Randomized Discontinuation Study of Lapatinib Versus Placebo in Subjects With Documented Tumor Progression After Chemotherapy, or Where no Approved Therapy Exists

A Phase II, Placebo Controlled, Double-Blind, Randomized, Discontinuation Study of Lapatinib Administered Orally to Subjects With ErbB2 Positive Ovarian, Gastric/Esophageal Adenocarcinoma, Uterine Serous Papillary, or Bladder Cancer

This study will examine the efficacy and safety of lapatinib in patients with ErbB2 positive ovarian, gastric/esophageal adenocarcinoma, uterine serous papillary, or bladder cancers.

Inclusion Criteria:

• Signed written informed consent.
• Age >= 18 years old.
• Life expectancy of at least 12 weeks.
• Have histologically confirmed ovarian, gastric/esophageal adenocarcinoma, uterine serous papillary, or bladder cancer.
• Have ErbB2-positive cancer as determined by Fluorescence In Situ Hybridization (FISH) assay.
• Have documented tumor progression after receiving all standard/approved chemotherapies per National Comprehensive Cancer Network (NCCN) guidelines (V1) for their specific cancer and no approved therapy exists.
• Have one or more tumors measurable by medical imaging and assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Have archived tumor tissue available for biomarker analysis.
• Have a negative serum pregnancy test if female of childbearing potential.
• Any chemotherapy, major surgery, or irradiation must have been completed at least 3 weeks prior to receiving study drug (6 weeks for mitomycin-C or nitrosourea) and subject must have recovered from all toxicities incurred as a result of previous therapy.
• Have a gastrointestinal tract intact enough to swallow and assure absorption of the drug.
• Women of childbearing potential must have a negative serum pregnancy test at screening and must use an approved contraceptive method, if appropriate (for example, intrauterine device, birth control pills, or barrier device) beginning 2 weeks before the first dose of investigational product and for 28 days after the final dose of investigational product. Males able to father a child must practice adequate methods of birth control or practice complete abstinence from intercourse from the first dose of investigational treatment until one week after the final dose of investigational treatment.
• Have a cardiac ejection fraction within institutional range of normal as measured by either echocardiogram or multigated acquisition scans. The same method of cardiac evaluation must be used consistently throughout the study.
• Subjects must have adequate organ function:

Hematologic:

absolute neutrophil count >1.5 x 109/L hemoglobin >9 g/dL platelets >75 x 109/L

Hepatic:

albumin >2.5 g/dL serum bilirubin <1.25 x upper limit of normal aspartate aminotransferase/alanine aminotransferase <3 x ULN if no documented liver metastases aspartate aminotransferase/alanine aminotransferase <5 x ULN with documented liver metastases

Renal:

serum creatinine <2.0 mg/dL

• OR - calculated creatinine clearance1 >40 mL/min

Exclusion Criteria:

• Have New York Heart Association Class III or IV, cardiac disease, myocardial infarction within past 6 months, unstable arrhythmia or evidence of ischemia on electrocardiogram.
• Subjects who have had chemotherapy or radiotherapy within 3 weeks prior to entering the study or who have unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment.
• Concurrent treatment with an investigational agent or participation in another treatment clinical trial.
• Prior lapatinib therapy.
• ECOG Performance Status 2 or greater.
• Subjects receiving concurrent chemotherapy, radiation therapy, immunotherapy, biologic therapy (including an ErbB1 and/or ErbB2 inhibitor), or hormonal therapy for treatment of their cancer. Concurrent treatment with bisphosphonates is allowed.
• History of allergic reactions attributed to compounds of similar chemical composition (quinazolines) to lapatinib.
• Concurrent treatment with prohibited medications.
• Malabsorption syndrome, resection of the small bowel or active, uncontrolled ulcerative colitis.
• Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical or psychiatric disorder that would interfere with the subject's safety.
• Uncontrolled infection.
• Pregnant or lactating females.