ErbB2 Over-expressing Metastatic Breast Cancer Study Using Paclitaxel, Trastuzumab, and Lapatinib

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00272987
First received: January 4, 2006
Last updated: August 18, 2014
Last verified: July 2014
  Purpose

Patients will be randomised to a 1:1 ratio to receive either paclitaxel 80 mg/m2 IV weekly for three weeks of a four week cycle, trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly IV, and oral lapatinib 1000 mg QD or paclitaxel 80 mg/m2 IV weekly for three weeks of a four week cycle, trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly IV plus placebo. The primary objective of this study is to evaluate and compare time to progression (TTP). Secondary objectives will be to evaluate and compare the two treatment arms with respect to: overall response rates, clinical benefit, time to response, duration of response, progression-free survival, and overall survival. The study will first enroll an open label safety cohort of 20 patients to assess the tolerability of the triplet combination.


Condition Intervention Phase
Neoplasms, Breast
Drug: lapatinib
Drug: paclitaxel
Drug: trastuzumab
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized, Double Blind, Placebo-Controlled, Multicenter, Phase III Study Comparing the Activity of Paclitaxel Plus Trastuzumab Plus Lapatinib to Paclitaxel Plus Trastuzumab Plus Placebo in Women With ErbB2 Overexpressing Metastatic Breast Cancer

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Extent of Exposure to Lapatinib, Trastuzumab and Paclitaxel [ Time Frame: From the date of the first dose of the investigational product up to withdrawal/study completion (up to Study Week 164) ] [ Designated as safety issue: No ]
    Extent of exposure is defined as the duration of the treatment administered during the study. The mean duration of exposure to lapatinib, trastuzumab and paclitaxel is calculated as the number of weeks between the start and end of treatment.

  • Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) [ Time Frame: From the date of the first dose of investigational product until 30 days after the last dose of investigational product (up to Study Week 164) ] [ Designated as safety issue: No ]
    An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Medical or scientific judgment was exercised in deciding whether reporting was appropriate in other situations. Refer to the general AE/SAE module for a list of non-serious AEs and SAEs.

  • Number of Participants Who Died Due to Any Cause [ Time Frame: From the date of the first dose of investigational product until 30 days after the last dose of investigational product (up to Study Week 164) ] [ Designated as safety issue: No ]
    Number of participants who died due to any cause during the study or after completion of study were reported.

  • Number of Events of Diarrhea With the Indicated Characteristics [ Time Frame: From the date of the first dose of investigational product until 30 days after the last dose of investigational product (up to Study Week 164) ] [ Designated as safety issue: No ]
    Events of diarrhea are characterized as serious, related to investigational product, leading to withdrawal from the study and fatal. Participants could have been counted in more than one category.

  • Number of Participants With the Maximum Toxicity Grade for the Indicated Clinical Hematology Parameters [ Time Frame: Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up (up to Study Week 164) ] [ Designated as safety issue: No ]
    Blood samples for clinical laboratory evaluation were taken at Baseline prior to the administration of investigational product and thereafter at each scheduled visit. Haematology parameters included haemoglobin, total white blood cell count (WBC), neutrophils, lymphocytes and platelets. Hematology data was summarized by the National Cancer Institute's Common toxicity criteria for adverse events (NCI CTCAE) toxicity grade (Version 3.0). Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling; Grade 5, death.

  • Number of Participants With the Maximum Toxicity Grade for the Indicated Clinical Chemistry Parameters [ Time Frame: Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up (up to Study Week 164) ] [ Designated as safety issue: No ]
    Blood samples for clinical laboratory evaluation were taken at Baseline prior to the administration of investigational product and thereafter at each scheduled visit. Clinical chemistry parameters included values > upper limit of normal (ULN)=Hyper; values < lower limit of normal (LLN)=Hypo of sodium (Hypernatraemia and Hyponatraemia), potassium (Hyperkalaemia and Hypokalaemia), calcium (Hypercalcaemia and Hypocalcaemia), glucose (Hyperglycaemia and Hyperglycaemia), creatinine (if >2 milligram per deciliter [mg/dL]), aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phophatase, total bilirubin (if available bilirubin fractionation is recommended if the total bilirubin is > twice of ULN), and albumin. Clinical chemistry data was summarized by National Cancer Institute's Common toxicity criteria for adverse events (NCI CTCAE) toxicity grade (Version 3.0). Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling; Grade 5, death.

  • Number of Events of Hepatotoxicity With the Indicated Characteristics [ Time Frame: From the date of the first dose of investigational product until 30 days after the last dose of investigational product (up to Study Week 164) ] [ Designated as safety issue: No ]
    Events of hepatotoxicity are characterized as serious, related to investigational product, leading to withdrawal from the study and fatal. Participants could have been counted in more than one category.

  • Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points [ Time Frame: Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up (up to Study Week 164) ] [ Designated as safety issue: No ]
    Blood pressure measurement included systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Baseline and every 4 weeks thereafter up to withdrawal/study completion and at the 30 day follow-up visit. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  • Change From Baseline in Heart Rate at the Indicated Time Points [ Time Frame: Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up (up to Study Week 164) ] [ Designated as safety issue: No ]
    Heart rate was measured at Baseline and every 4 weeks thereafter up to withdrawal/study completion and at the 30 day follow-up visit. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  • Change From Baseline in Body Temperature at the Indicated Time Points [ Time Frame: Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up (up to Study Week 164) ] [ Designated as safety issue: No ]
    Body temperature was measured at Baseline and every 4 weeks thereafter up to withdrawal/study completion and at the 30 day follow-up visit. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  • Number of Events of Left Ventricular Ejection Fraction Decrease With the Indicated Characteristics [ Time Frame: Baseline and every 8 weeks thereafter up to withdrawal/study completion and 30 day follow-up (up to Study Week 164) ] [ Designated as safety issue: No ]
    Events of left ventricular ejection fraction (LVEF) decrease were characterized as serious, related to investigational product, leading to withdrawal from the study and fatal. A participant could have been counted in more than one category.

  • Number of Participants With the Indicated Eastern Cooperative Oncology Group (ECOG) Performance Status Value [ Time Frame: Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up (up to Study Week 164) ] [ Designated as safety issue: No ]
    The Eastern Cooperative Oncology Group (ECOG) performance status scales and grades/criteria are used to assess how a participant's disease is progressing, to assess how the disease affects the daily living abilities of the participant, and to determine appropriate treatment and prognosis. Grade 0, fully active, able to carry on all pre-disease performance without restriction. Grade 1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. Grade 2, ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about more than 50% of waking hours. Grade 3, capable of only limited selfcare; confined to bed or chair more than 50% of waking hours. Grade 4, completely disabled; cannot carry on any selfcare; totally confined to bed or chair. Grade 5, dead.

  • Number of Participants Who Received Any Concomitant Medications During the Study Period [ Time Frame: withdrawal/study completion (up to Study Week 164) ] [ Designated as safety issue: No ]
    Number of participants who received any concomitant medication along with study drugs (lapatinib, trastuzumab and paclitaxel) were counted during the treatment period.

  • Overall Response (OR): Percentage of Participants With a Best Overall Response (OR) of Confirmed Complete Response (CR) or Confirmed Partial Response (PR) as Assessed by the Investigator [ Time Frame: From the date of the first dose of investigational product to the first documented evidence of a confirmed CR or PR (up to Study Week 164) ] [ Designated as safety issue: No ]
    OR is defined as the number of participants achieving either a CR or PR, per Response Evaluation Criteria in Solid Tumors (RECIST). The best OR is defined as the best response recorded from the start of treatment until progressive disease (PD)/recurrence. CR is defined as the disappearance of all target lesions (TLs) and non-TLs. PR is defined as at least a 30% decrease in the sum of the longest diameters (LD) of TLs, taking as a reference the Baseline sum LD and no PD, or complete resolution of TLs and the persistence of one or more non-TL(s), as assessed by the IRC. PD is defined as at least a 20% increase in the sum of the LD of TLs, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions or unequivocal progression of existing non-TLs. Responses were confirmed at subsequent assessments made >=28 days after the original response. Participants with an unknown or missing response are treated as non-responders.


Secondary Outcome Measures:
  • Time to Response as Assessed by the Investigator [ Time Frame: From the date of the first dose of investigational product until the first documented evidence of a PR or CR (up to Study Week 164) ] [ Designated as safety issue: No ]
    Time to response is defined as the time from randomization until the first documented evidence of a PR or CR (whichever status is recorded first). Analysis was based on responses confirmed at a repeat assessment made at least 4 weeks after the initial response, with the time to response taken as the first time the response was observed, not the confirmation assessment. Participants who withdraw with no tumor response were censored at the date of withdrawal from the study. CR is defined as the disappearance of all TLs and non-TLs. PR is defined as at least a 30% decrease in the sum of the LD of TLs, taking as a reference the Baseline sum LD and no PD, or complete resolution of TLs and the persistence of one or more non-TL(s). PD is defined as at least a 20% increase in the sum of the LD of TLs, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions or unequivocal progression of existing non-TLs.

  • Duration of Response (DoR), as Assessed by the Investigator [ Time Frame: From the first documented evidence of a PR or CR until the earlier of the date of disease progression or the date of death due to breast cancer (up to Study Week 164) ] [ Designated as safety issue: No ]
    DoR is defined for the subset of participants who had a confirmed CR (disappearance of all TLs and non-TLs) or PR (>=30% decrease in the sum of the LD of TLs, taking as a reference the Baseline sum LD and no PD, or complete resolution of TLs and the persistence of one or more non-TL[s]) as the time from the first documented evidence of a CR or PR until the first documentation of radiological PD or death due to breast cancer, if sooner. PD is defined as >=20% increase in the sum of the LD of TLs, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions or unequivocal progression of existing non-TLs. For participants who did not progress or die, DoR was censored on the date of the last radiological scan. If a participant had only a Baseline visit or did not have a date of a radiological scan that was later than the date of initiation of anti-cancer therapy, DoR was censored at the start date of treatment.

  • Number of Participants With Clinical Benefit (CR, PR, and Stable Disease [SD] for at Least 24 Weeks) as Assessed by Investigator [ Time Frame: From the date of the first dose of investigational product until the first documented evidence of a PR or CR or SD until the earlier of the date of disease progression or the date of death due to breast cancer (up to Study Week 164) ] [ Designated as safety issue: No ]
    Clinical benefit is defined as the numer of participants achieving either a CR or PR or SD (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of the LD of target lesions, taking as a reference, the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions), taking as reference, the smallest sum LD since the treatment started) for at least 24 weeks. This was based on confirmed responses from the investigator assessment of clinical benefit.

  • Progression-free Survival as Assessed by the Investigator [ Time Frame: From the date of the first dose of investigational product until the earlier of the date of disease progression or death due to any cause (up to Study Week 164) ] [ Designated as safety issue: No ]
    Progression-free survival is defined as the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. Disease progression was based on the investigator's assessments of the objective evidence (e.g., radiological scans and medical photographs). For participants who do not progress, or die, progression-free survival was censored at the time of the last investigator assessed radiological scan preceding the initiation of any alternative anti-cancer therapy. Progression-free survival was summarized using Kaplan-Meier curves.


Enrollment: 63
Study Start Date: December 2005
Estimated Study Completion Date: December 2015
Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1
Open label safety phase. All patients received paclitaxel + trastuzumab + lapatinib.
Drug: lapatinib
(GW572016) 1000 mg QD
Drug: paclitaxel
80 mg/m2 IV weekly for three weeks
Drug: trastuzumab
4 mg/kg loading dose and 2 mg/kg weekly IV

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Histologically confirmed invasive breast cancer with stage IV disease If trastuzumab was administered in the adjuvant setting, >12 months must have elapsed since discontinuation of trastuzumab therapy
  • If a taxane was administered in the neoadjuvant or adjuvant setting, progression must have occurred 12 months after completion of this treatment
  • Had tumors that overexpress ErbB2 (Immunohistochemistry 3+ or Fluorescent in-situ hybridisation gene amplification)
  • Patients must have tumor tissue available for central testing Measurable lesion(s)
  • Subjects must be females of at least 18 years Non-childbearing potential or Childbearing potential but using adequate contraception
  • Radiotherapy to a limited area other than the sole site of measurable and assessable disease is allowed; however, patients must have completed treatment and recovered from all acute treatment-related toxicities prior to administration of the first dose of study medication
  • Bisphosphonate therapy for bone metastases is allowed; however, treatment must be initiated prior to the first dose of randomized therapy. Prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1
  • For those patients whose disease is estrogen receptor positive+ and/or progesterone receptor + one the following criteria should be met: Patients with visceral disease that requires chemotherapy (eg., patients with liver or lung metastases) or Rapidly progressing/life threatening disease, as determined by the investigator or Patients who received hormonal therapy and are no longer benefiting from this therapy;
  • Able to swallow and retain oral medication
  • Cardiac ejection fraction within institutional range of normal
  • Patient must have adequate organ function

Exclusion criteria:

  • Pregnant or lactating females;
  • Received prior chemotherapy, immunotherapy, biologic therapy, or anti-ErbB1/ErbB2 therapy for metastatic disease, prior hormonal therapy is permitted but must be discontinued a minimum of 7 days prior to randomization; Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel.
  • Patients with ulcerative colitis are also excluded;
  • History of other malignancy; however, patients who have been disease-free for five years, or patients 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 patient inappropriate for study participation, or any serious medical disorder that would interfere with the patient's safety;
  • Unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment;
  • Peripheral neuropathy of Grade 2 or greater;
  • 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, conduction abnormalities or congestive heart failure;
  • Known history or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis;
  • Concurrent cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy); Concurrent treatment with an investigational agent or participation in another clinical trial;
  • Concurrent treatment with any medication on the prohibited medications list.
  • Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of treatment. Hormonal therapy needs to be discontinued at least 7 days before the first dose of treatment.
  • Prior therapy with an ErbB2 inhibitor, other than trastuzumab in the adjuvant setting;
  • A known immediate or delayed hypersensitivity reaction to drugs chemically related to lapatinib or excipients;
  • A known immediate or delayed hypersensitivity reaction to drugs chemically related to paclitaxel or excipients;
  • A known immediate or delayed hypersensitivity reaction to drugs chemically related to trastuzumab or excipients;
  • Non compliance with any of the screening procedures
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00272987

  Show 28 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Publications:
Esteva FJ, Franco SX, Hagan MK, Somer R, Dombroski C, Florance A, Turner S, Stein S, Perez A. An Evaluation of the Safety and Efficacy of Lapatinib Plus Trastuzumab Plus Paclitaxel in First-Line HER2+ Metastatic Breast Cancer. 32nd Annual San Antonio Breast Cancer Symposium. 2009.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00272987     History of Changes
Other Study ID Numbers: EGF104383
Study First Received: January 4, 2006
Results First Received: July 28, 2014
Last Updated: August 18, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
trastuzumab
ErbB2
paclitaxel
Herceptin
Taxol
ErbB1
metastatic breast cancer
Stage IV breast cancer
lapatinib

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Trastuzumab
Lapatinib
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 29, 2014