2141 Background: Pemetrexed (Alimta), a multi-targeted anti-folate, is synergisitic with gemcitabine in preclinical models. The optimal sequence and schedule of both drugs is currently unknown. This is the first study that will examine a biweekly schedule. The purpose of this study was to establish a maximum-tolerated dose (MTD) and recommend a phase 2 dose. Methods: Gemcitabine (G) was infused over 30 minutes, followed immediately by pemetrexed (P) given intravenously over 10 minutes once on day 1 every 14 days. The dose levels examined are shown in Table 1. Table 1. Dose Escalation Levels with DLTs Results: Thus far, 24 patients (13 female, 11 male) with 1 or no prior chemotherapy; median age 61 (range 39 – 80); ECOG PS 0 (11), 1 (13); diagnoses: lung (10), malignant pleural mesothelioma (3), pancreas (3), breast (2), atypical carcinoid tumor (2), head and neck (1), ovarian (1), skin (1), unknown primary (1) have received a current total of 87 cycles (range 1–13/ patient). MTD was established at dose level 5 (G 1500 mg/m2 and P 600 mg/m2) with two patients out of 6 experiencing neutropenic fever (NF). Dose level 4 was then expanded to treat 6 additional patients; no DLTs were seen in any of these 9 patients. Conclusions: G 1500 mg/m2 and P 500mg/m2 was selected as the phase 2 recommended dose. Preliminary response information suggests activity across multiple dose levels with specifics to be discussed at presentation. Plans are to study this schedule in phase 2 trials in many tumor types where G and P are known to be active.