A Phase I Study Of Ec0225 Administered Weeks 1 And 2 Of A 4-Week Cycle

3082 Background: The folate receptor (FR) is expressed on many human tumors (e.g., ovarian, NSCLC, etc.) where it functions as a high-affinity receptor for folic acid. The FR is minimally expressed in normal tissue, making it a logical target for anticancer therapy. Indeed, the relevance of FR as a molecular target for antitumor agents was discussed in detail at the 2008 ASCO Annual Meeting. Folic acid can be used as a carrier molecule to deliver covalently-linked therapeutic and diagnostic moieties to the FR and EC0225 is a conjugate of folic acid coupled to mitomycin-C and desacetyl vinblastine hydrazide (DAVLBH). The EC0225 conjugate is a high-affinity ligand for the folate receptor (FR). This phase I study assessed the safety of escalating intravenous bolus doses of EC0225. Methods: Eligible patients with adequate performance status and organ function that had previously failed standard therapy were treated with EC0225 on days 1, 3, 5 (week 1) and 8, 10, 12 (week 2) of a 28-day cycle. Patients in the final cohort received drug on days 1, 3, 5 and 15, 17, 19 of a 28-day schedule. Endpoints included identification of the maximally-tolerated dose (MTD), the toxicity profile and any evidence of antitumor effect. Results: As of DEC 2009, 63 patients had received EC0225 at doses of 0.38, 0.8, 1.1, 1.5, 2.3, 3.1 and 3.9 mg (flat dose) and at 2.3 and 2.88 mg/m2; (where n =10, 8, 4, 14, 4, 5, 4, 7 and 7, respectively). EC0225 was generally well tolerated at dose levels ≤ 2.3 mg/m2. The most frequent treatment-related adverse events (all grades) included anemia (25%), constipation (17%), leukopenia (12%) and fatigue (10%). Grade 3 hypotension and Grade 4 neutropenia occurred in 1 patient each at the highest dose tested (2.88 mg/m2) defining the MTD at 2.3 mg/m2. Longer-term disease stabilization (≥ 4 months) occurred in patients with colorectal (4, 6 mo.), breast (4 mo.) and prostate cancer (10 mo.) and in patients with leiomyosarcoma (4 mo.) and mesothelioma (4 mo.). Traditional MMC- related pulmonary toxicities were not identified in this study. Conclusions: EC0225, a conjugate of folate, mitomycin-C and DAVLBH may be administered safely as a 2.3 mg/m2 intravenous bolus dose on days 1, 3, 5 and 8, 10, 12 of a 28-day schedule. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Endocyte Endocyte