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Drug: Lapatinib, Vinorelbine Lapatinib 1250mg orally once daily continuously

plus

Vinorelbine 20 mg/m2 intravenously (IV) once weekly \[Days 1 and 8\] for 2 weeks, followed by a rest week in a 3-week cycle.

Lapatinib 1250mg orally once daily continuously

plus

Vinorelbine 20 mg/m2 intravenously (IV) once weekly \[Days 1 and 8\] for 2 weeks, followed by a rest week in a 3-week cycle.

Lapatinib, Vinorelbine

Istvan Lang, MD

The objective of this phase II study is to gain first information on the efficacy (PFS, ORR and OS) and safety of lapatinib plus vinorelbine in patients with HER2 positive metastatic breast cancer pretreated with a combination therapy (chemotherapy and/or hormonal therapy) including lapatinib and presenting with tumor progression.

Primary objective is to assess the efficacy with respect to the percentage of patients surviving without disease progression as assessed by RECIST criteria.

Secondary objectives are to assess the efficacy of the study treatment with respect to the objective response rates as assessed by RECIST criteria version 1.1, the overall survival and to evaluate the safety profile of the combination by recording the adverse events and abnormal laboratory values associated with the study treatments.

The main efficacy endpoints will be investigated both for the intent-to-treat (ITT) population and the per-protocol (PP) population.

The objective of this phase II study is to gain first information on the efficacy (PFS, ORR and OS) and safety of lapatinib plus vinorelbine in patients with HER2 positive breast cancer pretreated with a combination therapy (chemotherapy, hormonal therapy) including lapatinib for metastatic disease.

The sample size is not based on statistical consideration. Thirty 30 patients are considered appropriate for a phase II study to gain first information on the efficacy and safety of the study treatment in the study indication.

Only descriptive statistical methods will be used to summarize the study results. Kaplan-Meier estimates will be calculated for PFS and OS. Median PFS and OS time and corresponding two sided 95% confidence intervals will be provided.

Categorical endpoints will be summarized in frequency tables and 95% confidence intervals will be calculated for the objective response rate (ORR) using RECIST.

All safety variables will be summarized descriptively The incidence of adverse events will be summarized by MedDRA terms in a descriptive manner.

The progression free survival time (PFS) is the primary efficacy endpoint of the study. Secondary outcomes are overall survival (OS) and objective response rates (ORR) using RECIST.

Safety outcomes are adverse events, safety laboratory data, physical examinations, vital signs, LVEF, ECG data and ECOG performance status

Definitions:

The objective response rate is the rate of subjects with complete response (CR) or partial response (PR).

Progression-free survival:

The time to progression or death is defined as the time from study entry until the first observation of disease progression or death due to any cause (whichever occurred earlier). Only those death will be considered, which occurs within 84 days of the last tumor assessment or study entry (whichever is later).

If a patient has no progression before a clinical cut-off or the death date is beyond the above-mentioned time interval after last tumor assessment, time to progression/death is censored on the date of last tumor assessment or study entry (in case of no post-baseline tumor assessment).

Overall survival will be calculated from study entry until death. For patients lost to follow-up, data will be censored at the time the patient was last determined to be alive.

As efficacy data of vinorelbine plus lapatinib are not available so far and the current protocol is applied as 2nd or 3rd line therapy for metastatic disease an ORR from 30-40% and a median PFS from 4-6 months is expected.

A Study Evaluating the Efficacy and Safety of Lapatinib + Vinorelbine in ErbB2 Positive Metastatic Breast Cancer Patients

A Phase II Study Evaluating the Efficacy and Safety of Lapatinib + Vinorelbine in ErbB2 Positive Metastatic Breast Cancer Patients Pretreated With Chemotherapy or Hormonal Treatment in Combination With Lapatinib for Metastatic Disease

Number of Participants with Adverse Events as a Measure of Safety and Tolerability

* assess the efficacy of the study treatment with respect to the objective response rates as assessed by RECIST criteria version 1.1 the overall survival
* evaluate the safety profile of the combination by recording the adverse events and abnormal laboratory values associated with the study treatments.

Central European Cooperative Oncology Group

Vinorelbine intravenously once weekly for 3 weeks, followed by a rest week in a 4-week cycle) plus lapatinib daily

GSK Clinical Trials

This is an open-label, single-arm, multi-center, Phase II study to determine the activity of vinorelbine plus lapatinib in either first- or second-line setting in women with ErbB2 overexpressing metastatic breast cancer (MBC). Sixty subjects will be enrolled in the study. Subjects will receive vinorelbine intravenously once weekly for 3 weeks, followed by a rest week in a 4-week cycle) plus lapatinib daily. Subjects will receive treatment until disease progression or withdrawal from the study. The primary objective of this study is to evaluate overall tumor response rate of lapatinib in combination with vinorelbine. Secondary objectives include progression-free survival, overall survival, duration of response, time to response and time to progression and safety. Safety and efficacy assessments will be performed at 4, 8 and 12 week intervals, and at the end of treatment.

Subject: Metastatic Breast Cancer, ErbB2, First-line or Second-line therapy, Lapatinib, Vinorelbine

Lapatinib + Vinorelbine in ErbB2 Overexpressing, First or Second Line Metastatic Breast Cancer Subjects

A Phase II, Single-Arm, Multi-Center Study Evaluating the Combination of Vinorelbine and Lapatinib in Women With ErbB2 Overexpressing Metastatic Breast Cancer

OR is defined as the number of participants achieving either a confirmed complete response (CR: the disappearance of all target lesions \[TLs\]) or partial response (PR: a \>=30% decrease in the sum of the longest diameter \[LD\] of the TLs, taking as a reference the baseline sum LD) as assessed by the investigator as the best OR. The best OR is the best response recorded from the start of treatment until disease progression (PD: a \>=20% increase in the sum of the LD of TLs, taking as a reference the smallest sum LD recorded since treatment started or the appearance of \>=1 new lesions)/recurrence.

PFS is defined as the time from the start of treatment until the earliest date of disease progression (PD) or death due to any cause, if sooner. PD is defined as 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.

Duration of response, for the subset of participants who had a confirmed CR (the disappearance of all TLs) or PR (a \>=30% decrease in the sum of the LD of the TLs, taking as a reference the baseline sum LD), is defined as the time from the first documented evidence of CR or PR until the first documented sign of disease progression (a \>=20% increase in the sum of the LD of TLs, taking as a reference the smallest LD recorded since treatment started or the appearance of \>=1 new lesions) or death due to any cause, if sooner.

Time to response, for the subset of participants who had a confirmed CR (the disappearance of all TLs) or PR (a \>=30% decrease in the sum of the LD of the TLs, taking as a reference the baseline sum LD), is defined as the time from the start of treatment until the first documented evidence of CR or PR (whichever status was recorded first). When tumor response was confirmed at a repeat assessment, the time to response was taken to be the first time that the response was observed.

TTP is defined as the time from the start of treatment until the earliest date of disease progression (a \>=20% increase in the sum of the LD of TLs, taking as a reference the smallest LD recorded since treatment started or the appearance of \>=1 new lesions) or death due to breast cancer, if sooner.

Qualitative and quantitative toxicities associated with the combination of lapatinib and vinorelbine during the study are those adverse events (AEs) that are judged to be related to the study treatment by the investigator. Those AEs occuring in more than 5 participants in the ITT Population are listed here.

OS is defined as the time from the start of study treatment to the date of death. In the absence of confirmation of death, survival time was to be censored at the last date the participant was known to be alive. Overall survival was not assessed because the study was terminated due to low screening and a low enrollment rate after 3 years. There were no-survival follow-up visits required.

GlaxoSmithKline

SAEs and non-serious AE data are reported for the ITT Population, comprised of all participants who received at least one dose of investigational product.

Participants received vinorelbine (20 mg/m\^2) IV once weekly for 3 weeks (on Days 1, 8, and 15 of a 4-week cycle, followed by a rest week) plus oral lapatinib (1500 mg once daily). Participants received study treatment until disease progression or withdrawal.

Vinorelbine 20 mg/m^2 Plus Lapatinib 1500 mg

Age, Continuous

Sex: Female, Male

White

African American/African Heritage

Race/Ethnicity, Customized

The study was terminated due to low screening and a low enrollment rate after 3 years.

GSK Response Center

Intent-to-Treat (ITT) Population: participants who received \>=1 dose of investigational product. To be assigned a status of PR/CR, a confirmatory disease assessment (including bone scan/positron emission tomography scan documenting that progression/ new lesions hasn't occurred) had to be performed \>=4 weeks after response criteria were first met.

Number of Participants With Overall Response (OR), as Assessed by the Investigator

ITT Population. Participants who had neither progressed nor died were censored at the date of the last adequate tumor assessment at the time of the cut-off. Censoring is defined as being alive without the event of interest (progression or death).

Progression-Free Survival (PFS), as Assessed by the Investigator

ITT Population. Only participants with a confirmed CR/PR were assessed for duration of response. To be assigned a status of PR/CR, a confirmatory disease assessment (including bone scan/positron emission tomography scan documenting that progression/ new lesions hasn't occurred) had to be performed \>=4 weeks after response criteria were first met.

Duration of Response, as Assessed by the Investigator

Time to Response, as Assessed by the Investigator

Time to Progression (TTP), as Assessed by the Investigator

Diarrhoea

Nausea

Constipation

Vomiting

Abdominal pain

Stomatitis

Neutropenia

Anaemia

Fatigue

Mucosal inflammation

Rash

Neutrophil count decreased

Haemoglobin decreased

White blood cell count decreased

Neuropathy peripheral

Arthralgia

Decreased appetite

Number of Participants With the Indicated Adverse Events Occurring in at Least 5 Participants and Related to the Combination of Lapatinib and Vinorelbine

Overall Survival

Participants received vinorelbine (20 milligrams per meters squared \[mg/m\^2\]) intravenously (IV) once weekly for 3 weeks (on Days 1, 8, and 15 of a 4-week cycle, followed by a rest week) plus oral lapatinib (1500 mg once daily). Participants received study treatment until disease progression or withdrawal.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study Evaluating the Efficacy and Safety of Lapatinib + Vinorelbine in ErbB2 Positive Metastatic Breast Cancer Patients	NCT01161368	Metastatic Brea...	Lapatinib, Vino...	18 Years -	Central European Cooperative Oncology Group
Lapatinib + Vinorelbine in ErbB2 Overexpressing, First or Second Line Metastatic Breast Cancer Subjects	NCT00709618	Neoplasms, Brea...	Lapatinib, Vino...	18 Years -	GlaxoSmithKline

Spots Global Cancer Trial Database for lapatinib, vinorelbine