Background: The folate receptor (FR) is expressed in many cancers, with limited expression in most normal tissues. EC1456, a potent SMDC of FA and the anti-tubulin cytotoxic TubBH, targets delivery of TubBH to FR-expressing cells. EC1456 demonstrated potent activity in paclitaxel- and cisplatin-resistant FR expressing cells. In murine models of FR-expressing xenografts, EC1456 caused complete tumor regression without significant toxicity. Enhanced anti-tumor activity was observed when EC1456 was combined with platinum, taxanes, and topotecan in preclinical models. These data led to this clinical evaluation of EC1456 in advanced CA pts. Methods: The primary objective is to determine the MTD of EC1456 administered on 2 schedules (BIW: days 1, 4, 8, 11 q 21 or 28 days [dosages: 0.5-6.0 mg/m²)], or QW: days 1, 8 q 21 days (dosage: 1.5-6.0 mg/m²). Key inclusion criteria: age ≥ 18 years, ECOG PS 0–1, and adequate organ function. ^99mTc-etarfolatide scan to evaluate FR status is to be obtained on enrolled pts. Dose escalation follows the “3+3” protocol for BIW cohort, and continuous reassessment method for QW cohort. Cycle 1 DLT evaluation must be completed for each schedule cohort prior to dosing a new cohort. Results: 16 pts have been treated: median age: 67.5 (48-86), M/F: 7/16. 11 pts have received 50 cycles of EC1456 BIW (median 2; range: 1-16), and 5 pts have received 19 cycles of EC1456 QW (median 4; range: 1-8). The only DLT and treatment related (TR) SAE occurred at 4.5 mg/m² QW schedule (Grade 3 infusion reaction). There have been no TR-deaths, Grade 4 toxicity, or toxicity causing dose delay, omission or reduction. Most TR-AEs have been Grade 1-2. Stable disease > 14 cycles has been observed in 2 pts with FR expression on ^99mTc-etarfolatide SPECT scan (mesothelioma; GEJ CA) on BIW schedule, and SD > 6 cycles in 1 pt (leiomyosarcoma) on QW schedule. Conclusions: Due to the DLT on the QW schedule, cohort expansion is ongoing at 3.5 mg/m². Dose escalation of EC1456 BIW is ongoing. EC1456 is generally well tolerated. PK data are anticipated in May 2015. Clinical trial information: 001999738.