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

NCT00272987 | Terminated Phase 3 Results DMC FDA Drug

• 3 other identifiers: EGF1043832005-003432-22CLAP016A2301
• Study Type: interventional
• Target: 63
• Locations: 2 countries
• Sites: 16

Brief Summary

This study was originally designed as a Phase III randomized, double blind, placebo controlled study to assess the safety and tolerability, and efficacy of paclitaxel plus trastuzumab plus lapatinib compared with paclitaxel plus trastuzumab plus placebo in women with ErbB2 overexpressing metastatic breast cancer. The planned study was a two stage design with an initial open-label safety stage to be conducted in approximately 65 subjects followed by a randomized phase conducted in a further 700 subjects. The open-label part of the study sequentially enrolled three cohorts with patients receiving a different dose combination of paclitaxel, trastuzumab and lapatinib. Following poor recruitment rate in the open label stage, the randomized stage of the study was terminated, thus no subjects were enrolled into the randomization stage.

Conditions

Neoplasms, Breast

Keywords

trastuzumab; ErbB2; paclitaxel; Herceptin; Taxol; ErbB1; metastatic breast cancer; Stage IV breast cancer; lapatinib

Outcome Measures

Primary Outcomes (16)

• Extent of Exposure to Lapatinib, Trastuzumab and Paclitaxel by Mean/Standard Deviation

  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.

  From the date of the first dose of the investigational product to end of study, up to approx. 14 years

• Extent of Exposure to Lapatinib, Trastuzumab and Paclitaxel by Median/Min-Max

  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.

  From the date of the first dose of the investigational product to end of study, up to approx. 14 years

• Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

  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.

  From the date of the first dose of investigational product until 30 days after the last dose of investigational product, up to approx. 14 years

• Number of Participants Who Died Due to Any Cause

  Number of participants who died due to any cause throughout the study including off-treatment deaths (on-treatment deaths are reported for the All-Cause Mortality in the AE section).

  From the date of the first dose of investigational product until last patient last visit, up to approximately 14 years

• Number of Events of Diarrhea With the Indicated Characteristics

  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.

  From the date of the first dose of investigational product until 30 days after the last dose of investigational product, up to approx. 3.5 years

• Number of Events of Rash With the Indicated Characteristics

  Events of rash 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.

  From the date of the first dose of investigational product until 30 days after the last dose of investigational product, up to approx. 3.5 years

• Number of Participants With the Maximum Toxicity Grade for the Indicated Clinical Hematology Parameters

  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.

  Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years

• Number of Participants With the Maximum Toxicity Grade for the Indicated Clinical Chemistry Parameters

  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.

  Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years

• Number of Events of Hepatotoxicity With the Indicated Characteristics

  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.

  From the date of the first dose of investigational product until 30 days after the last dose of investigational product, up to approx. 3.5 years

• Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points

  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.

  Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years

• Change From Baseline in Heart Rate at the Indicated Time Points

  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.

  Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years

• Change From Baseline in Body Temperature at the Indicated Time Points

  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.

  Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years

• Number of Participants With at Least 1 Event of Left Ventricular Ejection Fraction Decrease With the Indicated Characteristics

  Events of left ventricular ejection fraction (LVEF) decrease were based on the number of participants who had an actual event and was characterized as serious, related to investigational product, leading to withdrawal from the study and/or fatal.

  Baseline and every 8 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years

• Number of Participants With the Indicated Eastern Cooperative Oncology Group (ECOG) Performance Status Value

  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.

  Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years

• Number of Participants Who Received Any Concomitant Medications During the Study Period

  Number of participants who received any concomitant medication along with study drugs (lapatinib, trastuzumab and paclitaxel) were counted during the treatment period.

  withdrawal/study completion, up to approx. 3.5 years

• 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

  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.

  From the date of the first dose of investigational product to end of study, up to approx. 7 years

Secondary Outcomes (4)

• Time to Response as Assessed by the Investigator

  From the date of the first dose of investigational product until the first documented evidence of a PR or CR, up to approx. 7 years

• Duration of Response (DoR), as Assessed by the Investigator

  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 approx. 7 years

• Percentage of Participants With Clinical Benefit (Complete Response (CR), Partial Response (PR), and Stable Disease [SD] for at Least 24 Weeks) as Assessed by Investigator

  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 approx. 7 years

• Progression-free Survival as Assessed by the Investigator

  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 approx. 7 years

Study Arms (3)

Cohort 1

EXPERIMENTAL

Participants received: paclitaxel 80mg/m2 IV weekly for 3 weeks of a 4 week cycle plus trastuzumab 4 mg/kg IV loading dose and 2 mg/kg IV weekly plus lapatinib 1000 mg PO daily

Drug: lapatinib; Drug: paclitaxel; Drug: trastuzumab

Cohort 2

EXPERIMENTAL

Participants received paclitaxel 70mg/m2 IV weekly for 3 weeks of a 4 week cycle plus trastuzumab 4 mg/kg IV loading dose and 2 mg/kg IV weekly plus lapatinib 1000 mg PO daily.

Drug: lapatinib; Drug: paclitaxel; Drug: trastuzumab

Cohort 3

EXPERIMENTAL

Participants in this arm received 80mg/m2 IV weekly for 3 weeks of a 4 week cycle plus trastuzumab 4 mg/kg IV loading dose and 2 mg/kg IV weekly plus lapatinib 750 mg PO

Drug: lapatinib; Drug: paclitaxel; Drug: trastuzumab

Interventions

lapatinib DRUG

(GW572016) 1000 mg QD

Cohort 1; Cohort 2; Cohort 3

paclitaxel DRUG

80 mg/m2 IV weekly for three weeks

Cohort 1; Cohort 2; Cohort 3

trastuzumab DRUG

4 mg/kg loading dose and 2 mg/kg weekly IV

Cohort 1; Cohort 2; Cohort 3

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 defined as either: 3+ by IHC OR c-erbB2 gene amplification by FISH OR 0, 1+, 2+ by IHC and c-erbB2 gene amplification by FISH.
• Patients must have tumor tissue available for central testing, and must have Measurable lesion(s) according to RECIST
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (16)

Novartis Investigative Site

Roswell, Georgia, 30076, United States

Location

Novartis Investigative Site

Joliet, Illinois, 60435, United States

Location

Novartis Investigative Site

Detroit, Michigan, 48202, United States

Location

Novartis Investigative Site

Jackson, Mississippi, 39202, United States

Location

Novartis Investigative Site

Voorhees Township, New Jersey, 08043, United States

Location

Novartis Investigative Site

Winston-Salem, North Carolina, 27103, United States

Location

Novartis Investigative Site

Canton, Ohio, 44718, United States

Location

Novartis Investigative Site

Columbus, Ohio, 43219, United States

Location

Novartis Investigative Site

Middletown, Ohio, 45042, United States

Location

Novartis Investigative Site

Charleston, South Carolina, 29406, United States

Location

Novartis Investigative Site

Amarillo, Texas, 79106, United States

Location

Novartis Investigative Site

Houston, Texas, 77030-4009, United States

Location

Novartis Investigative Site

Houston, Texas, 77030, United States

Location

Novartis Investigative Site

Richmond, Virginia, 23230, United States

Location

Novartis Investigative Site

Arlon, 6700, Belgium

Location

Novartis Investigative Site

Liège, 4000, Belgium

Location

Related Publications (1)

• Esteva FJ, Franco SX, Hagan MK, Brewster AM, Somer RA, Williams W, Florance AM, Turner S, Stein S, Perez A. An open-label safety study of lapatinib plus trastuzumab plus paclitaxel in first-line HER2-positive metastatic breast cancer. Oncologist. 2013 Jun;18(6):661-6. doi: 10.1634/theoncologist.2012-0129. Epub 2013 May 22.

  PMID: 23697602 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Lapatinib; Paclitaxel; Trastuzumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Clinical Disclosure Office
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 4, 2006
• First Posted: January 9, 2006
• Study Start: December 13, 2005
• Primary Completion: July 31, 2009
• Study Completion: October 21, 2019
• Last Updated: April 28, 2023
• Results First Posted: August 20, 2014

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will share

Locations

US (14); BE (2)