Neoplasms, BreastPhase 3NCT00272987
ErbB2 Over-expressing Metastatic Breast Cancer Study Using Paclitaxel, Trastuzumab, and Lapatinib
A Phase 3 study testing lapatinib, paclitaxel and trastuzumab in people with Neoplasms, Breast, run by Novartis Pharmaceuticals at 16 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Neoplasms, Breast
- What is being tested?
- lapatinib, paclitaxel and trastuzumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 63 participants
- Where
- 16 sitesin 2 countries
- Study dates
- 13 Dec 2005to 21 Oct 2019
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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;
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- 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
Trial locations and contacts
16 sites in 2 countries.
16 sites in 2 countries
United States14 sites
Novartis Investigative Site
Amarillo, Texas, 79106
Novartis Investigative Site
Canton, Ohio, 44718
Novartis Investigative Site
Charleston, South Carolina, 29406
Novartis Investigative Site
Columbus, Ohio, 43219
Novartis Investigative Site
Detroit, Michigan, 48202
Novartis Investigative Site
Houston, Texas, 77030-4009
Novartis Investigative Site
Houston, Texas, 77030
Novartis Investigative Site
Jackson, Mississippi, 39202
Novartis Investigative Site
Joliet, Illinois, 60435
Novartis Investigative Site
Middletown, Ohio, 45042
Novartis Investigative Site
Richmond, Virginia, 23230
Novartis Investigative Site
Roswell, Georgia, 30076
Novartis Investigative Site
Voorhees Township, New Jersey, 08043
Novartis Investigative Site
Winston-Salem, North Carolina, 27103
Belgium2 sites
Novartis Investigative Site
Arlon, 6700
Novartis Investigative Site
Liège, 4000
About this study
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
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.
Read the detailed description
The primary objective of this study was to evaluate and compare time to progression (TTP). The Primary objective for open label phase was to determine the safety and tolerability of lapatinib when administered in combination with both paclitaxel and trastuzumab. The study first enrolled an open label safety cohort of 20 patients to assess the tolerability of the triplet combination. This was a 1 arm, 3 cohort study stage.
Open-label Phase: Patients were sequentially enrolled into three cohorts and received an open-label combination of paclitaxel, trastuzumab and lapatinib: Cohort 1 received paclitaxel 80mg/m2 IV weekly for 3 weeks of a 4 week cycle, trastuzumab 4 mg/kg IV loading dose and 2 mg/kg IV weekly, and lapatinib 1000 mg PO daily. Cohort 2 received paclitaxel 70mg/m2 IV weekly for 3 weeks of a 4 week cycle, trastuzumab 4 mg/kg IV loading dose and 2 mg/kg IV weekly, and lapatinib 1000 mg PO daily. Cohort 3 paclitaxel 80mg/m2 IV weekly for 3 weeks of a 4 week cycle, trastuzumab 4 mg/kg IV loading dose and 2 mg/kg IV weekly, and lapatinib 750 mg PO daily.
Randomized Phase: was terminated following the poor recruitment rate in the open-label safety stage. No subjects were enrolled into the randomization stage.
In summary, at approximately 3.5 years the primary analysis which included demographics, efficacy and safety were conducted; at approximately 7 years protocol amendment 7 cancelled collection of efficacy endpoints, and only key safety endpoints were to be collected; the final analysis was performed at approximately 14 years.
- Conditions
- Neoplasms, Breast
- Being tested
- lapatinib, paclitaxel, trastuzumab
- Keywords
- trastuzumab, ErbB2, paclitaxel, Herceptin, Taxol, ErbB1, metastatic breast cancer, Stage IV breast cancer, lapatinib
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
lapatinibDrug
(GW572016) 1000 mg QD
paclitaxelDrug
80 mg/m2 IV weekly for three weeks
trastuzumabDrug
4 mg/kg loading dose and 2 mg/kg weekly IV
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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. Receives: 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 Receives: Drug: lapatinib; Drug: paclitaxel; Drug: trastuzumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Time to Response was defined for subjects who had a confirmed CR or PR as the time from first dose until first documented evidence of partial or complete tumour response (whichever status was recorded first). CR is defined as the disappearance of all TLs \& 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.
Measured: 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
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.
Measured: 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
Clinical benefit is defined as the percentage 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.
Measured: 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
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.
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jan 2006 (estimated)
- Study start13 Dec 2005
- Primary completion31 Jul 2009
- Study completion21 Oct 2019
Why it stopped: Enrollment was closed after the open label stage due to poor recruitment rate (randomized stage never opened).
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Neoplasms, BreastStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 63 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00272987
- Sponsor's protocol ID
- EGF104383
- Other IDs
- 2005-003432-22, CLAP016A2301, 2005
- Status last verified
- Apr 2023
- First submitted
- 4 Jan 2006
- Last updated
- 28 Apr 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
Publications
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.
PubMed 23697602
Study at a glance
From the registry record, last updated by the sponsor on 28 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00272987
- Acronym / sponsor ID
- EGF104383
- Conditions
- Neoplasms, Breast
- Keywords
- trastuzumab, ErbB2, paclitaxel, Herceptin, Taxol, ErbB1, metastatic breast cancer, Stage IV breast cancer
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Enrollment was closed after the open label stage due to poor recruitment rate (randomized stage never opened).
- Enrolment
- 63 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 13 Dec 2005 (actual)
- Primary completion
- 31 Jul 2009 (actual)
- Study completion
- 21 Oct 2019 (actual)
- First posted
- 9 Jan 2006 (estimated)
- Results
- Posted 20 Aug 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
The primary objective of this study was to evaluate and compare time to progression (TTP). The Primary objective for open label phase was to determine the safety and tolerability of lapatinib when administered in combination with both paclitaxel and trastuzumab. The study first enrolled an open label safety cohort of 20 patients to assess the tolerability of the triplet combination. This was a 1 arm, 3 cohort study stage.
Open-label Phase: Patients were sequentially enrolled into three cohorts and received an open-label combination of paclitaxel, trastuzumab and lapatinib: Cohort 1 received paclitaxel 80mg/m2 IV weekly for 3 weeks of a 4 week cycle, trastuzumab 4 mg/kg IV loading dose and 2 mg/kg IV weekly, and lapatinib 1000 mg PO daily. Cohort 2 received paclitaxel 70mg/m2 IV weekly for 3 weeks of a 4 week cycle, trastuzumab 4 mg/kg IV loading dose and 2 mg/kg IV weekly, and lapatinib 1000 mg PO daily. Cohort 3 paclitaxel 80mg/m2 IV weekly for 3 weeks of a 4 week cycle, trastuzumab 4 mg/kg IV loading dose and 2 mg/kg IV weekly, and lapatinib 750 mg PO daily.
Randomized Phase: was terminated following the poor recruitment rate in the open-label safety stage. No subjects were enrolled into the randomization stage.
In summary, at approximately 3.5 years the primary analysis which included demographics, efficacy and safety were conducted; at approximately 7 years protocol amendment 7 cancelled collection of efficacy endpoints, and only key safety endpoints were to be collected; the final analysis was performed at approximately 14 years.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 | Experimental | Drug: lapatinib, Drug: paclitaxel, Drug: trastuzumabParticipants 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 |
| Cohort 2 | Experimental | Drug: lapatinib, Drug: paclitaxel, Drug: trastuzumabParticipants 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. |
| Cohort 3 | Experimental | Drug: lapatinib, Drug: paclitaxel, Drug: trastuzumabParticipants 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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
Key exclusion criteria (20 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| lapatinib(GW572016) 1000 mg QD | Drug | Cohort 1, Cohort 2, Cohort 3 |
| paclitaxel80 mg/m2 IV weekly for three weeks | Drug | Cohort 1, Cohort 2, Cohort 3 |
| trastuzumab4 mg/kg loading dose and 2 mg/kg weekly IV | Drug | Cohort 1, Cohort 2, Cohort 3 |
Primary outcome
Extent of Exposure to Lapatinib, Trastuzumab and Paclitaxel by Mean/Standard Deviation
Time frame: From the date of the first dose of the investigational product to end of study, up to approx. 14 years
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.
Extent of Exposure to Lapatinib, Trastuzumab and Paclitaxel by Median/Min-Max
Time frame: From the date of the first dose of the investigational product to end of study, up to approx. 14 years
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 approx. 14 years
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 last patient last visit, up to approximately 14 years
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).
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 approx. 3.5 years
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 Events of Rash 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 approx. 3.5 years
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.
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 approx. 3.5 years
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 approx. 3.5 years
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 approx. 3.5 years
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 approx. 3.5 years
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 approx. 3.5 years
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 approx. 3.5 years
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 Participants With at Least 1 Event 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 approx. 3.5 years
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.
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 approx. 3.5 years
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 approx. 3.5 years
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 end of study, up to approx. 7 years
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.
4 secondary outcomes
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 approx. 7 years
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 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
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 approx. 7 years
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 approx. 7 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Apr 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 23697602Esteva 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.
- Individual participant dataSharing planned: Yes. Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
16 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing lapatinib, paclitaxel and trastuzumab in people with Neoplasms, Breast, run by Novartis Pharmaceuticals at 16 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 28 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 16 sites in United States, Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Aug 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Extent of Exposure to Lapatinib, Trastuzumab and Paclitaxel by Mean/Standard Deviation (time frame: From the date of the first dose of the investigational product to end of study, up to approx. 14 years). The study lists 16 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00272987, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Apr 2023.