Clincosm LogoSign in Get a demo

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

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Terminated
CT.gov ID
NCT00272987
Collaborator
(none)
63
Enrollment
16
Locations
3
Arms
166.2
Actual Duration (Months)
3.9
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 3

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

Study Type:
Interventional
Actual Enrollment :
63 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (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
Actual Study Start Date :
Dec 13, 2005
Actual Primary Completion Date :
Jul 31, 2009
Actual Study Completion Date :
Oct 21, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cohort 1

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
(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
Experimental: Cohort 2

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
(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
Experimental: Cohort 3

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
(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

Outcome Measures

Primary Outcome Measures

  1. Extent of Exposure to Lapatinib, Trastuzumab and Paclitaxel by Mean/Standard Deviation [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.

  2. Extent of Exposure to Lapatinib, Trastuzumab and Paclitaxel by Median/Min-Max [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.

  3. Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) [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.

  4. Number of Participants Who Died Due to Any Cause [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).

  5. Number of Events of Diarrhea With the Indicated Characteristics [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.

  6. Number of Events of Rash With the Indicated Characteristics [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.

  7. Number of Participants With the Maximum Toxicity Grade for the Indicated Clinical Hematology Parameters [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.

  8. Number of Participants With the Maximum Toxicity Grade for the Indicated Clinical Chemistry Parameters [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.

  9. Number of Events of Hepatotoxicity With the Indicated Characteristics [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.

  10. Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points [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.

  11. Change From Baseline in Heart Rate at the Indicated Time Points [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.

  12. Change From Baseline in Body Temperature at the Indicated Time Points [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.

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

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

  15. Number of Participants Who Received Any Concomitant Medications During the Study Period [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.

  16. 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 [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.

Secondary Outcome Measures

  1. 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]

    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.

  2. 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]

    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.

  3. 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]

    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.

  4. 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]

    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.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
Female
Accepts Healthy Volunteers:
No
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 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

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

Locations

Site City State Country Postal Code
1 Novartis Investigative Site Roswell Georgia United States 30076
2 Novartis Investigative Site Joliet Illinois United States 60435
3 Novartis Investigative Site Detroit Michigan United States 48202
4 Novartis Investigative Site Jackson Mississippi United States 39202
5 Novartis Investigative Site Voorhees New Jersey United States 08043
6 Novartis Investigative Site Winston-Salem North Carolina United States 27103
7 Novartis Investigative Site Canton Ohio United States 44718
8 Novartis Investigative Site Columbus Ohio United States 43219
9 Novartis Investigative Site Middletown Ohio United States 45042
10 Novartis Investigative Site Charleston South Carolina United States 29406
11 Novartis Investigative Site Amarillo Texas United States 79106
12 Novartis Investigative Site Houston Texas United States 77030-4009
13 Novartis Investigative Site Houston Texas United States 77030
14 Novartis Investigative Site Richmond Virginia United States 23230
15 Novartis Investigative Site Arlon Belgium 6700
16 Novartis Investigative Site Liege Belgium 4000

Sponsors and Collaborators

  • Novartis Pharmaceuticals

Investigators

  • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT00272987
Other Study ID Numbers:
  • EGF104383
  • 2005-003432-22
  • CLAP016A2301
First Posted:
Jan 9, 2006
Last Update Posted:
Dec 30, 2020
Last Verified:
Dec 1, 2020
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Novartis Pharmaceuticals
trastuzumab
ErbB2
paclitaxel
Herceptin
Taxol
ErbB1
metastatic breast cancer
Stage IV breast cancer
lapatinib
Additional relevant MeSH terms:
Breast Neoplasms
Paclitaxel
Trastuzumab
Lapatinib

Study Results

Participant Flow

Recruitment Details Female participants (par.) with histologically confirmed invasive breast cancer (Stage IV disease) whose tumors overexpressed the ErbB2 protein, documented by either Immunohistochemistry (IHC) or fluorescence in situ hybridisation (FISH), were eligible for inclusion in this study.
Pre-assignment Detail Participants who met inclusion criteria were sequentially enrolled into three cohorts and received the open-label triple combination of paclitaxel, trastuzumab and lapatinib. The planned randomized phase of the study was terminated following the poor recruitment rate in the Open-label Phase.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Period Title: Overall Study
STARTED 29 14 20
COMPLETED 20 10 9
NOT COMPLETED 9 4 11

Baseline Characteristics

Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg Total
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated. Total of all reporting groups
Overall Participants 29 14 20 63
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]
51.5
(11.08)
56.1
(11.92)
52.2
(13.00)
52.7
(11.84)
Sex: Female, Male (Count of Participants)
Female
29
100%
14
100%
20
100%
63
100%
Male
0
0%
0
0%
0
0%
0
0%
Race/Ethnicity, Customized (Number) [Number]
African American/African Heritage
7
24.1%
2
14.3%
4
20%
13
20.6%
Native Hawaiian or Other Pacific Islander
0
0%
1
7.1%
0
0%
1
1.6%
White - White/Caucasian/European Heritage
22
75.9%
11
78.6%
16
80%
49
77.8%

Outcome Measures

1. Primary Outcome
Title Extent of Exposure to Lapatinib, Trastuzumab and Paclitaxel by Mean/Standard Deviation
Description 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.
Time Frame From the date of the first dose of the investigational product to end of study, up to approx. 14 years

Outcome Measure Data

Analysis Population Description
Safety Population: all participants who were randomized and received at least one dose of investigational product.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
Lapatinib
70.9
(115.44)
93.1
(147.92)
82.5
(135.79)
Trastuzumab
60.7
(72.07)
72.2
(88.66)
62.3
(75.52)
Paclitaxel
26.9
(16.88)
29.4
(23.00)
23.8
(14.87)
2. Primary Outcome
Title Extent of Exposure to Lapatinib, Trastuzumab and Paclitaxel by Median/Min-Max
Description 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.
Time Frame From the date of the first dose of the investigational product to end of study, up to approx. 14 years

Outcome Measure Data

Analysis Population Description
Safety Population: all participants who were randomized and received at least one dose of investigational product.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
Lapatinib
33.0
38.5
32.5
Trastuzumab
33.0
37.0
31.5
Paclitaxel
22.0
23.5
22.0
3. Primary Outcome
Title Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
Description 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.
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

Outcome Measure Data

Analysis Population Description
Safety Population: all participants who were randomized and received at least one dose of investigational product.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
Any AEs
29
100%
14
100%
20
100%
Any SAEs
14
48.3%
6
42.9%
5
25%
4. Primary Outcome
Title Number of Participants Who Died Due to Any Cause
Description 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).
Time Frame From the date of the first dose of investigational product until last patient last visit, up to approximately 14 years

Outcome Measure Data

Analysis Population Description
Safety Population: all participants who were randomized and received at least one dose of investigational product.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
Number [Participants]
12
41.4%
2
14.3%
1
5%
5. Primary Outcome
Title Number of Events of Diarrhea With the Indicated Characteristics
Description 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.
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

Outcome Measure Data

Analysis Population Description
Safety Population. Only the participants with at least one event of diarrhea were analyzed.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 28 13 13
Any Event
358
90
37
Serious
4
0
0
Related to investigational product
347
75
26
Leading to withdrawal from study
2
1
1
Fatal
0
0
0
6. Primary Outcome
Title Number of Events of Rash With the Indicated Characteristics
Description 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.
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

Outcome Measure Data

Analysis Population Description
Safety Population. Only the participants with at least one event of rash were analyzed.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 24 8 15
Any Event
69
23
20
Serious
2
0
0
Related to investigational product
55
12
7
Leading to withdrawal from study
3
0
0
Fatal
0
0
0
7. Primary Outcome
Title Number of Participants With the Maximum Toxicity Grade for the Indicated Clinical Hematology Parameters
Description 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.
Time Frame Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years

Outcome Measure Data

Analysis Population Description
Safety Population: all participants who were randomized and received at least one dose of investigational product.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
Haemaglobin, Grade 1
19
65.5%
11
78.6%
11
55%
Haemaglobin, Grade 2
7
24.1%
1
7.1%
6
30%
Haemaglobin, Grade 3
2
6.9%
0
0%
1
5%
Haemaglobin, Grade 4
1
3.4%
0
0%
0
0%
Platelets, Grade 1
3
10.3%
0
0%
0
0%
Platelets, Grade 2
1
3.4%
0
0%
0
0%
Platelets, Grade 3
0
0%
0
0%
0
0%
Platelets, Grade 4
1
3.4%
0
0%
0
0%
Total WBC, Grade 1
10
34.5%
6
42.9%
7
35%
Total WBC, Grade 2
8
27.6%
4
28.6%
2
10%
Total WBC, Grade 3
3
10.3%
1
7.1%
4
20%
Total WBC, Grade 4
1
3.4%
0
0%
0
0%
Neutrophils, Grade 1
7
24.1%
2
14.3%
5
25%
Neutrophils, Grade 2
7
24.1%
4
28.6%
4
20%
Neutrophils, Grade 3
3
10.3%
1
7.1%
5
25%
Neutrophils, Grade 4
3
10.3%
0
0%
0
0%
Lymphocytes, Grade 1
5
17.2%
3
21.4%
7
35%
Lymphocytes, Grade 2
10
34.5%
4
28.6%
4
20%
Lymphocytes, Grade 3
5
17.2%
3
21.4%
1
5%
Lymphocytes, Grade 4
1
3.4%
0
0%
1
5%
8. Primary Outcome
Title Number of Participants With the Maximum Toxicity Grade for the Indicated Clinical Chemistry Parameters
Description 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.
Time Frame Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants available at the specified time points were analyzed.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
Hypernatraemia, Grade 1
0
0%
1
7.1%
1
5%
Hypernatraemia, Grade 2
1
3.4%
0
0%
0
0%
Hypernatraemia, Grade 3
0
0%
0
0%
0
0%
Hypernatraemia, Grade 4
0
0%
0
0%
0
0%
Hyponatraemia, Grade 1
8
27.6%
1
7.1%
1
5%
Hyponatraemia, Grade 2
0
0%
0
0%
0
0%
Hyponatraemia, Grade 3
0
0%
1
7.1%
0
0%
Hyponatraemia, Grade 4
0
0%
0
0%
0
0%
Hyperkalaemia, Grade 1
2
6.9%
0
0%
0
0%
Hyperkalaemia, Grade 2
2
6.9%
1
7.1%
1
5%
Hyperkalaemia, Grade 3
0
0%
0
0%
0
0%
Hyperkalaemia, Grade 4
1
3.4%
0
0%
1
5%
Hypokalaemia, Grade 1
11
37.9%
6
42.9%
6
30%
Hypokalaemia, Grade 2
0
0%
0
0%
0
0%
Hypokalaemia, Grade 3
6
20.7%
2
14.3%
0
0%
Hypokalaemia, Grade 4
0
0%
0
0%
0
0%
Hypercalcaemia, Grade 1
1
3.4%
0
0%
0
0%
Hypercalcaemia, Grade 2
0
0%
0
0%
0
0%
Hypercalcaemia, Grade 3
0
0%
0
0%
0
0%
Hypercalcaemia, Grade 4
0
0%
0
0%
0
0%
Hypocalcaemia, Grade 1
10
34.5%
3
21.4%
4
20%
Hypocalcaemia, Grade 2
7
24.1%
2
14.3%
3
15%
Hypocalcaemia, Grade 3
3
10.3%
0
0%
1
5%
Hypocalcaemia, Grade 4
0
0%
0
0%
0
0%
Hyperglycaemia, Grade 1
15
51.7%
9
64.3%
6
30%
Hyperglycaemia, Grade 2
3
10.3%
3
21.4%
2
10%
Hyperglycaemia, Grade 3
5
17.2%
0
0%
2
10%
Hyperglycaemia, Grade 4
0
0%
0
0%
0
0%
Hypoglycemia, Grade 1
5
17.2%
2
14.3%
2
10%
Hypoglycemia, Grade 2
0
0%
1
7.1%
1
5%
Hypoglycemia, Grade 3
0
0%
0
0%
0
0%
Hypoglycemia, Grade 4
0
0%
0
0%
0
0%
Albumin, Grade 1
5
17.2%
3
21.4%
1
5%
Albumin, Grade 2
3
10.3%
0
0%
0
0%
Albumin, Grade 3
1
3.4%
0
0%
0
0%
Albumin, Grade 4
0
0%
0
0%
0
0%
Total Bilirubin, Grade 1
2
6.9%
1
7.1%
3
15%
Total Bilirubin, Grade 2
2
6.9%
2
14.3%
1
5%
Total Bilirubin, Grade 3
1
3.4%
1
7.1%
0
0%
Total Bilirubin, Grade 4
0
0%
0
0%
0
0%
Creatinine, Grade 1
2
6.9%
0
0%
0
0%
Creatinine, Grade 2
2
6.9%
0
0%
0
0%
Creatinine, Grade 3
1
3.4%
0
0%
0
0%
Creatinine, Grade 4
0
0%
0
0%
0
0%
Alkaline Phophatase, Grade 1
14
48.3%
3
21.4%
5
25%
Alkaline Phophatase, Grade 2
2
6.9%
0
0%
0
0%
Alkaline Phophatase, Grade 3
2
6.9%
0
0%
0
0%
Alkaline Phophatase, Grade 4
0
0%
0
0%
0
0%
ALT, Grade 1
7
24.1%
1
7.1%
3
15%
ALT, Grade 2
3
10.3%
3
21.4%
2
10%
ALT, Grade 3
0
0%
0
0%
0
0%
ALT, Grade 4
0
0%
0
0%
0
0%
AST, Grade 1
6
20.7%
3
21.4%
6
30%
AST, Grade 2
1
3.4%
1
7.1%
0
0%
AST, Grade 3
1
3.4%
1
7.1%
0
0%
AST, Grade 4
0
0%
0
0%
0
0%
9. Primary Outcome
Title Number of Events of Hepatotoxicity With the Indicated Characteristics
Description 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.
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

Outcome Measure Data

Analysis Population Description
Safety Population. Only the participants with at least one of event of hepatotoxicity were analyzed.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 6 0 2
Any Event
6
2
Serious
0
0
Related to investigational product
5
0
Leading to withdrawal from study
0
0
Fatal
0
0
10. Primary Outcome
Title Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points
Description 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.
Time Frame Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years

Outcome Measure Data

Analysis Population Description
Safety Population: all participants who were randomized and received at least one dose of investigational product. Only those participants available at the specified time points were analyzed.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
SBP, Week 4
0.5
(16.29)
-7.2
(20.70)
-3.9
(22.76)
SBP, Week 8
4.6
(12.35)
-8.6
(22.25)
-2.7
(24.73)
SBP, Week 12
3.2
(18.46)
-6.9
(17.09)
-9.3
(23.54)
SBP, Week 16
0.8
(18.10)
-6.6
(15.26)
-7.9
(24.43)
SBP, Week 20
1.7
(17.80)
-11.5
(14.69)
-13.8
(25.15)
SBP, Week 24
2.9
(13.87)
-1.8
(11.81)
-7.8
(26.06)
SBP, Week 28
2.3
(19.10)
-5.7
(20.38)
-5.2
(10.71)
SBP, Week 32
3.2
(23.11)
-16.4
(10.03)
-6.3
(5.51)
SBP, Week 36
1.6
(15.85)
-8.7
(12.19)
-26.7
(37.75)
SBP, Week 40
-2.2
(24.44)
-3.4
(9.62)
-34.0
(38.18)
SBP, Week 44
2.7
(14.47)
-3.8
(9.83)
-38.0
(32.53)
SBP, Week 48
6.5
(18.76)
-6.7
(11.18)
-84.0
(NA)
SBP, Week 52
7.7
(14.47)
-3.8
(24.78)
SBP, Week 56
8.4
(13.53)
-8.2
(18.74)
SBP, Week 60
9.3
(22.07)
-17.0
(9.31)
SBP, Week 64
3.5
(16.53)
-11.3
(11.24)
SBP, Week 68
0.1
(10.71)
-6.5
(12.02)
SBP, Week 72
7.1
(13.25)
-20.0
(NA)
SBP, Week 76
4.5
(12.96)
SBP, Week 80
8.7
(6.92)
SBP, Week 84
7.0
(20.20)
SBP, Week 88
-2.7
(16.32)
SBP, Week 92
10.4
(16.59)
SBP, Week 96
-0.5
(4.12)
SBP, Week 100
10.8
(7.53)
SBP, Week 104
7.0
(16.00)
SBP, Week 108
4.6
(7.89)
SBP, Week 112
12.3
(10.72)
SBP, Week 116
9.3
(15.22)
SBP, Week 120
13.3
(19.86)
SBP, Week 124
7.3
(8.50)
SBP, Week 128
-11.0
(9.90)
SBP, Week 132
-10.5
(10.61)
SBP, Week 136
-4.0
(18.38)
SBP, Week 140
4.5
(23.33)
SBP, Week 144
10.0
(0)
SBP, Week 148
25.0
(NA)
SBP, Withdrawal/Study Conclusion
0.5
(16.13)
-1.3
(15.64)
7.0
(20.28)
SBP, 30 Day Follow-up
2.4
(19.18)
-3.9
(17.03)
13.8
(19.25)
DBP, Week 4
-2.5
(10.36)
-3.9
(10.50)
-4.8
(11.10)
DBP, Week 8
-0.6
(11.41)
-8.9
(11.54)
-1.2
(12.46)
DBP, Week 12
-0.3
(10.19)
-6.2
(10.37)
-4.2
(12.87)
DBP, Week 16
-3.4
(12.98)
-3.2
(8.42)
-4.4
(15.18)
DBP, Week 20
-3.0
(12.65)
-1.6
(9.53)
-9.1
(13.65)
DBP, Week 24
-1.2
(11.30)
-1.8
(6.56)
-5.2
(13.08)
DBP, Week 28
-1.8
(14.27)
-2.1
(8.15)
-2.0
(5.05)
DBP, Week 32
-2.2
(13.70)
-6.3
(10.24)
-4.7
(6.51)
DBP, Week 36
-7.2
(6.48)
-3.3
(6.40)
-10.7
(11.02)
DBP, Week 40
-9.3
(11.36)
-0.7
(13.76)
-8.0
(19.80)
DBP, Week 44
-9.0
(6.59)
-2.3
(10.33)
-19.5
(6.36)
DBP, Week 48
-3.9
(7.57)
-0.2
(8.13)
-34.0
(NA)
DBP, Week 52
-7.4
(13.46)
-3.0
(12.33)
DBP, Week 56
-5.1
(8.62)
-3.4
(7.99)
DBP, Week 60
-3.6
(11.56)
-6.3
(6.24)
DBP, Week 64
-7.7
(12.27)
-5.3
(8.54)
DBP, Week 68
-11.0
(6.40)
-3.5
(7.78)
DBP, Week 72
3.0
(9.26)
-16.0
(NA)
DBP, Week 76
-4.8
(5.00)
DBP, Week 80
-3.5
(5.58)
DBP, Week 84
-5.8
(9.50)
DBP, Week 88
-9.3
(11.48)
DBP, Week 92
-3.8
(5.26)
DBP, Week 96
-7.3
(6.29)
DBP, Week 100
-4.4
(6.50)
DBP, Week 104
-4.6
(9.10)
DBP, Week 108
-2.0
(5.89)
DBP, Week 116
-8.5
(9.33)
DBP, Week 120
-6.0
(7.94)
DBP, Week 124
-6.0
(6.00)
DBP, Week 128
-12.5
(0.71)
DBP, Week 132
-14.5
(4.95)
DBP, Week 136
-17.0
(4.24)
DBP, Week 140
-7.5
(10.61)
DBP, Week 144
0.0
(0)
DBP, Week 148
1.0
(NA)
DBP, Withdrawal/Study Conclusion
-0.5
(11.39)
-0.4
(12.08)
2.1
(8.64)
DBP, 30 Day Follow-up
-0.8
(11.96)
0.8
(11.62)
3.2
(9.98)
11. Primary Outcome
Title Change From Baseline in Heart Rate at the Indicated Time Points
Description 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.
Time Frame Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years

Outcome Measure Data

Analysis Population Description
Safety Population. Safety Population: all participants who were randomized and received at least one dose of investigational product. Only those participants available at the specified time points were analyzed.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
Week 4
-1.714
(10.9099)
-3.417
(26.3593)
3.333
(12.1268)
Week 8
-5.667
(14.7908)
-3.231
(16.8481)
5.353
(10.7642)
Week 12
-0.217
(10.7109)
-0.417
(15.6812)
-2.875
(10.6074)
Week 16
-0.478
(13.4667)
2.625
(15.1369)
-1.917
(10.9084)
Week 24
-0.476
(16.7768)
-5.300
(15.1808)
5.167
(10.2843)
Week 28
-4.313
(16.0155)
-1.429
(17.7281)
3.600
(8.5615)
Week 32
-4.933
(16.6496)
-0.500
(11.1098)
0.333
(10.5987)
Week 36
-5.000
(13.0128)
4.857
(18.4791)
7.000
(11.5326)
Week 40
-1.000
(14.1614)
-3.571
(17.6149)
-2.500
(9.1924)
Week 44
-3.000
(11.1624)
-5.000
(17.9778)
-0.500
(10.6066)
Week 48
-5.500
(8.1955)
-2.500
(12.9422)
-14.000
(NA)
Week 52
-1.889
(14.4866)
-2.000
(11.8533)
Week 56
-2.000
(13.4907)
-2.000
(15.2151)
Week 60
-2.600
(13.3766)
1.500
(15.0222)
Week 64
-4.667
(16.1245)
0.000
(15.3840)
Week 68
-8.286
(21.1638)
1.000
(25.4558)
Week 72
-0.714
(21.0295)
19.000
(NA)
Week 76
-0.500
(16.6463)
Week 80
0.800
(14.4810)
Week 84
9.200
(21.1234)
Week 88
2.200
(24.6110)
Week 92
-2.400
(10.1390)
Week 96
-8.250
(7.6322)
Week 100
-6.750
(13.1751)
Week 104
-6.800
(15.3525)
Week 108
-8.750
(6.4485)
Week 112
-0.667
(15.0444)
Week 116
-4.667
(14.5717)
Week 120
-7.667
(9.4516)
Week 124
-5.333
(13.2035)
Week 128
1.000
(21.2132)
Week 132
-4.000
(14.1421)
Week 136
-4.000
(15.5563)
Week 140
-3.500
(16.2635)
Week 144
3.000
(NA)
Week 148
6.000
(NA)
Withdrawal/Study Conclusion
-1.435
(19.3481)
-7.900
(19.3990)
7.750
(9.8814)
30 Day Follow-up
0.560
(13.1564)
-7.889
(17.3526)
13.200
(11.6060)
12. Primary Outcome
Title Change From Baseline in Body Temperature at the Indicated Time Points
Description 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.
Time Frame Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years

Outcome Measure Data

Analysis Population Description
Safety Population: all participants who were randomized and received at least one dose of investigational product. Only those participants available at the specified time points were analyzed
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
Week 4
-0.229
(0.5062)
-0.242
(0.3605)
0.078
(0.5976)
Week 8
0.011
(0.5250)
-0.154
(0.4294)
0.247
(0.4652)
Week 12
0.021
(0.4374)
-0.567
(0.4960)
0.173
(0.4636)
Week 16
-0.052
(0.5814)
-0.127
(0.4880)
0.121
(0.5494)
Week 20
0.018
(0.5712)
-0.238
(0.4138)
0.300
(0.3536)
Week 24
0.157
(0.5006)
-0.100
(0.4138)
0.017
(0.5193)
Week 28
-0.094
(0.4956)
-0.529
(0.4751)
0.300
(0.3536)
Week 32
-0.156
(0.6077)
-0.237
(0.2134)
0.000
(0.2000)
Week 36
-0.215
(0.5728)
-0.129
(0.3946)
0.533
(0.3786)
Week 40
0.045
(0.4634)
-0.314
(0.1952)
0.450
(0.9192)
Week 44
-0.182
(0.4729)
-0.217
(0.3920)
0.250
(0.0707)
Week 48
-0.109
(0.4571)
-0.200
(0.1414)
0.300
(NA)
Week 52
-0.222
(1.0616)
-0.340
(0.3286)
Week 56
0.111
(0.6489)
-0.240
(0.6427)
Week 60
-0.070
(0.5889)
-0.225
(0.2754)
Week 64
-0.080
(0.4662)
-0.150
(0.1732)
Week 68
0.286
(0.6744)
-0.550
(0.0707)
Week 72
0.057
(0.7390)
-0.400
(NA)
Week 76
0.017
(0.4834)
Week 80
-0.150
(0.6442)
Week 84
0.067
(0.5610)
Week 88
-0.267
(0.4131)
Week 92
-0.200
(0.8155)
Week 96
-0.125
(0.4573)
Week 100
-0.100
(0.9083)
Week 104
-0.160
(0.7436)
Week 108
0.080
(0.6099)
Week 112
0.050
(0.5000)
Week 116
0.250
(0.6403)
Week 120
0.200
(0.4359)
Week 124
0.167
(0.8083)
Week 128
0.200
(1.4142)
Week 132
-0.150
(1.2021)
Week 136
0.000
(1.2728)
Week 140
0.450
(1.3435)
Week 144
1.300
(NA)
Week 148
0.700
(NA)
Withdrawal/Study Conclusion
-0.083
(0.6833)
-0.020
(0.4367)
0.237
(0.5999)
30 Day Follow-up
-0.092
(0.6238)
-0.400
(0.5074)
0.140
(0.5320)
13. Primary Outcome
Title Number of Participants With at Least 1 Event of Left Ventricular Ejection Fraction Decrease With the Indicated Characteristics
Description 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.
Time Frame Baseline and every 8 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years

Outcome Measure Data

Analysis Population Description
Safety Population. Only the participants with at least one of event of LVEF decrease were analyzed.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
Number [Participants]
8
27.6%
2
14.3%
0
0%
14. Primary Outcome
Title Number of Participants With the Indicated Eastern Cooperative Oncology Group (ECOG) Performance Status Value
Description 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.
Time Frame Baseline and every 4 weeks thereafter up to withdrawal/study completion and 30 day follow-up, up to approx. 3.5 years

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants available at the specified time points were analyzed (represented by n=X, X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the safety population.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
Screening, Grade 3
0
0%
0
0%
0
0%
Screening, Grade 4
0
0%
0
0%
0
0%
Screening, Grade 5
0
0%
0
0%
0
0%
Day 1 pre-dose, Grade 3
0
0%
0
0%
0
0%
Day 1 pre-dose, Grade 4
0
0%
0
0%
0
0%
Day 1 pre-dose, Grade 5
0
0%
0
0%
0
0%
Week 4, Grade 3
0
0%
0
0%
0
0%
Week 4, Grade 4
0
0%
0
0%
0
0%
Week 4, Grade 5
0
0%
0
0%
0
0%
Week 8, Grade 3
0
0%
0
0%
0
0%
Week 8, Grade 4
0
0%
0
0%
0
0%
Week 8, Grade 5
0
0%
0
0%
0
0%
Week 12, Grade 3
0
0%
0
0%
0
0%
Week 12, Grade 4
0
0%
0
0%
0
0%
Week 12, Grade 5
0
0%
0
0%
0
0%
Week 16, Grade 3
0
0%
0
0%
0
0%
Week 16, Grade 4
0
0%
0
0%
0
0%
Week 16, Grade 5
0
0%
0
0%
0
0%
Week 20, Grade 3
0
0%
0
0%
0
0%
Week 20, Grade 4
0
0%
0
0%
0
0%
Week 20, Grade 5
0
0%
0
0%
0
0%
Week 24, Grade 3
0
0%
0
0%
0
0%
Week 24, Grade 4
0
0%
0
0%
0
0%
Week 24, Grade 5
0
0%
0
0%
0
0%
Week 28, Grade 3
0
0%
0
0%
0
0%
Week 28, Grade 4
0
0%
0
0%
0
0%
Week 28, Grade 5
0
0%
0
0%
0
0%
Week 32, Grade 3
0
0%
0
0%
0
0%
Week 32, Grade 4
0
0%
0
0%
0
0%
Week 32, Grade 5
0
0%
0
0%
0
0%
Week 36, Grade 3
0
0%
0
0%
0
0%
Week 36, Grade 4
0
0%
0
0%
0
0%
Week 36, Grade 5
0
0%
0
0%
0
0%
Week 40, Grade 3
0
0%
0
0%
0
0%
Week 40, Grade 4
0
0%
0
0%
0
0%
Week 40, Grade 5
0
0%
0
0%
0
0%
Week 44, Grade 3
0
0%
0
0%
0
0%
Week 44, Grade 4
0
0%
0
0%
0
0%
Week 44, Grade 5
0
0%
0
0%
0
0%
Week 48, Grade 3
0
0%
0
0%
0
0%
Week 48, Grade 4
0
0%
0
0%
0
0%
Week 48, Grade 5
0
0%
0
0%
0
0%
Week 52, Grade3
0
0%
0
0%
Week 52, Grade4
0
0%
0
0%
Week 52, Grade5
0
0%
0
0%
Week 56, Grade 3
0
0%
0
0%
Week 56, Grade 4
0
0%
0
0%
Week 56, Grade 5
0
0%
0
0%
Week 60, Grade 3
0
0%
0
0%
Week 60, Grade 4
0
0%
0
0%
Week 60, Grade 5
0
0%
0
0%
Week 64, Grade 3
0
0%
0
0%
Week 64, Grade 4
0
0%
0
0%
Week 64, Grade 5
0
0%
0
0%
Week 68, Grade3
0
0%
0
0%
Week 68, Grade4
0
0%
0
0%
Week 68, Grade5
0
0%
0
0%
Week 72, Grade 3
0
0%
0
0%
Week 72, Grade 4
0
0%
0
0%
Week 72, Grade 5
0
0%
0
0%
Week 76, Grade3
0
0%
Week 76, Grade4
0
0%
Week 76, Grade5
0
0%
Week 80, Grade 3
0
0%
Week 80, Grade 4
0
0%
Week 80, Grade 5
0
0%
Week 84, Grade 3
0
0%
Week 84, Grade 4
0
0%
Week 84, Grade 5
0
0%
Week 88, Grade 3
0
0%
Week 88, Grade 4
0
0%
Week 88, Grade 5
0
0%
Week 92, Grade 3
0
0%
Week 92, Grade 4
0
0%
Week 92, Grade 5
0
0%
Week 96, Grade 3
0
0%
Week 96, Grade 4
0
0%
Week 96, Grade 5
0
0%
Week 100, Grade 3
0
0%
Week 100, Grade 4
0
0%
Week 100, Grade 5
0
0%
Week 104, Grade 3
0
0%
Week 104, Grade 4
0
0%
Week 104, Grade 5
0
0%
Week 108, Grade 3
0
0%
Week 108, Grade 4
0
0%
Week 108, Grade 5
0
0%
Week 112, Grade 3
0
0%
Week 112, Grade 4
0
0%
Week 112, Grade 5
0
0%
Week 116, Grade 3
0
0%
Week 116, Grade 4
0
0%
Week 116, Grade 5
0
0%
Week 120, Grade 3
0
0%
Week 120, Grade 4
0
0%
Week 120, Grade 5
0
0%
Week 124, Grade 3
0
0%
Week 124, Grade 4
0
0%
Week 124, Grade 5
0
0%
Week 128, Grade 3
0
0%
Week 128, Grade 4
0
0%
Week 128, Grade 5
0
0%
Week 132, Grade 3
0
0%
Week 132, Grade 4
0
0%
Week 132, Grade 5
0
0%
Week 136, Grade 3
0
0%
Week 136, Grade 4
0
0%
Week 136, Grade 5
0
0%
Week 140, Grade 3
2
6.9%
Week 140, Grade 4
0
0%
Week 140, Grade 5
0
0%
Week 144, Grade 3
0
0%
Week 144, Grade 4
0
0%
Week 144, Grade 5
0
0%
Week 148, Grade 3
0
0%
Week 148, Grade 4
0
0%
Week 148, Grade 5
0
0%
Withdrawal/Study conclusion, Grade 3
0
0%
0
0%
0
0%
Withdrawal/Study conclusion, Grade 4
0
0%
0
0%
0
0%
Withdrawal/Study conclusion, Grade 5
0
0%
0
0%
0
0%
15. Primary Outcome
Title Number of Participants Who Received Any Concomitant Medications During the Study Period
Description Number of participants who received any concomitant medication along with study drugs (lapatinib, trastuzumab and paclitaxel) were counted during the treatment period.
Time Frame withdrawal/study completion, up to approx. 3.5 years

Outcome Measure Data

Analysis Population Description
Safety Population: all participants who were randomized and received at least one dose of investigational product.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
Number [Participants]
29
100%
14
100%
20
100%
16. Primary Outcome
Title 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
Description 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.
Time Frame From the date of the first dose of investigational product to end of study, up to approx. 7 years

Outcome Measure Data

Analysis Population Description
Safety Population: all participants who were randomized and received at least one dose of investigational product.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
Number (95% Confidence Interval) [Percentage of participants]
79.3
273.4%
71.4
510%
70.0
350%
17. Secondary Outcome
Title Time to Response as Assessed by the Investigator
Description 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.
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

Outcome Measure Data

Analysis Population Description
Safety Population. Safety Population: all participants who were randomized and received at least one dose of investigational product. Only those participants with CR or PR were analyzed.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 23 10 14
Week 8
15
51.7%
8
57.1%
8
40%
Week 12
5
17.2%
1
7.1%
1
5%
Week 16
2
6.9%
1
7.1%
3
15%
Week 20
0
0%
0
0%
1
5%
Week 24
1
3.4%
0
0%
0
0%
Week 28
0
0%
0
0%
1
5%
18. Secondary Outcome
Title Duration of Response (DoR), as Assessed by the Investigator
Description 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.
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

Outcome Measure Data

Analysis Population Description
Safety Population. Safety Population: all participants who were randomized and received at least one dose of investigational product. Only those participants with CR or PR were analyzed.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
Median (Inter-Quartile Range) [Weeks]
56.6
59.0
70.6
19. Secondary Outcome
Title 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
Description 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.
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

Outcome Measure Data

Analysis Population Description
Safety Population. Safety Population: all participants who were randomized and received at least one dose of investigational product. Only those participants with CR, PR and SD for at least 24 weeks were analyzed.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
Number (95% Confidence Interval) [Percentage of Participants]
79.3
273.4%
71.4
510%
70.0
350%
20. Secondary Outcome
Title Progression-free Survival as Assessed by the Investigator
Description 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.
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

Outcome Measure Data

Analysis Population Description
Safety Population: all participants who were randomized and received at least one dose of investigational product. Only those participants with CR, PR and SD for at least 24 weeks were analyzed.
Arm/Group Title Cohort 1: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
Measure Participants 29 14 20
Median (95% Confidence Interval) [Weeks]
64.7
55.0
78.4

Adverse Events

Time Frame Adverse Events (AEs) and Serious adverse events (SAEs) were collected from the first dose of investigational product to 30 days after the last dose of investigational product, up to approx.12 years (maximum exposure to Lapatinib (615 weeks) plus 30 days.
Adverse Event Reporting Description AEs and SAEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of investigational product, according to the actual treatment received.
Arm/Group Title Cohort 1: Paclitaxel 80mg/Trastuzumab 4 mg/Lapatinib 1000mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Arm/Group Description Participants received an intravenous (IV) infusion of paclitaxel 80 milligrams per meter squared (mg/m^2) over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg per kilogram (mg/kg) loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. Participants received an IV infusion of paclitaxel 70 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 4 tablets of lapatinib (total daily dose 1000 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The paclitaxel dose was systematically increased to 80 mg/m^2 after 2 cycles if 70 mg/m^2 was tolerated. Participants received an IV infusion of paclitaxel 80 mg/m^2 over 60 minutes weekly for 3 weeks of a 4-week cycle plus an IV infusion of trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly plus a daily dose of 3 tablets of lapatinib (total daily dose 750 mg) at approximately the same time every day, either 1 hour (or more) before a meal or 1 hour (or more) after a meal. The lapatinib dose was systematically increased to 1000 mg after 2 cycles if the 750 mg dose was tolerated.
All Cause Mortality
Cohort 1: Paclitaxel 80mg/Trastuzumab 4 mg/Lapatinib 1000mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/29 (0%) 0/14 (0%) 0/20 (0%)
Serious Adverse Events
Cohort 1: Paclitaxel 80mg/Trastuzumab 4 mg/Lapatinib 1000mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 14/29 (48.3%) 6/14 (42.9%) 5/20 (25%)
Blood and lymphatic system disorders
Neutropenia 2/29 (6.9%) 0/14 (0%) 0/20 (0%)
Thrombocytopenia 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Cardiac disorders
Left ventricular dysfunction 2/29 (6.9%) 1/14 (7.1%) 0/20 (0%)
Gastrointestinal disorders
Diarrhoea 2/29 (6.9%) 1/14 (7.1%) 0/20 (0%)
Nausea 1/29 (3.4%) 0/14 (0%) 1/20 (5%)
Small intestinal obstruction 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Vomiting 1/29 (3.4%) 0/14 (0%) 1/20 (5%)
General disorders
Fatigue 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Mucosal inflammation 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Pyrexia 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Hepatobiliary disorders
Cholelithiasis 0/29 (0%) 0/14 (0%) 1/20 (5%)
Immune system disorders
Drug hypersensitivity 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Infections and infestations
Cellulitis 0/29 (0%) 2/14 (14.3%) 0/20 (0%)
Cellulitis streptococcal 0/29 (0%) 0/14 (0%) 1/20 (5%)
Clostridium difficile colitis 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Infectious colitis 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Pneumonia 0/29 (0%) 1/14 (7.1%) 1/20 (5%)
Injury, poisoning and procedural complications
Compression fracture 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Rib fracture 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Spinal compression fracture 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Investigations
Ejection fraction decreased 2/29 (6.9%) 1/14 (7.1%) 0/20 (0%)
Metabolism and nutrition disorders
Dehydration 5/29 (17.2%) 0/14 (0%) 1/20 (5%)
Hypocalcaemia 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Hypokalaemia 2/29 (6.9%) 0/14 (0%) 0/20 (0%)
Hypomagnesaemia 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Hypophosphataemia 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Nervous system disorders
Guillain-Barre syndrome 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Renal and urinary disorders
Renal failure 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Reproductive system and breast disorders
Ovarian cyst 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Pelvic pain 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Epistaxis 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Pleural effusion 0/29 (0%) 1/14 (7.1%) 1/20 (5%)
Skin and subcutaneous tissue disorders
Rash 1/29 (3.4%) 0/14 (0%) 0/20 (0%)
Other (Not Including Serious) Adverse Events
Cohort 1: Paclitaxel 80mg/Trastuzumab 4 mg/Lapatinib 1000mg Cohort 2: Paclitaxel 70 mg/Trastuzumab 4 mg/Lapatinib 1000 mg Cohort 3: Paclitaxel 80 mg/Trastuzumab 4 mg/Lapatinib 750 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 29/29 (100%) 13/14 (92.9%) 20/20 (100%)
Blood and lymphatic system disorders
Anaemia 11/29 (37.9%) 2/14 (14.3%) 3/20 (15%)
Eosinophilia 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Iron deficiency anaemia 1/29 (3.4%) 1/14 (7.1%) 0/20 (0%)
Leukopenia 5/29 (17.2%) 0/14 (0%) 1/20 (5%)
Neutropenia 4/29 (13.8%) 1/14 (7.1%) 4/20 (20%)
Cardiac disorders
Left ventricular dysfunction 1/29 (3.4%) 1/14 (7.1%) 0/20 (0%)
Ear and labyrinth disorders
Ear pain 1/29 (3.4%) 0/14 (0%) 2/20 (10%)
Vertigo 0/29 (0%) 1/14 (7.1%) 1/20 (5%)
Eye disorders
Eye irritation 2/29 (6.9%) 0/14 (0%) 0/20 (0%)
Lacrimation increased 3/29 (10.3%) 0/14 (0%) 2/20 (10%)
Ocular hyperaemia 1/29 (3.4%) 1/14 (7.1%) 0/20 (0%)
Vision blurred 2/29 (6.9%) 1/14 (7.1%) 1/20 (5%)
Visual impairment 3/29 (10.3%) 0/14 (0%) 0/20 (0%)
Gastrointestinal disorders
Abdominal hernia 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Abdominal pain 5/29 (17.2%) 1/14 (7.1%) 3/20 (15%)
Abdominal pain upper 4/29 (13.8%) 3/14 (21.4%) 1/20 (5%)
Cheilitis 0/29 (0%) 2/14 (14.3%) 0/20 (0%)
Constipation 7/29 (24.1%) 7/14 (50%) 5/20 (25%)
Diarrhoea 28/29 (96.6%) 13/14 (92.9%) 15/20 (75%)
Dyspepsia 7/29 (24.1%) 3/14 (21.4%) 2/20 (10%)
Dysphagia 3/29 (10.3%) 0/14 (0%) 0/20 (0%)
Eructation 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Flatulence 2/29 (6.9%) 2/14 (14.3%) 0/20 (0%)
Gastritis 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Gastrooesophageal reflux disease 4/29 (13.8%) 1/14 (7.1%) 3/20 (15%)
Gingival bleeding 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Nausea 16/29 (55.2%) 11/14 (78.6%) 13/20 (65%)
Oesophagitis 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Oral pain 0/29 (0%) 0/14 (0%) 2/20 (10%)
Rectal haemorrhage 1/29 (3.4%) 1/14 (7.1%) 0/20 (0%)
Stomatitis 8/29 (27.6%) 3/14 (21.4%) 6/20 (30%)
Toothache 2/29 (6.9%) 0/14 (0%) 1/20 (5%)
Vomiting 17/29 (58.6%) 6/14 (42.9%) 4/20 (20%)
General disorders
Asthenia 1/29 (3.4%) 1/14 (7.1%) 1/20 (5%)
Chest pain 2/29 (6.9%) 1/14 (7.1%) 0/20 (0%)
Chills 4/29 (13.8%) 1/14 (7.1%) 0/20 (0%)
Fatigue 21/29 (72.4%) 12/14 (85.7%) 13/20 (65%)
Mucosal inflammation 8/29 (27.6%) 6/14 (42.9%) 2/20 (10%)
Non-cardiac chest pain 0/29 (0%) 4/14 (28.6%) 2/20 (10%)
Oedema peripheral 5/29 (17.2%) 4/14 (28.6%) 0/20 (0%)
Pain 4/29 (13.8%) 3/14 (21.4%) 4/20 (20%)
Peripheral swelling 1/29 (3.4%) 1/14 (7.1%) 0/20 (0%)
Pyrexia 6/29 (20.7%) 5/14 (35.7%) 5/20 (25%)
Hepatobiliary disorders
Cholelithiasis 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Immune system disorders
Drug hypersensitivity 0/29 (0%) 0/14 (0%) 2/20 (10%)
Hypersensitivity 3/29 (10.3%) 2/14 (14.3%) 0/20 (0%)
Seasonal allergy 1/29 (3.4%) 1/14 (7.1%) 0/20 (0%)
Infections and infestations
Angular cheilitis 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Bronchitis 2/29 (6.9%) 0/14 (0%) 1/20 (5%)
Candida infection 2/29 (6.9%) 0/14 (0%) 0/20 (0%)
Cellulitis 1/29 (3.4%) 1/14 (7.1%) 0/20 (0%)
Conjunctivitis 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Cystitis 3/29 (10.3%) 1/14 (7.1%) 1/20 (5%)
Ear infection 2/29 (6.9%) 2/14 (14.3%) 0/20 (0%)
Fungal skin infection 1/29 (3.4%) 1/14 (7.1%) 0/20 (0%)
Gastroenteritis viral 0/29 (0%) 1/14 (7.1%) 2/20 (10%)
Herpes zoster 0/29 (0%) 1/14 (7.1%) 1/20 (5%)
Infection 3/29 (10.3%) 1/14 (7.1%) 1/20 (5%)
Laryngitis 2/29 (6.9%) 0/14 (0%) 0/20 (0%)
Localised infection 5/29 (17.2%) 1/14 (7.1%) 0/20 (0%)
Nail infection 2/29 (6.9%) 0/14 (0%) 1/20 (5%)
Nasopharyngitis 1/29 (3.4%) 0/14 (0%) 2/20 (10%)
Paronychia 2/29 (6.9%) 0/14 (0%) 1/20 (5%)
Pneumonia 1/29 (3.4%) 1/14 (7.1%) 0/20 (0%)
Sinusitis 3/29 (10.3%) 3/14 (21.4%) 1/20 (5%)
Skin infection 0/29 (0%) 1/14 (7.1%) 1/20 (5%)
Upper respiratory tract infection 8/29 (27.6%) 6/14 (42.9%) 3/20 (15%)
Urinary tract infection 5/29 (17.2%) 3/14 (21.4%) 2/20 (10%)
Vaginal infection 3/29 (10.3%) 0/14 (0%) 0/20 (0%)
Vulvovaginal mycotic infection 2/29 (6.9%) 1/14 (7.1%) 0/20 (0%)
Injury, poisoning and procedural complications
Postoperative wound complication 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Sunburn 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Investigations
Alanine aminotransferase increased 3/29 (10.3%) 1/14 (7.1%) 0/20 (0%)
Aspartate aminotransferase increased 2/29 (6.9%) 1/14 (7.1%) 1/20 (5%)
Blood alkaline phosphatase increased 4/29 (13.8%) 0/14 (0%) 1/20 (5%)
Blood creatinine increased 2/29 (6.9%) 1/14 (7.1%) 1/20 (5%)
Blood potassium decreased 2/29 (6.9%) 0/14 (0%) 1/20 (5%)
Blood pressure decreased 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Ejection fraction decreased 6/29 (20.7%) 1/14 (7.1%) 1/20 (5%)
Haemoglobin decreased 2/29 (6.9%) 0/14 (0%) 2/20 (10%)
Lymphocyte count decreased 2/29 (6.9%) 0/14 (0%) 0/20 (0%)
Neutrophil count decreased 2/29 (6.9%) 1/14 (7.1%) 1/20 (5%)
Weight decreased 7/29 (24.1%) 3/14 (21.4%) 0/20 (0%)
Weight increased 1/29 (3.4%) 1/14 (7.1%) 0/20 (0%)
White blood cell count decreased 3/29 (10.3%) 1/14 (7.1%) 3/20 (15%)
White blood cell count increased 2/29 (6.9%) 0/14 (0%) 1/20 (5%)
Metabolism and nutrition disorders
Decreased appetite 8/29 (27.6%) 2/14 (14.3%) 3/20 (15%)
Dehydration 8/29 (27.6%) 2/14 (14.3%) 1/20 (5%)
Hyperglycaemia 2/29 (6.9%) 1/14 (7.1%) 0/20 (0%)
Hyperkalaemia 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Hypoalbuminaemia 2/29 (6.9%) 0/14 (0%) 0/20 (0%)
Hypocalcaemia 5/29 (17.2%) 0/14 (0%) 1/20 (5%)
Hypokalaemia 12/29 (41.4%) 3/14 (21.4%) 2/20 (10%)
Hypomagnesaemia 3/29 (10.3%) 0/14 (0%) 0/20 (0%)
Hyponatraemia 4/29 (13.8%) 1/14 (7.1%) 0/20 (0%)
Hypophosphataemia 2/29 (6.9%) 1/14 (7.1%) 0/20 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia 6/29 (20.7%) 1/14 (7.1%) 6/20 (30%)
Back pain 5/29 (17.2%) 3/14 (21.4%) 3/20 (15%)
Bone pain 3/29 (10.3%) 0/14 (0%) 1/20 (5%)
Muscle spasms 2/29 (6.9%) 2/14 (14.3%) 1/20 (5%)
Muscle twitching 1/29 (3.4%) 1/14 (7.1%) 0/20 (0%)
Muscular weakness 2/29 (6.9%) 1/14 (7.1%) 0/20 (0%)
Musculoskeletal chest pain 3/29 (10.3%) 0/14 (0%) 3/20 (15%)
Musculoskeletal pain 4/29 (13.8%) 2/14 (14.3%) 1/20 (5%)
Myalgia 11/29 (37.9%) 3/14 (21.4%) 4/20 (20%)
Neck pain 5/29 (17.2%) 2/14 (14.3%) 1/20 (5%)
Pain in extremity 7/29 (24.1%) 3/14 (21.4%) 5/20 (25%)
Trismus 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to bone 2/29 (6.9%) 1/14 (7.1%) 0/20 (0%)
Nervous system disorders
Amnesia 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Dizziness 5/29 (17.2%) 3/14 (21.4%) 4/20 (20%)
Dysgeusia 3/29 (10.3%) 1/14 (7.1%) 2/20 (10%)
Headache 8/29 (27.6%) 5/14 (35.7%) 5/20 (25%)
Hyperaesthesia 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Hypoaesthesia 1/29 (3.4%) 1/14 (7.1%) 1/20 (5%)
Neuropathy peripheral 5/29 (17.2%) 6/14 (42.9%) 4/20 (20%)
Paraesthesia 7/29 (24.1%) 1/14 (7.1%) 5/20 (25%)
Peripheral sensory neuropathy 6/29 (20.7%) 2/14 (14.3%) 3/20 (15%)
Syncope 1/29 (3.4%) 1/14 (7.1%) 0/20 (0%)
Toxic neuropathy 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Psychiatric disorders
Anxiety 2/29 (6.9%) 3/14 (21.4%) 2/20 (10%)
Confusional state 1/29 (3.4%) 1/14 (7.1%) 1/20 (5%)
Depression 3/29 (10.3%) 3/14 (21.4%) 1/20 (5%)
Insomnia 6/29 (20.7%) 7/14 (50%) 3/20 (15%)
Renal and urinary disorders
Dysuria 3/29 (10.3%) 1/14 (7.1%) 0/20 (0%)
Ureteric stenosis 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Reproductive system and breast disorders
Breast pain 2/29 (6.9%) 1/14 (7.1%) 0/20 (0%)
Vaginal discharge 2/29 (6.9%) 0/14 (0%) 0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Cough 12/29 (41.4%) 3/14 (21.4%) 4/20 (20%)
Dyspnoea 5/29 (17.2%) 6/14 (42.9%) 4/20 (20%)
Dyspnoea exertional 2/29 (6.9%) 0/14 (0%) 0/20 (0%)
Epistaxis 10/29 (34.5%) 2/14 (14.3%) 1/20 (5%)
Lower respiratory tract congestion 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Nasal congestion 6/29 (20.7%) 3/14 (21.4%) 1/20 (5%)
Oropharyngeal pain 9/29 (31%) 2/14 (14.3%) 5/20 (25%)
Pleuritic pain 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Productive cough 1/29 (3.4%) 2/14 (14.3%) 1/20 (5%)
Sinus congestion 3/29 (10.3%) 1/14 (7.1%) 1/20 (5%)
Upper respiratory tract congestion 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Upper-airway cough syndrome 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Skin and subcutaneous tissue disorders
Alopecia 22/29 (75.9%) 8/14 (57.1%) 11/20 (55%)
Dermatitis contact 1/29 (3.4%) 2/14 (14.3%) 0/20 (0%)
Dry skin 5/29 (17.2%) 3/14 (21.4%) 3/20 (15%)
Hyperhidrosis 0/29 (0%) 2/14 (14.3%) 0/20 (0%)
Nail discolouration 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Nail disorder 7/29 (24.1%) 6/14 (42.9%) 3/20 (15%)
Nail ridging 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Pain of skin 0/29 (0%) 1/14 (7.1%) 1/20 (5%)
Palmar-plantar erythrodysaesthesia syndrome 1/29 (3.4%) 2/14 (14.3%) 0/20 (0%)
Photosensitivity reaction 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Pruritus 6/29 (20.7%) 5/14 (35.7%) 3/20 (15%)
Rash 25/29 (86.2%) 9/14 (64.3%) 17/20 (85%)
Rash follicular 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Rash papular 1/29 (3.4%) 1/14 (7.1%) 1/20 (5%)
Skin discolouration 2/29 (6.9%) 0/14 (0%) 0/20 (0%)
Skin fissures 1/29 (3.4%) 1/14 (7.1%) 1/20 (5%)
Telangiectasia 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Surgical and medical procedures
Mastectomy 1/29 (3.4%) 0/14 (0%) 2/20 (10%)
Prophylaxis 0/29 (0%) 1/14 (7.1%) 0/20 (0%)
Vascular disorders
Flushing 2/29 (6.9%) 0/14 (0%) 0/20 (0%)
Hot flush 5/29 (17.2%) 2/14 (14.3%) 3/20 (15%)
Hypotension 2/29 (6.9%) 0/14 (0%) 0/20 (0%)
Lymphoedema 4/29 (13.8%) 1/14 (7.1%) 1/20 (5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.

Results Point of Contact

Name/Title Clinical Disclosure Office
Organization Novartis Pharmaceuticals
Phone 862-778-8300
Email
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT00272987
Other Study ID Numbers:
  • EGF104383
  • 2005-003432-22
  • CLAP016A2301
First Posted:
Jan 9, 2006
Last Update Posted:
Dec 30, 2020
Last Verified:
Dec 1, 2020