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

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.

• Lapatinib in combination with weekly paclitaxel (Drug): 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.

Primary outcomes

• 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.
• 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 outcomes

• 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.
• 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.
• 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.
• 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.
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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

Sex: Female, ages: 18 Years to any

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).

Participant flow

Outcome results

• Number of Participants With Intolerable Toxicities in Phase I of the Study (Primary), Number, Participants: Lapatinib 1500 mg + Paclitaxel 80 mg/m^2 1
• Overall Survival (Primary), Median, Months: Lapatinib 1500 mg + Paclitaxel 80 mg/m^2 35.6 (23.9 to NA)
• Progression-free Survival (PFS) (Secondary), Median, Months: Lapatinib 1500 mg + Paclitaxel 80 mg/m^2 13.9 (7.6 to 27.9)
• Time to Response (Secondary), Median, Months: Lapatinib 1500 mg + Paclitaxel 80 mg/m^2 1.9 (1.8 to 1.9)
• Duration of Response (Secondary), Median, Months: Lapatinib 1500 mg + Paclitaxel 80 mg/m^2 14.5 (9.1 to 26.3)
• Number of Partcipants With a Best Overall Response (OR) as Determined by the Response Evaluation Criteria in Solid Tumors (RECIST) (Secondary), Number, Participants: Lapatinib 1500 mg + Paclitaxel 80 mg/m^2 0
• Number of Participants With Clinical Benefit Response (CBR) (Secondary), Number, Participants: Lapatinib 1500 mg + Paclitaxel 80 mg/m^2 0
• Maximum Plasma Concentration (Cmax) of Lapatinib and Paclitaxel (Secondary), Geometric mean, Nanogram per milliliter ng/mL: Lapatinib 1500 mg + Paclitaxel 80 mg/m^2 5945.022 (3077.881 to 11482.989)
• Area Under the Concentration-time Curve (AUC) (0-24) of Lapatinib and Paclitaxel (Secondary), Geometric mean, hours * nanograms/milliliter (hr*ng/mL): Lapatinib 1500 mg + Paclitaxel 80 mg/m^2 79518.047 (34664.607 to 182408.525)
• AUC From Time Zero to Infinity (0-INF) of Paclitaxel (Secondary), Geometric mean, hr*ng/mL: Lapatinib 1500 mg + Paclitaxel 80 mg/m^2 5125.908 (4371.289 to 6010.798)
• Time to the Maximum Drug Concentration (Tmax) of Lapatinib and Paclitaxel (Secondary), Median, Hr: Lapatinib 1500 mg + Paclitaxel 80 mg/m^2 4.992 (1.50 to 6.08)
• Distribution Volume at Steady State (Vss) of Paclitaxel (Secondary), Geometric mean, milliliter per meters squared (mL/m^2): Lapatinib 1500 mg + Paclitaxel 80 mg/m^2 98909.326 (73404.017 to 133276.831)
• Half-life (t1/2) of Paclitaxel (Secondary), Geometric mean, Hr: Lapatinib 1500 mg + Paclitaxel 80 mg/m^2 12.186 (10.055 to 14.768)
• Drug Clearance (CL) of Paclitaxel (Secondary), Geometric mean, mL/hour/m^2: Lapatinib 1500 mg + Paclitaxel 80 mg/m^2 15606.990 (13309.380 to 18301.238)

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).

Serious adverse events by term

Other adverse events by term

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• GSK Clinical Trials, Study director, GlaxoSmithKline