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Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 25, No 18S (June 20 Supplement), 2007: 2577
© 2007 American Society of Clinical Oncology
A phase I study of EC145 administered weeks 1 and 3 of a 4-week cycle in patients with refractory solid tumors
E. Sausville,
P. LoRusso,
M. Quinn,
K. Forman,
C. Leamon,
D. Morganstern,
S. Bever and
R. Messmann
University of Maryland, Baltimore, MD; Karmanos Cancer Center, Detroit, MI; Endocyte Inc, West Lafayette, IN
2577
Background: Folic acid is internalized via two main pathways; a reduced folate carrier (RFC) or a folate-specific receptor (FR). While FR is minimally distributed in normal tissues, it is over-expressed in many human tumors, including cancers of the ovary, lung and kidney. Experimental data indicate that EC145, a conjugate of folic acid and the vinca alkaloid desacetylvinblastine hydrazide (DAVLBH), is a high-affinity ligand for the folate receptor (FR) but not for RFC. EC145 is also highly active against FR-positive KB tumors in vivo. This phase I trial assessed the safety and pharmacokinetics (PK) of escalating bolus doses of EC145. Methods: The phase I study treated eligible patients with EC145 as an intravenous bolus according to a ‘flat dose‘ escalation plan on days 1, 3, 5 (week 1) and 15, 17, 19 (week 3) of a 4-week cycle. Endpoints included determination of a safe and tolerable EC145 dose, development of a PK model, and identification of antitumor activity. Results: As of Dec 2006, 16 patients had received bolus EC145 (1.2, 2.5 or 4 mg; n = 3, 11 and 2, respectively). EC145 was generally well tolerated at bolus doses < 2.5 mg with one patient continuing on study for 6 cycles. Overall, the most common side effects were fatigue (n = 9), constipation (n = 7) and neuropathy (n = 6). DLT at 4 mg included reversible ileus and neuropathy. Formal PK analysis will be available at the time of presentation. One patient has had a minor response and another has exhibited disease stabilization > 5 months (both ovarian cancer patients). Upon declaration of the bolus MTD, the trial was amended to explore the utility of a 1-hour EC145 infusion to take full advantage of potential high affinity interaction between EC145 and the FR to effect drug targeting. As of Jan 2, 2007, three patients had been accrued to a dose level of 2.5 mg over 1 hr, and all tolerated the therapy without significant toxicity. Conclusions: EC145 may be administered safely as a 2.5 mg intravenous bolus dose on days 1, 3, 5 (week 1) and 15, 17, 19 (week 3) of a 28-day schedule.
No significant financial relationships to disclose.
Abstract presentation from the 2007 ASCO Annual Meeting
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