Trial of Afatinib in Combination With Weekly Paclitaxel in the Second Line Treatment

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma or poorly differentiated carcinoma of the intrathoracic esophagus, gastrointestinal junction or stomach.
• Tumor must be HER2 positive 3+ by immunohistochemistry or positive by Fluorescence in situ hybridization (FISH) analysis if 2+ by immunohistochemistry.
• Received and failed at least one prior cytotoxic chemotherapy regimen for advanced disease that included trastuzumab.
• Age greater than or equal to 18 years.
• At least one measurable lesion as defined by modified RECIST criteria.
• ECOG performance status less than or equal to 2.
• Life expectancy of at least 12 weeks.
• Normal organ and marrow function as defined.
• Able to swallow and retain oral medication.
• Left ventricular ejection fraction (LVEF) within institutional range of normal as measured by echocardiogram (ECHO).
• Prior malignancy is acceptable if the subject is considered to be cured.
• Ability to understand and the willingness to sign a written informed consent document.
• All subjects of childbearing potential must agree to use acceptable methods of birth control (Men and Women).
• Willingness to consent to the use of baseline diagnostic tumor specimen for correlative studies.

Exclusion Criteria:

• Squamous cell carcinoma.
• History of clinically relevant cardiovascular abnormalities within 6 months.
• Baseline (less than 1 month before treatment) cardiac left ventricular function with resting ejection fraction of less than 50 percent measured by multigated blood pool imaging of the heart (MUGA scan) or echocardiogram.
• Pregnant and lactating women are excluded from the study.
• Significant or recent acute gastrointestinal disorders with diarrhea.
• More than 2 prior cytotoxic chemotherapy regimens for relapsed or metastatic disease.
• Major surgery, chemotherapy, radiation therapy or other cancer therapy within 3 weeks of treatment day 1.
• Use of any investigational drug within 4 weeks.
• Prior treatment with taxanes if given as full-dose chemotherapy for advanced disease.
• Prior treatment with afatinib or any other HER2 inhibitor other than trastuzumab.
• Front-line chemotherapy that did not contain trastuzumab.
• Active central nervous system disease (CNS) metastases.
• Planned concurrent anti-cancer 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
• 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.
• Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to paclitaxel
• Prior anthracycline therapy with a cumulative dose of doxorubicin (or equivalent) greater than or equal to 400 mg/m2
• Pre-existing or current interstitial lung disease
• Known Hypersensitivity to Afatinib (BIBW 2992) or the excipients of any of the trial drugs.
• Patients unable to comply with the protocol.
• Active hepatitis B infection, active hepatitis C infection or known human immunodeficiency virus HIV carrier.
• Known or suspected active drug or alcohol abuse.
• Concomitant treatment with strong inhibitors or inducers of P-glycoprotein.