Brain Metastases In ErbB2-Positive Breast Cancer

Neoplasms, Breast Clinical Trial

Official title:

Study EGF107671 - a Phase II Study of Lapatinib Plus Topotecan or Lapatinib Plus Capecitabine in the Treatment of Recurrent Brain Metastases From ErbB2-Positive Breast Cancer Following Cranial Radiotherapy

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00437073
• Other study ID #: 107671
• Status: Terminated
• Phase: Phase 2
• First received: February 15, 2007
• Last updated: September 24, 2015
• Start date: May 2007
• Est. completion date: February 2010

Study information

• Verified date: October 2012
• 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 is for patients with ErbB2 overexpressing breast cancer that has spread to the brain and is still progressing there even after radiation treatment using WBRT (whole brain radiotherapy) or SRS (stereotactic radiosurgery) to the brain. The study will determine how safe and effective lapatinib is when given in combination with capecitabine to treat patients with ErbB2 overexpressing breast cancer that has spread to the brain. Lapatinib is an oral drug that will be taken every day. Tests for safety and efficacy will be performed regularly during the course of the study.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 22
• Est. completion date: February 2010
• Est. primary completion date: January 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

Subjects eligible for enrollment in the study must meet all of the following criteria:

• Signed written informed consent;

• Females or males age = 18 years old;

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1;

• Life expectancy of at least 12 weeks;

• Subjects must have histologically or cytologically confirmed invasive breast cancer, with Stage IV disease;

• ErbB2 overexpressing breast cancer, defined as 3+ staining by immunohistochemistry (IHC), or 2+ staining by IHC in conjunction with ErbB 2 gene amplification by FISH, or ErbB 2 gene amplification by FISH alone (in subjects whose tumor blocks were not assessed by IHC). Subjects with tumors that are 2+ by IHC but negative or borderline by FISH assay are ineligible. For subjects with a history of more than one primary breast cancer, each breast cancer must be ErbB2 overexpressing to be eligible;

• ErbB2 overexpressing breast cancer, defined as 3+ staining by immunohistochemistry (IHC), or 2+ staining by IHC in conjunction with ErbB2 gene amplification by FISH, or ErbB2 gene amplification by FISH alone (in subjects whose tumor blocks were not assessed by IHC). ErbB2 gene amplification is defined by: > 6 ErbB2 gene copies/nucleus for test systems without an internal control probe or an ErbB2/CEP 17 ratio of more than 2.2. Subjects with tumors that are 2+ by IHC but negative or borderline by FISH assay are ineligible. For subjects with a history of more than one primary breast cancer, each breast cancer must be ErbB2 overexpressing to be eligible;

• Prior treatment of brain metastases with WBRT and/or SRS;

• Unequivocal evidence of new and / or progressive lesions in the brain on an imaging study; Note: Subjects with progressive brain lesions are not required to meet RECIST criteria for CNS progression in order to be eligible for this study.

• Prior treatment with trastuzumab, either alone or in combination with chemotherapy is required. Trastuzumab will be discontinued at least 2 weeks prior to enrollment on study;

• Cardiac ejection fraction within institutional range of normal as measured by echocardiogram. Subjects who require cardiac medications (e.g. positive inotropic agents or afterload reducers) for normal ejection fraction are ineligible. MUGA scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive;

• At least 2 weeks since prior radiotherapy, last chemotherapy, immunotherapy, biologic therapy, or hormonal therapy for cancer, and sufficiently recovered or stabilized from side effects associated with prior therapy. Concurrent treatment with bisphosphonates is permitted;

• At least 3 weeks since major surgical procedures;

• Able to swallow and retain oral medications;

• 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. Males able to father a child must practice adequate methods of birth control or practice complete abstinence from intercourse from the first dose of investigational treatment until one week after the final dose of investigational treatment.

• Subjects must complete all screening assessments as outlined in the protocol;

• Normal organ and marrow function as defined by these LABORATORY VALUES : ANC (absolute neutrophil count) = 1.5 x 10^9/L; Hemoglobin = 10 g/dL (after transfusion if needed); Platelets = 100 x 10^9/L; Albumin = 2.5 g/dL; Serum bilirubin = 1.5x ULN unless due to Gilbert's syndrome; AST and ALT = 5x ULN if documented liver metastases = 3x ULN without liver metastases; Serum Creatinine = 1.2 mg/dL or Calculated Creatinine Clearance1 = 50 mL/min

Exclusion Criteria:

Subjects meeting any of the following criteria must not be enrolled in the study:

• Subjects who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or who have unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment;

• Concurrent treatment with an investigational agent or participation in another treatment clinical trial;

• Prior therapy with a topoisomerase 1 inhibitor;

• Prior lapatinib therapy;

• Prior therapy with capecitabine;

• Known dihydropyrimidine dehydrogenase (DPD) deficiency;

• ECOG Performance Status 2 or greater;

• Subjects receiving concurrent chemotherapy, radiation therapy, immunotherapy, biologic therapy (including an ErbB1 and/or ErbB2 inhibitor), or hormonal therapy for treatment of their cancer. Hormone therapy for ovarian suppression which has been used for > 6 months, during which time there has been disease progression in the brain, is allowed. Concurrent treatment with bisphosphonates is allowed;

• Subjects with evidence of leptomeningeal carcinomatosis at screening;

• History of allergic reactions attributed to compounds of similar chemical composition (quinazolines) to lapatinib;

• History of allergic reactions attributed to compounds chemically related to capecitabine, fluorouracil or any excipients;

• Concurrent treatment with medications listed as Prohibited Medications;

• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with active, uncontrolled ulcerative colitis are also excluded;

• History of immediate or delayed hypersensitivity reaction to gadolinium contrast agents, or other contraindication to gadolinium contrast;

• Other known contraindication to MRI, such as a cardiac pacemaker, implanted cardiac defibrillator, brain aneurysm clips, cochlear implant, ocular foreign body, or shrapnel;

• Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical or psychiatric disorder that would interfere with the subject's safety;

• Anticoagulant therapy (other than coumadin or aspirin as catheter prophylaxis) at study entry;

• Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent, unless a legally acceptable representative could provide informed consent (if in accord with the policies of the local Ethics Committee);

• Pre-existing severe cerebral vascular disease, such as stroke involving a major vessel, CNS vasculitis, or malignant hypertension;

• Active cardiac disease, defined as one or more of the following:

• History of uncontrolled or symptomatic angina

• History of arrhythmias requiring medications, or clinically significant

• Myocardial infarction < 6 months from study entry

• Uncontrolled or symptomatic congestive heart failure

• Ejection fraction below the institutional normal limit

• Any other cardiac condition, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient;

• Uncontrolled infection;

• Pregnant or lactating females;

• History of other malignancy, except for curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix. Subjects with other malignancies who have been disease-free for at least 5 years are eligible.

• Have current active hepatic or biliary disease (with exception of subjects with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).

Study Design

Allocation: Non-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:
• capecitabine
capecitabine 2000mg/m2/day orally, Days 1-14, every 21 days
• topotecan
topotecan intravenous (IV, in the vien) 3.2mg/m2 Days 1, 8 and 15; every 28 days
• lapatinib
lapatinib administered 1250mg once daily orally

Locations

Country	Name	City	State
Austria	GSK Investigational Site	Salzburg
Austria	GSK Investigational Site	Vienna
Belgium	GSK Investigational Site	Bruxelles
Canada	GSK Investigational Site	Edmonton	Alberta
Canada	GSK Investigational Site	Quebec
Canada	GSK Investigational Site	Vancouver	British Columbia
France	GSK Investigational Site	Besançon
France	GSK Investigational Site	Lille Cedex
France	GSK Investigational Site	Paris
France	GSK Investigational Site	Paris Cedex 5
France	GSK Investigational Site	Saint-Herblain
Germany	GSK Investigational Site	Bremen
Germany	GSK Investigational Site	Frankfurt am Main	Hessen
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Troisdorf	Nordrhein-Westfalen
Greece	GSK Investigational Site	Heraklion, Crete
Greece	GSK Investigational Site	Neo Faliro
Israel	GSK Investigational Site	Petach Tikva
Israel	GSK Investigational Site	Ramat Gan
Israel	GSK Investigational Site	Zrifin
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Perugia	Umbria
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Hospitalet de Llobregat, Barcelona
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Pamplona
Spain	GSK Investigational Site	Santiago de Compostela
Spain	GSK Investigational Site	Valencia
Sweden	GSK Investigational Site	Uppsala
United States	GSK Investigational Site	Albuquerque	New Mexico
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Cary	North Carolina
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Indianapolis	Indiana
United States	GSK Investigational Site	Minneapolis	Minnesota
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Pittsburgh	Pennsylvania
United States	GSK Investigational Site	Portland	Oregon
United States	GSK Investigational Site	Rochester	Minnesota
United States	GSK Investigational Site	Sioux City	Iowa
United States	GSK Investigational Site	Spartanburg	South Carolina
United States	GSK Investigational Site	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  France,  Germany,  Greece,  Israel,  Italy,  Spain,  Sweden, 

References & Publications (1)

Lin NU, Eierman W, Greil R, Campone M, Kaufman B, Steplewski K, Lane SR, Zembryki D, Rubin SD, Winer EP. Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. J Neurooncol. 2011 Dec;105(3):613-20. doi: 10.1007/s11060-011-0629-y. Epub 2011 Jun 26. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With the Indicated Central Nervous System (CNS) Objective Response (OR)	CNS OR is defined as the number of participants with either a complete response (CR) or partial response (PR) as assessed by volumetric analysis of brain magnetic resonance imaging (MRI) and Response Evaluation Criteria In Solid Tumors (RECIST). CR: complete resolution of all evaluable and non-evaluable brain metastases; PR: =>50% reduction in the volumetric sum of all evaluable brain metastases compared to baseline.	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	No
Primary	Number of Participants With the Indicated CNS Responses	CNS responses were assessed by volumetric (V) analysis of brain MRI and RECIST. CR: complete resolution of all evaluable and non-evaluable brain metastases (BMs). PR: =>50% reduction in the V sum of all evaluable BMs compared to baseline. A response of "Other" was used for participants who discontinued the study prior to the first efficacy assessment. Stable Disease (SD): disease that does not meet CR, PR, or CNS progression criteria. Progressive disease (PD): a requirement for a new steroid or an increasing steroid dose for the treatment of worsening neurological signs/symptoms due to BMs.	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	No
Secondary	Duration of CNS Objective Response (Defined as the Time From the First Documented Evidence of CNS PR or CR Until the First Documented Sign of Disease Progression or Death, if Sooner)	CNS OR is defined as the number of participants with either a CR or PR as assessed by volumetric analysis of brain MRI and RECIST. CR: complete resolution of all evaluable and non-evaluable brain metastases; PR: =>50% reduction in the volumetric sum of all evaluable brain metastases compared to baseline. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	No
Secondary	Percentage of Participants With Clinical Benefit	Clinical benefit is defined as CR (complete resolution of all evaluable and non-evaluable brain metastases), PR (=>50% reduction in the volumetric sum of all evaluable brain metastases compared to baseline), or stable disease (disease that does not meet CR, PR, or CNS progression criteria) for at least 6 months. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	No
Secondary	Percentage of Participants (Par.) With Objective Response by RECIST in Non-CNS Disease	Non-CNS disease (for par. with measurable baseline non-CNS disease) OR is defined as the number of par. with either a CR or PR as assessed by computed tomography (CT) or MRI scan and RECIST. CR: disappearance of all target lesions; PR: at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough par. enrolled in the study to provide statistically valid analyses.	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	No
Secondary	Time to CNS Objective Response (Defined as the Time From the Start of Treatment Until the First Documented Evidence of Partial or Complete Tumor Response [Whichever Status is Recorded First])	CNS OR is defined as the number of participants with either a CR or PR as assessed by volumetric analysis of brain MRI and RECIST. CR: complete resolution of all evaluable and non-evaluable brain metastases; PR: =>50% reduction in the volumetric sum of all evaluable brain metastases compared to baseline. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	No
Secondary	Number of Participants With the Indicated Site of Initial Disease Progression	The site of initial disease will be determined by taking the earliest date of known progression and assigning the appropriate category (CNS or non-CNS) based on the source of the earliest date. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	No
Secondary	Progression-free Survival	Progression-free survival is defined as the time from the start of treatment until the first documented sign of disease progression at any site or death due to any cause, if sooner. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	No
Secondary	Overall Survival	Overall survival is defined as the time from the start of treatment until death due to any cause. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	No
Secondary	Percentage of Participants With Baseline Tumor-related (TR) Neurological Signs and Symptoms (NSS), Who Experienced Improvement in NSS as Measured by the Neurological Examination Worksheet (NEW)	TR NSS was to be recorded by the Investigator on the NEW, using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE V3.0). Improvement was to be defined as a decrease of 1 or more CTCAE grades from baseline of any TR NSS. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	No
Secondary	Percentage of Participants With Disease Stabilization for 6 Months or More	The percentage participants with disease stabiliztion for 6 months or more were defined as those treated participants with a best CNS objective response of SD whose disease stabilization lasted 6 months or more from the start of treatment. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.	From the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	No
Secondary	Percentage of Participants With a >=20% Volumetric Reduction in CNS Lesions	The percentage of participants with a >=20% volumetric reduction in CNS lesions was defined as the percentage of treated participants achieving at least a 20% volumetric reduction in CNS lesions relative to baseline. This study was closed before full enrollment was achieved; thus, predefined secondary efficacy endpoints were not assessed because there were not enough participants enrolled in the study to provide statistically valid analyses.	Baseline; from the start of treatment until disease progression, death, or discontinuation from the study, up to a maximum of Week 88	No