GSK Investigational Site	Warszawa
Poland	GSK Investigational Site	Wroclaw
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Hospitalet de Llobregat (Barcelona)
Spain	GSK Investigational Site	Lerida
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Santa Cruz de Tenerife
Spain	GSK Investigational Site	Valencia
United Kingdom	GSK Investigational Site	Huddersfield
United Kingdom	GSK Investigational Site	Ipswich
United Kingdom	GSK Investigational Site	London
United States	GSK Investigational Site	Albany	New York
United States	GSK Investigational Site	Arlington	Texas
United States	GSK Investigational Site	Austin	Texas
United States	GSK Investigational Site	Beaumont	Texas
United States	GSK Investigational Site	Bedford	Texas
United States	GSK Investigational Site	Boca Raton	Florida
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Bryn Mawr	Pennsylvania
United States	GSK Investigational Site	Canton	Ohio
United States	GSK Investigational Site	Cary	North Carolina
United States	GSK Investigational Site	Cedar Rapids	Iowa
United States	GSK Investigational Site	Charlotte	North Carolina
United States	GSK Investigational Site	Columbia	Missouri
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Denton	Texas
United States	GSK Investigational Site	Durham	North Carolina
United States	GSK Investigational Site	Edmunds	Washington
United States	GSK Investigational Site	El Paso	Texas
United States	GSK Investigational Site	Fort Myers	Florida
United States	GSK Investigational Site	Fort Worth	Texas
United States	GSK Investigational Site	Fredericksburg	Texas
United States	GSK Investigational Site	Gainesville	Florida
United States	GSK Investigational Site	Green Bay	Wisconsin
United States	GSK Investigational Site	Greenville	South Carolina
United States	GSK Investigational Site	Hershey	Pennsylvania
United States	GSK Investigational Site	Hickory	North Carolina
United States	GSK Investigational Site	Highland	California
United States	GSK Investigational Site	Hollywood	Florida
United States	GSK Investigational Site	Indianapolis	Indiana
United States	GSK Investigational Site	Indianapolis	Indiana
United States	GSK Investigational Site	Jacksonville	Florida
United States	GSK Investigational Site	Kansas City	Kansas
United States	GSK Investigational Site	Kettering	Ohio
United States	GSK Investigational Site	Kingston	Pennsylvania
United States	GSK Investigational Site	Las Vegas	Nevada
United States	GSK Investigational Site	Las Vegas	Nevada
United States	GSK Investigational Site	Lawrenceville	Georgia
United States	GSK Investigational Site	Lewisville	Texas
United States	GSK Investigational Site	Longview	Texas
United States	GSK Investigational Site	McAllen	Texas
United States	GSK Investigational Site	Mesquite	Texas
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	Midland	Texas
United States	GSK Investigational Site	Minneapolis	Minnesota
United States	GSK Investigational Site	Montclair	New Jersey
United States	GSK Investigational Site	Morristown	New Jersey
United States	GSK Investigational Site	Nashville	Tennessee
United States	GSK Investigational Site	New Brunswick	New Jersey
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Newark	Delaware
United States	GSK Investigational Site	Niles	Illinois
United States	GSK Investigational Site	Norfolk	Virginia
United States	GSK Investigational Site	Ocala	Florida
United States	GSK Investigational Site	Ocoee	Florida
United States	GSK Investigational Site	Odessa	Texas
United States	GSK Investigational Site	Oklahoma City	Oklahoma
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Overland Park	Kansas
United States	GSK Investigational Site	Paris	Texas
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Phoenix	Arizona
United States	GSK Investigational Site	Pittsburgh	Pennsylvania
United States	GSK Investigational Site	Richmond	Virginia
United States	GSK Investigational Site	Robbinsdale	Minnesota
United States	GSK Investigational Site	Sacramento	California
United States	GSK Investigational Site	Salem	Virginia
United States	GSK Investigational Site	San Diego	California
United States	GSK Investigational Site	San Francisco	California
United States	GSK Investigational Site	Santa Rosa	California
United States	GSK Investigational Site	Seattle	Washington
United States	GSK Investigational Site	Sedona	Arizona
United States	GSK Investigational Site	Spokane	Washington
United States	GSK Investigational Site	St. Joseph	Missouri
United States	GSK Investigational Site	Summit	New Jersey
United States	GSK Investigational Site	Terre Haute	Indiana
United States	GSK Investigational Site	Tulsa	Oklahoma
United States	GSK Investigational Site	Tyler	Texas
United States	GSK Investigational Site	Vallejo	California
United States	GSK Investigational Site	Vancouver	Washington
United States	GSK Investigational Site	Voorhees	New Jersey
United States	GSK Investigational Site	Waco	Texas
United States	GSK Investigational Site	West Palm Beach	Florida
United States	GSK Investigational Site	West Reading	Pennsylvania
United States	GSK Investigational Site	Yakima	Washington

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Austria,  Bulgaria,  Canada,  Croatia,  Czech Republic,  Finland,  Germany,  Greece,  Italy,  Poland,  Spain,  United Kingdom, 

References & Publications (2)

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. — View 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):2582-90. doi: 10.1093/annonc/mdr014. Epub 2011 Mar 15. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-Free Survival (PFS)	PFS was defined as the time from randomization until the first documented sign of disease progression or death due to any cause.	Baseline to disease progression or death due to any cause or 30 days after last dose (up to 216 weeks)	No
Secondary	Overall Survival (OS)	OS was defined as the time from randomization until death due to any cause. For participants who did not die, OS was censored at the time of last contact.	Baseline to death or 30 days after last dose for the last participant (up to 216 weeks)	No
Secondary	Overall Tumor Response (OR)	OR was defined as the percentage of participants experiencing either a confirmed complete response (CR) or a confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.0. CR was defined as the disappearance of all lesions (target and/or non-target). PR was defined as at least a 30% decrease in the sum of the longest dimensions (LD) of target lesions taking as a reference the baseline sum LD, with non-target lesions not increased or absent.	Baseline to disease progression or death or discontinuation from study or 30 days after last dose (up to 216 weeks)	No
Secondary	Clinical Benefit Response (CBR)	CBR: percentage of participants with confirmed CR or PR or stable disease (SD) for at least 24 weeks according to RECIST criteria. CR: disappearance of all lesions (target and/or non-target). PR: at least a 30% decrease in the sum of the LD of target lesions taking as reference baseline sum LD, with non-target lesions not increased or absent. SD: neither had sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) in target lesions, taking as reference the smallest sum LD since treatment started; persistence of 1 or more non-target lesions.	Baseline to disease progression or death or discontinuation from study or 30 days after last dose (up to 216 weeks)	No
Secondary	Time to Response (TTR)	TTR was defined as the time from randomization until the first documented evidence of CR or PR (whichever status was recorded first). TTR could not be analyzed because too few participants experienced a confirmed CR or PR.	Baseline until first documented evidence of CR or PR or 30 days after last dose (up to 216 weeks)	No
Secondary	Duration of Response (DR)	DR was defined for the subset of participants who showed a confirmed CR or PR, as the time from the first documented evidence of CR or PR until the first documented sign of disease progression or death. Because of the low number of participants experiencing a confirmed response in both treatment arms, analysis for this outcome measure was not performed.	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)	No
Secondary	Time to Progression (TTP)	TTP was defined as the interval between the date of randomization and the earlier of the date of disease progression or death due to breast cancer. Because this outcome measure was confounded by death due to other causes and was similar to PFS, it was not analyzed.	Baseline to disease progression or death or 30 days after last dose (up to 216 weeks)	No
Secondary	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	Quality of Life (QOL) was assessed using the FACT-B questionnaire, which was a 37-item (27 general and 10 breast cancer-specific questions) self-reporting instrument consisting of 5 dimensions: physical-, social/family-, emotional-, functional-well being, and a breast cancer subscale. Higher scores on the FACT-B scales indicate a higher QOL; each ranging from 0 (not at all) to 4 (very much). The score is transformed for FACT-B and results in a total score ranging from 0 to 144.	Baseline, Week 4, Week 12, Week 16, Week 24, and conclusion or withdrawal from study (up to Week 108)	No