Lapatinib in Combination With Weekly Paclitaxel in Patients With ErbB2 Amplified Advanced Gastric Cancer

Inclusion criteria:

Specific Information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the investigational product that may impact subject eligibility is provided in the Investigator's Brochure (IB) Pilot Part

Subjects eligible for enrollment in the Pilot Part of the study must meet all of the following criteria:

* Signed informed consent
* Male or female; ≥ 20 years (at the time of giving consent)
* Any histologically or cytologically confirmed gastric carcinoma independent of tumor ErbB2 status
* Subjects who have received one prior regimen for gastric carcinoma and developed disease progression or recurrence. The regimen must have contained 5-fluoropyrimidine and/or cisplatin
* Left ventricular ejection fraction (LVEF) within institutional range of normal as measured by echocardiogram (ECHO). Multigated acquisition (MUGA) scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive (LVEF of ≥50% required if normal range of LVEF is not provided by institution)
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1
* Able to swallow and retain oral medication
* Women and men with potential to have children must be willing to practice acceptable methods of birth control during the study
* Washout period from the prior last therapy as follows; Chemotherapy (except for agents below) 4 weeks (I.V) Chemotherapy (except for agents below) 2 weeks (P.O) Trastuzumab, Bevacizumab 4 weeks Mitomycin-C, nitrosourea 6 weeks Radiotherapy, Immunotherapy, Biologic therapy and Surgery (except for minor surgical procedure) 2 weeks
* Willing to complete all screening assessments as outlined in the protocol
* Adequate organ function as defined in Table 2 Baseline Laboratory Values
* Able to be hospitalized for PK analysis during cycle 1
* Life expectancy of at least 12 weeks from the first dose of study treatment)

Randomized Part

Subjects eligible for enrollment in the Randomized Part of the study must meet all of the following criteria:

* Signed informed consent
* Male or female; ≥ 20 years (at the time of giving consent)
* Histologically or cytologically confirmed gastric carcinoma with documented amplification of ErbB2 by fluorescence in situ hybridization (FISH) in primary or metastatic tumor tissue
* Subjects who received one prior regimen for gastric carcinoma and defined as progression disease. The regimen must be containing 5-fluoropyrimidine and/or cisplatin
* Measurable lesion(s) according to RECIST (Response Evaluation Criteria in Solid Tumors)
* Left ventricular ejection fraction (LVEF) within institutional range of normal as measured by echocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive (LVEF of ≥50% required if normal range of LVEF is not provided by institution)
* ECOG Performance Status of 0 to 1
* Able to swallow and retain oral medication
* Archived (or Biopsy ) tumor tissue available for FISH testing \[Wolff, 2007\] in central laboratory
* Women and men with potential to have children must be willing to practice acceptable methods of birth control during the study
* Washout period from the prior last therapy as follows; Chemotherapy (except for agents below) 4 weeks (IV) Chemotherapy (except for agents below) 2 weeks (P.O) Trastuzumab, Bevacizumab 4 weeks Mitomycin-C, nitrosourea 6 weeks Radiotherapy, Immunotherapy, Biologic therapy and Surgery (except for minor surgical procedure) 2 weeks
* Willing to complete all screening assessments as outlined in the protocol
* Adequate organ function as defined in Table 2
* Gastrectomy status depending on the result in the Pilot Part
* Life expectancy of at least 12 weeks from the first dose of study treatment

Table 2 Baseline Laboratory Values

SYSTEM LABORATORY (VALUES)

Hematologic:

ANC (absolute neutrophil count)

Hemoglobin:

Platelets (≥ 2.0 × 10\^9/L) (≥ 9 g/dL) (≥ 100 × 10\^9/L) Hepatic Albumin Serum bilirubin AST and ALT (≥ 2.5 g/dL) (≤ 1.25 x ULN) (≤ 2.5 × ULN without liver metastases) (≤ 5 × ULN if documented liver metastases) Renal Serum Creatinine

Calculate Creatinine Clearance (see Section 11.3) (≤ 2.0 mg/dL)

\- OR - (≥30 mL/min)

Exclusion criteria:

Subjects meeting any of the following criteria must not be enrolled in the study:

* Pregnant or lactating female at anytime during the study
* Planned concurrent anti-cancer therapy (chemotherapy, radiotherapy, immunotherapy, biologic therapy, hormonal therapy) while taking investigational treatment
* Unresolved or unstable, serious toxicity from prior cancer treatment (any toxicities greater than grade 2)
* Peripheral neuropathy of Grade 2 or greater
* Malabsorption syndrome, disease significantly affecting gastrointestinal function. Subjects with ulcerative colitis and Crohn's disease are also excluded
* History of other malignancy. However, subjects who have been disease-free for 5 years, or subjects 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 subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety
* Life threatening 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, or congestive heart failure
* Known history or clinical evidence of central nervous system (CNS) metastasis
* Concurrent treatment with prohibited medications, including herbal remedies and Chinese traditional medicines
* Concurrent treatment with an investigational agent within 28 days prior to the administration of paclitaxel and/or lapatinib
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to paclitaxel, including polyethoxylated castor oil, alcohol, or lapatinib or their excipients
* Anamnesis or diagnosis of pulmonary disorder, such as interstitial pneumonia, pulmonary fibrosis or serious hypoxia
* Gastrectomy surgery if Pilot Part of the study determines that partial gastrectomy (pylorus spared) or total/partial gastrectomy (pylorus removed) has a significant negative impact upon lapatinib PK and safety profile
* Known history of use of any EGFR agent (except Trastuzumab)
* Prior gastric cancer treatment which included a taxane.