Background: For the treatment of esophageal and GEJ carcinomas, weekly cisplatin (20-30 mg/m² weekly; total dose approximately 100 mg/m²) has demonstrated efficacy and tolerability. Pemetrexed (PEM) in combination with carboplatin and concomitant radiation has also shown activity for treatment of esophageal or lung carcinomas on a tri-weekly schedule, despite tolerability when administered weekly. This is the first phase I trial sought to establish the MTD of bi-weekly PEM in combination with weekly cisplatin and radiation in patients with locally advanced/metastatic esophageal and GEJ carcinomas. Methods: This is a phase I single institution, open-label dose-escalation trial (Fibonacci 3+3). Patients with stage III/IV esophageal cancer received PEM on weeks 1, 3, and 5 at doses of 300, 500, 750 mg/m² concurrently with weekly cisplatin (20 mg/m²) and 28 daily fractions of radiation (total 50.4 Gy). If 1 or fewer DLTs were observed, the next cohort of patients received an escalated dose. If two or more patients develop DLTs, then dose escalation halted. Primary endpoint was to determine MTD; secondary endpoints included tolerability and preliminary anti-tumor activity using RECIST (Version 1.0). Results: 8 patients enrolled; median age was 72 (range 56-81); 50% were male; ECOG range was 0-2; 50% of patients had adenocarcinoma (AC), remaining patients had squamous cell carcinoma (SCC); 63% and 37% of patients were stage III and IV, respectively. Dose-escalation proceeded to 750 mg/m² dose. The MTD was determined to be 500 mg/m² bi-weekly following grade 4 dehydration and esophagitis at 750 mg/m². DLTs observed were grade 4 thrombosis and grade 3 neutropenia at 300 and 500 mg/m², respectively. Complete response was observed in 50% of patients (75% stage III SCC), partial response in 25% of patients (100% Stage IV AC), and disease progression in 1 patient (Stage III AC). 38% of patients proceeded to surgery. Conclusions: The combination of bi-weekly pemetrexed 500 mg/m² and weekly cisplatin concomitantly with radiation demonstrates efficacy in patients with advanced or metastatic GEJ carcinomas with manageable safety profile. Clinical trial information: NCT00701857.