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

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.

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.

Eligibility Criteria:
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).