This is a single-arm phase I/Ib study of crenolanib combined with ramucirumab/paclitaxel as second line therapy for patients with advanced/metastatic adenocarcinoma of the esophagus, GEJ or stomach. Patients will be enrolled in two phases; dose escalation phase and dose expansion phase.

Inclusion Criteria:

• Pathologically confirmed adenocarcinoma of the esophagus, GEJ or stomach.
• Stage IV disease or locally advanced/unresectable tumors
• Prior progression on only 1 line of chemotherapy in the advanced/metastatic setting containing a fluoropyrimidine and/or platinum compound
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

Exclusion Criteria:

• Prior treatment with a taxane is not permitted in the dose-expansion phase. Patients in the dose escalation component may have received a taxane in the peri-operative setting, provided they developed disease recurrence >6 months after the completion of this therapy
• Known pre-existing liver disease (e.g. cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, sclerosing cholangitis)
• Patients with any clinically apparent ascites or who have undergone a paracentesis within 7 days of enrollment
• Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm Hg on repeated measurement) despite optimal medical management
• Active or clinically significant cardiac disease
• Patients with arterial thrombotic events, such as cerebrovascular accident or myocardial infarction, within 6 months of enrollment