Phase I/II Study of Lapatinib in Combination With Paclitaxel as 1L Chemotherapy for ErbB2-positive MBC

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01138046
• Collaborator: (none)
• Enrollment: 12
• Locations: 10
• Arm: 1
• Duration (Months): 45
• Patients Per Site: 1.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is an open-label, non-randomized, multi-center study of lapatinib plus paclitaxel to evaluate safety, tolerability and efficacy in Japanese patients with ErbB2 over expressing advanced or metastatic breast cancer. Lapatinib 1500mg/day will be administered in combination with paclitaxel 80mg/m2/week. Lapatinib and paclitaxel will be administered until disease progression or withdrawal from the study due to unacceptable toxicity.

The study will proceed in two phases. The first phase (Phase I part) will lead to evaluate safety and tolerability of lapatinib taken together with paclitaxel in the first 6 subjects. Pharmacokinetic profile also will be evaluated as the secondary objects.

Then the study will move to the next treatment phase (Phase II part) to evaluate further safety and clinical activity, if no major safety concerns are raised during Phase I part. The primary objective of the study is to evaluate overall survival (OS), and the secondary objectives are Objective tumour response rate (ORR), Duration of response, Time to response, Clinical benefit and Progression-free survival (PFS) in 12 subjects.

Condition or Disease	Intervention/Treatment	Phase
Neoplasms, Breast	Drug: Lapatinib in combination with weekly paclitaxel	Phase 2

Detailed Description

This is an open-label, single-arm, Phase I/II study to evaluate the efficacy, safety and tolerability of weekly paclitaxel and lapatinib in subjects with ErbB2-overexpressing advanced or metastatic breast cancer who have not received prior therapy for metastatic disease. These subjects will receive weekly paclitaxel (80 mg/m2 IV for 3 weeks in a 4 week cycle) plus lapatinib (1500 mg once daily). Subjects will receive a daily dose of lapatinib until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent. Subjects will be treated with paclitaxel for standard of 6 cycles, and may be continued at the discretion of investigators. If the subject experiences progression, an unacceptable toxicity related to paclitaxel, or termination of lapatinib therapy, paclitaxel therapy must be terminated any time of study period, even before 6 cycles of paclitaxel are given.

This study consists of the Phase I and Phase II parts:

Phase I part

Tolerability and pharmacokinetics in 6 subjects will be evaluated in Phase I part of study and the tolerability criteria are set as follow:

Tolerability criteria in first cycle; Concerning the safety tolerability of this trial, if 1 out of 6 first enrolled subjects meets the tolerability criteria, the study will proceed to phase II part and the regimen will judged as well tolerable. If 2 subjects meet the tolerability criteria, the sponsor will consult the safety review committee. GSK will finally judge based on the consultation regarding the tolerability and the medical significance.

Grade 4 hematologic toxicities. Thrombocytopenia less than or equal to 25,000/mm3 Grade 3 or 4 and clinically significant non-haematologic toxicities. Inability to start cycle 2 within 2 weeks of scheduled dosing due to unresolved toxicity.

For all 6 subjects enrolled, safety profiles occurred in cycle 1 are closely monitored individually. When considering the appropriateness of study continuation, not only the safety profiles noted in cycle 1 of this study, but also the safety profiles reported from pilot part of EGF104578 study and other relevant studies will be referred in order to make medical decisions.

Phase II part After tolerability in 6 subjects enrolled in Phase I part is confirmed, further 6 subjects to be enrolled for Phase II part (i.e. total of 12 subjects). Subjects will receive a daily dose of lapatinib until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent. All 12 subjects will be followed for survival.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Single-arm, Phase I/II Study of Lapatinib in Combination With Weekly Paclitaxel as First-line Chemotherapy for ErbB2-overexpressing Metastatic Breast Cancer Patients
• Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Lap+weekly Pacli These subjects will receive weekly paclitaxel (80 mg/m2 IV for 3 weeks in a 4 week cycle) plus lapatinib. Subjects will receive a daily dose of lapatinib until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.

Drug: Lapatinib in combination with weekly paclitaxel; These subjects will receive weekly paclitaxel (80 mg/m2 IV for 3 weeks in a 4 week cycle) plus lapatinib (1500 mg once daily, starting on the second day of phase I). Subjects will receive a daily dose of lapatinib until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent. Study completion is defined as deaths after administering study treatment for more than once. Subjects will be treated with paclitaxel for standard of 6 cycles, and may be continued at the discretion of investigators. If the subject experiences progression, an unacceptable toxicity related to paclitaxel, or termination of lapatinib therapy, paclitaxel therapy must be terminated any time of study period, even before 6 cycles of paclitaxel are given.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Intolerable Toxicities in Phase I of the Study [28 days]

   Investigational treatment was considered tolerable if one or more of the tolerability criteria were met by none or one of the 6 participants in the first cycle of Phase I. If one or more tolerability criteria were met by two or more participants, the issue was referred to the safety committee. Tolerability criteria for toxicities related to investigational treatment included grade 4 neutropenia persisting for 7 or more days, thrombocytopenia with a platelet count of less than or equal to 25,000/millimeter (mm)^3 , clinically significant Grade 3 or 4 non-haematologic toxicities (excluding nausea) and inability to start cycle 2 within 2 weeks of scheduled dosing due to unresolved toxicity.

2. Overall Survival [From the start of treatment until death due to any cause or study close, whichever occurred first (assessed up to a maximum of 1290 Days)]

   Overall survival is defined as the time from the start of treatment until death due to any cause. For participants who survived, time to death was censored at the time of the last confirmation of survival.

Secondary Outcome Measures

1. Progression-free Survival (PFS) [From the start of treatment until the earliest date of radiological disease progression or death due to any cause, whichever occured first (up to 1009 Days).]

   PFS is defined as the interval between the start of treatment and the earliest date of radiological disease progression or death due to any cause, whichever occurred first. PFS was based on the investigator's assessment. For participants who survived, time to death was censored at the time of the last confirmation of survival.

2. Time to Response [From the start of treatment until the first documented evidence of a PR or CR, whichever status is recorded first (up to 66 Days).]

   Time to response is defined as the time from the start of treatment until first documented evidence of partial response (PR) or a complete response (CR) (whichever status is recorded first). Analysis was based on responses confirmed at a repeat assessment made at least 4 weeks after the initial response, with the time to response taken as the first time the response was observed. 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 diameter (LD) of the target lesions, taking as a reference, the Baseline sum LD. Baseline measurements were obtained at the Screening Visit.

3. Duration of Response [From the first documented evidence of a CR or a PR until the first documented sign of disease progression or death, whichever occurred earlier (up to 953 Days).]

   Duration of response is defined as the time from the first documented evidence of a CR or a PR until the first documented sign of disease progression or death due to any cause (whichever occured earlier). The analysis was based on responses as evaluated by the investigator and was confirmed at a repeat assessment, with the duration of response taken from the first time the response was observed. CR is defined as the disappearance of all TLs and non-TLs. PR is defined as at least a 30% decrease in the sum of the LD of the target lesions, taking as a reference, the Baseline sum LD. Baseline measurements were obtained at the Screening Visit.

4. Number of Partcipants With a Best Overall Response (OR) as Determined by the Response Evaluation Criteria in Solid Tumors (RECIST) [From the start of treatment until progressive disease/death (up to 1009 Days).]

   Best OR was defined as the best response recorded from the start of treatment until progressive disease (PD)/death as assessed by the investigator. CR is defined as the disappearance of all TLs and non-TLs. PR is defined as at least a 30% decrease in the sum of the LD of the target lesions, taking as a reference, the Baseline sum LD. Baseline measurements were obtained at the Screening Visit. PD is defined as at least a 20% increase in the sum of the LD of target lesions or the appearance of 1 or more new lesions compared to the smallest sum LD recorded since the treatment started. Stable disease (SD) is defined as neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for PD compared to the smallest sum LD since the treatment started. Any participant who could not be classified by the four preceding definitions was considered Not evaluable.

5. Number of Participants With Clinical Benefit Response (CBR) [From the start of treatment until progressive disease/death (up to 1009 Days).]

   CBR is defined using RECIST as the number of participants who received at least one dose of study medication and achieved a best OR classified as CR, PR or SD for at least 6 months (24 weeks), i.e., CR + PR + SD for >=24 weeks. CBR was based on confirmed responses by the investigator. CR is defined as the disappearance of all TLs and non-TLs. PR is defined as at least a 30% decrease in the sum of the LD of the target lesions, taking as a reference, the Baseline sum LD. Baseline measurements were obtained at the Screening Visit. PD is defined as at least a 20% increase in the sum of the LD of TLs or the appearance of 1 or more new lesions compared to the smallest sum LD recorded since the treatment started. SD is defined as neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for PD compared to the smallest sum LD since the treatment started. Any participant who could not be classified by the the four preceding definitions was considered Not evaluable

6. Maximum Plasma Concentration (Cmax) of Lapatinib and Paclitaxel [Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 8 and Day 14 for lapatininb; Day 1 and Day 8 for paclitaxel]

   Cmax is defined as the maximum concentration of lapatinib and paclitaxel. Cmax was calculated from lapatinib plasma concentration-time data on Day 8 and Day 14 and paclitaxel plasma concentration-time data on Day 1 and Day 8 with model-independent analyses

7. Area Under the Concentration-time Curve (AUC) (0-24) of Lapatinib and Paclitaxel [Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 8 and Day 14 for lapatininb; Day 1 and Day 8 for paclitaxel]

   AUC is defined as the area under the lapatinib or paclitaxel concentration-time curve from time 0 to 24 hours (hrs). AUC (0-24) was calculated from lapatinib plasma concentration-time data on Day 8 and Day 14 and paclitaxel plasma concentration-time data on Day 1 and Day 8 with model-independent analyses

8. AUC From Time Zero to Infinity (0-INF) of Paclitaxel [Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 1 and Day 8 for paclitaxel]

   AUC(0-INF) is area under the plasma concentration-time curve from time 0 extrapolated to infinity. AUC (0-INF) was calculated from paclitaxel plasma concentration-time data on Day 1 and Day 8 with model-independent analyses

9. Time to the Maximum Drug Concentration (Tmax) of Lapatinib and Paclitaxel [Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 8 and Day 14 for lapatininb; Day 1 and Day 8 for paclitaxel]

   Tmax is defined as the time to peak concentration from initiation of lapatinib and paclitaxel dosing. Tmax was calculated from lapatinib plasma concentration-time data on Day 8 and Day 14 and paclitaxel plasma concentration-time data on Day 1 and Day 8 with model-independent analyses

10. Distribution Volume at Steady State (Vss) of Paclitaxel [Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 1 and Day 8 for paclitaxel]

    Vss is the volume of distribution at steady state of paclitaxel. Vss was calculated from paclitaxel plasma concentration-time data on Day 1 and Day 8 with model-independent analyses

11. Half-life (t1/2) of Paclitaxel [Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 1 and Day 8 for paclitaxel]

    Half-life is defined as the time required for the amount of the drug in the plasma to decrease by half. T1/2 was calculated from paclitaxel plasma concentration-time data on Day 1 and Day 8 with model-independent analyses

12. Drug Clearance (CL) of Paclitaxel [Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 1 and Day 8 for paclitaxel]

    CL is defined as the volume of plasma in the vascular compartment cleared of drug per unit time by the processes of metabolism and excretion. CL was calculated from paclitaxel plasma concentration-time data on Day 1 and Day 8 with model-independent analyses

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Prior written consent in participating in the study by the subject or his/her private attorney.

• Japanese female >=18 years of age.

• Invasive breast cancer with stage IV disease.

• Documentation by local laboratory of ErbB2 status by immunohistochemistry (IHC) or amplification by fluorescence in situ hybridization (FISH).

• If a taxane had been administered in the neoadjuvant or adjuvant setting, progression must have occurred >12 months after completion of this treatment and the patients recovered from all associated toxicities.

• Measurable lesion(s) according to RECIST criteria.

• Radiotherapy as palliative treatment for painful metastatic disease is permitted but must have been stopped within 2 weeks prior to initiation of any investigational treatment.

• For those patients whose disease is ER+ and/or PR+ one of the following criteria should be met:

• Patient with visceral disease that requires chemotherapy (e.g., patients with liver or lung metastases).

• Rapidly progressing or life threatening disease that are considered to be inapplicable to hormonal therapy, as determined by the investigator.

• Patients who received hormonal therapy and are no longer benefiting from this therapy and the hormonal treatment must have been stopped before the first dose of investigational treatment.

• Subjects recovered from all the associated toxicities by prior endocrine therapy.

• Eastern cooperative oncology group (ECOG) Performance status (PS) of 0 or 1.

• Able to swallow and retain oral medication.

• Cardiac ejection fraction within institutional range of normal as measured by echocardiogram. MUGA scan is accepted in cases where an echocardiogram cannot be performed or is inconclusive.

• Adequate organ function.

Exclusion Criteria:

• Pregnant or lactating females at anytime during the study.

• Received prior chemotherapy, immunotherapy, biologic therapy or anti-ErbB1/ErbB2 therapy for metastatic disease.

• History of other malignancy.

• Prior therapy with an ErbB1 and/or ErbB2 inhibitor, other than trastuzumab, in the adjuvant setting.

• Planned concurrent anti-cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy) while taking investigational treatment.

• Used an investigational drug within 30 days or five half-lives, whichever is longer, preceding the first dose of investigational treatment.

• Unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior anti-cancer treatment.

• Uncontrolled infection.

• Patients having at least positive antibody either to HBs or HBc.

• Patients who have had a positive HCV antibody.

• Peripheral neuropathy grade 2 or greater.

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

• Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.

• Known history or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis.

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

• Known history or concurrent condition of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure.

• Concurrent treatment with prohibited medications.

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to paclitaxel or lapatinib or their excipients.

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Aichi		Japan	464-8681
2	GSK Investigational Site	Ehime		Japan	791-0280
3	GSK Investigational Site	Hyogo		Japan	673-8558
4	GSK Investigational Site	Kagoshima		Japan	892-0833
5	GSK Investigational Site	Kanagawa		Japan	241-8515
6	GSK Investigational Site	Osaka		Japan	540-0006
7	GSK Investigational Site	Osaka		Japan	565-0871
8	GSK Investigational Site	Saitama		Japan	350-1298
9	GSK Investigational Site	Saitama		Japan	362-0806
10	GSK Investigational Site	Tokyo		Japan	113-8677

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01138046
• Other Study ID Numbers: 113806
• First Posted: Jun 7, 2010
• Last Update Posted: Oct 7, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by GlaxoSmithKline: advanced/metastatic breast cancer; lapatinib; ErbB2; ErbB2-overexpressing; pharmacokinetics; dual kinase inhibitor; HER-2/neu; EGFR; ErbB1
• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel; Lapatinib

Study Results

Participant Flow

Pre-assignment Detail	Six participants who met the eligibility criteria were enrolled into Phase I of the study. These 6 participants continued treatment into Phase II of the study, into which an additional 6 participants were enrolled. A total of 12 participants were followed until death or withdrawal from the study.

Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 milligrams (mg) once daily (QD) in combination with intravenous (IV) paclitaxel (80 milligrams per meters squared [mg/m^2]) weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Period Title: Overall Study
STARTED	12
COMPLETED	6
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Lapatinib 1500mg + Paclitaxel 80mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Overall Participants	12
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	58.1 (7.76)
Sex: Female, Male (Count of Participants)
Female	12 100%
Male	0 0%
Race/Ethnicity, Customized (Number) [Number]
Asian - Japanese Heritage	12 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Intolerable Toxicities in Phase I of the Study
Description	Investigational treatment was considered tolerable if one or more of the tolerability criteria were met by none or one of the 6 participants in the first cycle of Phase I. If one or more tolerability criteria were met by two or more participants, the issue was referred to the safety committee. Tolerability criteria for toxicities related to investigational treatment included grade 4 neutropenia persisting for 7 or more days, thrombocytopenia with a platelet count of less than or equal to 25,000/millimeter (mm)^3 , clinically significant Grade 3 or 4 non-haematologic toxicities (excluding nausea) and inability to start cycle 2 within 2 weeks of scheduled dosing due to unresolved toxicity.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

All Subjects Population: all participants who received at least one dose of study medication and participated in Phase I of the study.

Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Measure Participants	6
Number [Participants]	1 8.3%

2. Primary Outcome

Title	Overall Survival
Description	Overall survival is defined as the time from the start of treatment until death due to any cause. For participants who survived, time to death was censored at the time of the last confirmation of survival.
Time Frame	From the start of treatment until death due to any cause or study close, whichever occurred first (assessed up to a maximum of 1290 Days)

Outcome Measure Data

Analysis Population Description

All Subjects Population: all participants who received at least one dose of study medication

Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Measure Participants	12
Median (95% Confidence Interval) [Months]	35.6

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS is defined as the interval between the start of treatment and the earliest date of radiological disease progression or death due to any cause, whichever occurred first. PFS was based on the investigator's assessment. For participants who survived, time to death was censored at the time of the last confirmation of survival.
Time Frame	From the start of treatment until the earliest date of radiological disease progression or death due to any cause, whichever occured first (up to 1009 Days).

Outcome Measure Data

Analysis Population Description

All Subjects Population. Participants who met the following criteria were censored: no Baseline assessment, no progression, treatment discontinuation for undocumented progression, treatment discontinuation for toxicity or other reason, new anti-cancer treatment started, and death or progression after more than one missed visit.

Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Measure Participants	12
Median (95% Confidence Interval) [Months]	13.9

4. Secondary Outcome

Title	Time to Response
Description	Time to response is defined as the time from the start of treatment until first documented evidence of partial response (PR) or a complete response (CR) (whichever status is recorded first). Analysis was based on responses confirmed at a repeat assessment made at least 4 weeks after the initial response, with the time to response taken as the first time the response was observed. 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 diameter (LD) of the target lesions, taking as a reference, the Baseline sum LD. Baseline measurements were obtained at the Screening Visit.
Time Frame	From the start of treatment until the first documented evidence of a PR or CR, whichever status is recorded first (up to 66 Days).

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with a CR or a PR were assessed.

Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Measure Participants	10
Median (95% Confidence Interval) [Months]	1.9

5. Secondary Outcome

Title	Duration of Response
Description	Duration of response is defined as the time from the first documented evidence of a CR or a PR until the first documented sign of disease progression or death due to any cause (whichever occured earlier). The analysis was based on responses as evaluated by the investigator and was confirmed at a repeat assessment, with the duration of response taken from the first time the response was observed. CR is defined as the disappearance of all TLs and non-TLs. PR is defined as at least a 30% decrease in the sum of the LD of the target lesions, taking as a reference, the Baseline sum LD. Baseline measurements were obtained at the Screening Visit.
Time Frame	From the first documented evidence of a CR or a PR until the first documented sign of disease progression or death, whichever occurred earlier (up to 953 Days).

Outcome Measure Data

Analysis Population Description

All Subjects Population. Only those participants with a CR or a PR were assessed. For participants who did not progress or die, duration of response was censored on the date of the last assessment.

Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Measure Participants	10
Median (95% Confidence Interval) [Months]	14.5

6. Secondary Outcome

Title	Number of Partcipants With a Best Overall Response (OR) as Determined by the Response Evaluation Criteria in Solid Tumors (RECIST)
Description	Best OR was defined as the best response recorded from the start of treatment until progressive disease (PD)/death as assessed by the investigator. CR is defined as the disappearance of all TLs and non-TLs. PR is defined as at least a 30% decrease in the sum of the LD of the target lesions, taking as a reference, the Baseline sum LD. Baseline measurements were obtained at the Screening Visit. PD is defined as at least a 20% increase in the sum of the LD of target lesions or the appearance of 1 or more new lesions compared to the smallest sum LD recorded since the treatment started. Stable disease (SD) is defined as neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for PD compared to the smallest sum LD since the treatment started. Any participant who could not be classified by the four preceding definitions was considered Not evaluable.
Time Frame	From the start of treatment until progressive disease/death (up to 1009 Days).

Outcome Measure Data

Analysis Population Description

All Subjects Population. All participants who received at least one dose of study medication.

Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Measure Participants	12
CR	0 0%
PR	10 83.3%
SD	1 8.3%
PD	1 8.3%
Not evaluable	0 0%
Unkown	0 0%

7. Secondary Outcome

Title	Number of Participants With Clinical Benefit Response (CBR)
Description	CBR is defined using RECIST as the number of participants who received at least one dose of study medication and achieved a best OR classified as CR, PR or SD for at least 6 months (24 weeks), i.e., CR + PR + SD for >=24 weeks. CBR was based on confirmed responses by the investigator. CR is defined as the disappearance of all TLs and non-TLs. PR is defined as at least a 30% decrease in the sum of the LD of the target lesions, taking as a reference, the Baseline sum LD. Baseline measurements were obtained at the Screening Visit. PD is defined as at least a 20% increase in the sum of the LD of TLs or the appearance of 1 or more new lesions compared to the smallest sum LD recorded since the treatment started. SD is defined as neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for PD compared to the smallest sum LD since the treatment started. Any participant who could not be classified by the the four preceding definitions was considered Not evaluable
Time Frame	From the start of treatment until progressive disease/death (up to 1009 Days).

Outcome Measure Data

Analysis Population Description

All Subjects Population. All participants who received at least one dose of study medication.

Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Measure Participants	12
Complete response	0 0%
Partial response	10 83.3%
Stable disease >=24 weeks	0 0%
Stable disease <=24 weeks	1 8.3%
Progressive disease	1 8.3%
Not evaluable	0 0%
Unknown	0 0%

8. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Lapatinib and Paclitaxel
Description	Cmax is defined as the maximum concentration of lapatinib and paclitaxel. Cmax was calculated from lapatinib plasma concentration-time data on Day 8 and Day 14 and paclitaxel plasma concentration-time data on Day 1 and Day 8 with model-independent analyses
Time Frame	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 8 and Day 14 for lapatininb; Day 1 and Day 8 for paclitaxel

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: all participants who provided blood samples for PK evaluation

Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Measure Participants	6
Lapatinib 1500 mg, Day 14	5945.022
Lapatinib 1500 mg +Paclitaxel 80 mg/m^2, Day 8	9470.401
Paclitaxel 80 mg/m^2, Day 1	3485.229
Paclitaxel 80 mg/m2+ Lapatinib 1500 mg, Day 8	3412.332

9. Secondary Outcome

Title	Area Under the Concentration-time Curve (AUC) (0-24) of Lapatinib and Paclitaxel
Description	AUC is defined as the area under the lapatinib or paclitaxel concentration-time curve from time 0 to 24 hours (hrs). AUC (0-24) was calculated from lapatinib plasma concentration-time data on Day 8 and Day 14 and paclitaxel plasma concentration-time data on Day 1 and Day 8 with model-independent analyses
Time Frame	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 8 and Day 14 for lapatininb; Day 1 and Day 8 for paclitaxel

Outcome Measure Data

Analysis Population Description

PK Population: all participants who provided blood samples for PK evaluation

Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Measure Participants	6
Lapatinib 1500 mg, Day 14	79518.047
Lapatinib 1500 mg + Paclitaxel 80 mg/m^2, Day 8	113078.292
Paclitaxel 80 mg/m^2, Day 1	4657.218
Paclitaxel 80mg/m^2 + Lapatinib 1500 mg, Day 8	5786.123

10. Secondary Outcome

Title	AUC From Time Zero to Infinity (0-INF) of Paclitaxel
Description	AUC(0-INF) is area under the plasma concentration-time curve from time 0 extrapolated to infinity. AUC (0-INF) was calculated from paclitaxel plasma concentration-time data on Day 1 and Day 8 with model-independent analyses
Time Frame	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 1 and Day 8 for paclitaxel

Outcome Measure Data

Analysis Population Description

PK Population: all participants who provided blood samples for PK evaluation

Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Measure Participants	6
Paclitaxel 80 mg/m^2, Day 1	5125.908
Paclitaxel 80mg/m^2 + Lapatinib 1500 mg, Day 8	6279.964

11. Secondary Outcome

Title	Time to the Maximum Drug Concentration (Tmax) of Lapatinib and Paclitaxel
Description	Tmax is defined as the time to peak concentration from initiation of lapatinib and paclitaxel dosing. Tmax was calculated from lapatinib plasma concentration-time data on Day 8 and Day 14 and paclitaxel plasma concentration-time data on Day 1 and Day 8 with model-independent analyses
Time Frame	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 8 and Day 14 for lapatininb; Day 1 and Day 8 for paclitaxel

Outcome Measure Data

Analysis Population Description

PK Population: all participants who provided blood samples for PK evaluation

Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Measure Participants	6
Lapatinib 1500 mg, Day 14	4.992
Lapatinib 1500 mg + Paclitaxel 80 mg/m^2, Day 8	4.975
Paclitaxel 80 mg/m^2, Day 1	0.992
Paclitaxel 80mg/m^2 + Lapatinib 1500 mg, Day 8	0.975

12. Secondary Outcome

Title	Distribution Volume at Steady State (Vss) of Paclitaxel
Description	Vss is the volume of distribution at steady state of paclitaxel. Vss was calculated from paclitaxel plasma concentration-time data on Day 1 and Day 8 with model-independent analyses
Time Frame	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 1 and Day 8 for paclitaxel

Outcome Measure Data

Analysis Population Description

PK Population: all participants who provided blood samples for PK evaluation

Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Measure Participants	6
Paclitaxel 80 mg/m^2, Day 1	98909.326
Paclitaxel 80mg/m^2 + Lapatinib 1500 mg, Day 8	77460.104

13. Secondary Outcome

Title	Half-life (t1/2) of Paclitaxel
Description	Half-life is defined as the time required for the amount of the drug in the plasma to decrease by half. T1/2 was calculated from paclitaxel plasma concentration-time data on Day 1 and Day 8 with model-independent analyses
Time Frame	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 1 and Day 8 for paclitaxel

Outcome Measure Data

Analysis Population Description

PK Population: all participants who provided blood samples for PK evaluation

Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Measure Participants	6
Paclitaxel 80 mg/m^2, Day 1	12.186
Paclitaxel 80mg/m^2 + Lapatinib 1500 mg, Day 8	9.855

14. Secondary Outcome

Title	Drug Clearance (CL) of Paclitaxel
Description	CL is defined as the volume of plasma in the vascular compartment cleared of drug per unit time by the processes of metabolism and excretion. CL was calculated from paclitaxel plasma concentration-time data on Day 1 and Day 8 with model-independent analyses
Time Frame	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 1 and Day 8 for paclitaxel

Outcome Measure Data

Analysis Population Description

PK Population: all participants who provided blood samples for PK evaluation.

Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
Measure Participants	6
Paclitaxel 80 mg/m^2, Day 1	15606.990
Paclitaxel 80mg/m^2 + Lapatinib 1500 mg, Day 8	12738.926

Adverse Events

Time Frame	Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until 30 days after the last dose (up to 1045 Days).
Adverse Event Reporting Description	SAEs and non-serious AEs are reported for members of the All Subjects Population, comprised of all participants who had received at least one dose of the study medication.
Arm/Group Title	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
Arm/Group Description	Participants received lapatinib 1500 mg QD in combination with IV paclitaxel 80 mg/m^2 weekly on Day 1, Day 8, and Day 15 of a 4-week cycle until disease progression or withdrawal from study treatment due to unacceptable toxicity or withdrawal of consent.
All Cause Mortality
	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
	Affected / at Risk (%)	# Events
Total	3/12 (25%)
Cardiac disorders
Left ventricular dysfunction	1/12 (8.3%)
Infections and infestations
Pneumonia	1/12 (8.3%)
Investigations
Neutrophil count decreased	2/12 (16.7%)
Other (Not Including Serious) Adverse Events
	Lapatinib 1500 mg + Paclitaxel 80 mg/m^2
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Blood and lymphatic system disorders
Leukopenia	8/12 (66.7%)
Neutropenia	8/12 (66.7%)
Lymphopenia	6/12 (50%)
Erythropenia	3/12 (25%)
Cardiac disorders
Cardiomegaly	1/12 (8.3%)
Left ventricular dysfunction	1/12 (8.3%)
Ear and labyrinth disorders
Meniere's disease	1/12 (8.3%)
Eye disorders
Blepharitis	1/12 (8.3%)
Cataract	1/12 (8.3%)
Erythema of eyelid	1/12 (8.3%)
Eyelid oedema	1/12 (8.3%)
Vision blurred	1/12 (8.3%)
Gastrointestinal disorders
Diarrhoea	11/12 (91.7%)
Stomatitis	8/12 (66.7%)
Vomiting	6/12 (50%)
Nausea	5/12 (41.7%)
Abdominal pain upper	3/12 (25%)
Constipation	3/12 (25%)
Cheilitis	2/12 (16.7%)
Dental caries	2/12 (16.7%)
Haemorrhoids	2/12 (16.7%)
Abdominal distension	1/12 (8.3%)
Abdominal pain	1/12 (8.3%)
Gastritis	1/12 (8.3%)
Glossitis	1/12 (8.3%)
Periproctitis	1/12 (8.3%)
Proctalgia	1/12 (8.3%)
Toothache	1/12 (8.3%)
General disorders
Fatigue	8/12 (66.7%)
Oedema	3/12 (25%)
Oedema peripheral	3/12 (25%)
Pyrexia	3/12 (25%)
Mucosal inflammation	2/12 (16.7%)
Discomfort	1/12 (8.3%)
Feeling drunk	1/12 (8.3%)
Feeling hot	1/12 (8.3%)
Injection site reaction	1/12 (8.3%)
Malaise	1/12 (8.3%)
Infections and infestations
Paronychia	7/12 (58.3%)
Nasopharyngitis	6/12 (50%)
Gingivitis	2/12 (16.7%)
Bronchitis	1/12 (8.3%)
Cystitis	1/12 (8.3%)
Erysipelas	1/12 (8.3%)
Folliculitis	1/12 (8.3%)
Influenza	1/12 (8.3%)
Nail infection	1/12 (8.3%)
Subcutaneous abscess	1/12 (8.3%)
Injury, poisoning and procedural complications
Contusion	1/12 (8.3%)
Fractured coccyx	1/12 (8.3%)
Infusion related reaction	1/12 (8.3%)
Investigations
Haemoglobin decreased	10/12 (83.3%)
Alanine aminotransferase increased	7/12 (58.3%)
Aspartate aminotransferase increased	6/12 (50%)
Haematocrit decreased	6/12 (50%)
Blood alkaline phosphatase increased	5/12 (41.7%)
Weight decreased	4/12 (33.3%)
Blood albumin decreased	3/12 (25%)
Neutrophil count decreased	3/12 (25%)
White blood cell count decreased	3/12 (25%)
Basophil count decreased	2/12 (16.7%)
Blood bilirubin increased	2/12 (16.7%)
Monocyte count decreased	2/12 (16.7%)
Platelet count increased	2/12 (16.7%)
Red blood cell count decreased	2/12 (16.7%)
Blood glucose increased	1/12 (8.3%)
Blood potassium decreased	1/12 (8.3%)
Blood potassium increased	1/12 (8.3%)
Blood urea increased	1/12 (8.3%)
Electrocardiogram QT prolonged	1/12 (8.3%)
Eosinophil count decreased	1/12 (8.3%)
Neutrophil count increased	1/12 (8.3%)
White blood cell count increased	1/12 (8.3%)
Metabolism and nutrition disorders
Decreased appetite	7/12 (58.3%)
Dehydration	1/12 (8.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/12 (25%)
Myalgia	3/12 (25%)
Back pain	2/12 (16.7%)
Muscular weakness	1/12 (8.3%)
Musculoskeletal pain	1/12 (8.3%)
Musculoskeletal stiffness	1/12 (8.3%)
Osteoarthritis	1/12 (8.3%)
Pain in extremity	1/12 (8.3%)
Periarthritis	1/12 (8.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	1/12 (8.3%)
Nervous system disorders
Peripheral sensory neuropathy	8/12 (66.7%)
Dysgeusia	5/12 (41.7%)
Headache	2/12 (16.7%)
Hypoaesthesia	1/12 (8.3%)
Neuropathy peripheral	1/12 (8.3%)
Somnolence	1/12 (8.3%)
Psychiatric disorders
Insomnia	1/12 (8.3%)
Renal and urinary disorders
Neurogenic bladder	1/12 (8.3%)
Reproductive system and breast disorders
Vaginal discharge	1/12 (8.3%)
Vaginal inflammation	1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	5/12 (41.7%)
Cough	3/12 (25%)
Pneumonitis	2/12 (16.7%)
Oropharyngeal discomfort	1/12 (8.3%)
Pharyngeal inflammation	1/12 (8.3%)
Skin and subcutaneous tissue disorders
Alopecia	12/12 (100%)
Rash	8/12 (66.7%)
Nail disorder	6/12 (50%)
Dry skin	2/12 (16.7%)
Erythema	2/12 (16.7%)
Skin hyperpigmentation	2/12 (16.7%)
Acne	1/12 (8.3%)
Dermatitis	1/12 (8.3%)
Dermatitis acneiform	1/12 (8.3%)
Keratolysis exfoliativa acquired	1/12 (8.3%)
Palmar-plantar erythrodysaesthesia syndrome	1/12 (8.3%)
Pigmentation disorder	1/12 (8.3%)
Skin fissures	1/12 (8.3%)
Vascular disorders
Hot flush	1/12 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.